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1
Rosset, R., S. Douville, M. Ben Amor, and K. Walha. "L'inhibition de l'entartrage par les eaux géothermales du sud tunisien. Étude sur site." Revue des sciences de l'eau 12, no. 4 (April 12, 2005): 753–64. http://dx.doi.org/10.7202/705376ar.
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Une nappe d'eaux fossiles à grande profondeur (800 à 2 700 mètres) a été mise en exploitation dans le Sud-Tunisien pour alimenter une usine d'osmose inverse située à Gabès ayant une production de 15 000 m3 /jour, afin de lutter contre la désertification par irrigation et d'assurer le chauffage de serres pour la production de primeurs. La grande dureté (TH de l'ordre de 100 à 140 °F) de ces eaux géothermales a pour conséquence le colmatage rapide des conduites de distribution : 40 à 50 tonnes de tartre par forage, constitué essentiellement de carbonate de calcium, précipitent chaque année. Ce tartre est constitué d'aragonite comme le montrent la microscopie électronique à balayage et la diffraction des rayons X. Une technique électrochimique, la chronoélectrogravimétrie, permet d'étudier l'inhibition de l'entartrage par des composés de la famille des phosphates inorganiques, des phosphonates organiques et des polycarboxylates. La concentration efficace de chacun de ces inhibiteurs agissant par effet de seuil a été déterminée : elle est de l'ordre de 1,1 à 1,5 mg.l-1 pour l'eau du forage de EL HAMMA. Un essai sur le site de EL MANSOURA a été effectué en privilégiant un inhibiteur produit industriellement dans le Sud-Tunisien, le triphosphate de sodium. A la concentration de 1 mg.l-1 il évite l'entartrage du système de refroidissement de type cascade - piscines et des conduites de distribution.
2
Henry, E. "Une expérience clinique du pramipexole chez 64 patients déprimés uni ou bipolaires suivis en ambulatoire." European Psychiatry 30, S2 (November 2015): S58. http://dx.doi.org/10.1016/j.eurpsy.2015.09.162.
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Du fait de l’analogie entre apathie et dépression [1,2], nous avons utilisé le pramipexole [3] chez 64 patients déprimés (39 patients présentant une dépression uni ou bipolaire, 25 patients présentant des troubles dysthymiques). Tous les patients, depuis trois mois au moins, prenaient un traitement par inhibiteur sélectif de la recapture de la sérotonine (ISRS) maintenu sans modification. Il s’agit d’une étude rétrospective portant sur quatre années d’utilisation du pramipexole La sévérité de la dépression a été cotée par le patient sur l’échelle de Hamilton 21 items et par l’investigateur sur l’échelle Montgomery and Asberg Depression Rating Scale (MADRS). Tous les patients ont été revus un à deux mois après l’introduction du pramipexole. La posologie du pramipexole a été de 1,4 mg par jour atteinte en 16 jours. Les critères d’amélioration ont été définis comme l’obtention d’un score inférieur à 10 sur l’échelle de Hamilton et un score inférieur à 10 sur l’échelle MADRS. Parmi les 25 patients présentant un trouble dysthymique, 3 patients ont été améliorés Parmi les 39 patients présentant une dépression uni- ou bipolaire, 35 ont été améliorés. L’amélioration chez ces 38 patients est survenue 10 à 15 jours après le début du traitement. Tous les patients améliorés présentaient une variation franche de l’humeur au cours de la journée avec moindre intensité de la souffrance en fin de journée. La médiane de suivi a été de 23 mois. Les nausées (5 patients) et la somnolence (6 patients) n’ont pas nécessité de modification dans la progression de la posologie. Deux patients ont présenté un épisode maniaque résolutif en 5 à 10 jours après l’arrêt du pramipexole, 1 patient a présenté des hallucinations visuelles résolutives 15 jours après l’arrêt du pramipexole et 1 patient a présenté un priapisme résolutif dès l’arrêt du pramipexole. Aucun cas d’addiction au pramipexole n’a été observé. Au total, le pramipexole semble être un traitement bien toléré et efficace chez les patients présentant une dépression dans le cadre d’un trouble uni ou bipolaire. Il ne semble pas avoir d’indication lors de troubles dysthymiques.
3
Lemogne, C. "Une prise en charge psychologique peut-elle infléchir le risque cardiovasculaire ?" European Psychiatry 28, S2 (November 2013): 39. http://dx.doi.org/10.1016/j.eurpsy.2013.09.098.
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Après ajustement sur les facteurs de risque cardiovasculaires « classiques » (tabagisme, hypertension, hypercholestérolémie, sédentarité, diabète, etc.), la dépression est associée à un risque quasiment doublé de survenue d’un premier événement coronarien ainsi qu’à un risque augmenté de 25 à 50 % de survenue d’un accident vasculaire cérébral. Il en est de même pour les symptômes anxieux. De plus, après un premier événement coronarien, la présence de symptômes dépressifs est associée à un risque augmenté de 15 à 60 % de récidive voire de mortalité cardiovasculaire. Ce constat a conduit à la mise en place de plusieurs essais contrôlés randomisés de prévention secondaire visant à démontrer l’intérêt d’une intervention pharmacologique, psychologique ou mixte sur les symptômes dépressifs dans la prévention des récidives et de la mortalité chez les patients coronariens. Globalement, les résultats obtenus jusqu’à présent ont été plutôt décevants, en particulier en ce qui concerne les études de forte puissance statistique (SADHARD, ENRICHD, CREATE, MIND-IT). Parmi ces quatre essais, trois ont montré l’intérêt d’un traitement par inhibiteur sélectif de recapture de la sérotonine ou thérapie cognitive et comportementale sur la symptomatologie dépressive, mais sans effet préventif sur la récidive des événements coronariens et la mortalité cardiovasculaire. Ce résultat paradoxal pourrait résulter de facteurs confondants, par exemple génétiques, expliquant l’association entre dépression et risque cardiovasculaire sans lien causal direct. Toutefois, certaines pistes restent encourageantes, en particulier lorsque l’intervention cible des facteurs plus généraux que la dépression tels que la gestion du stress (p.ex. essai SUPPRIM) ou au contraire repose sur une prise en charge personnalisée de la dépression (p.ex. essai COPES).
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Xu, Bo, Ashish Bhattacharjee, Biswajit Roy, Hong-Min Xu, David Anthony, David A. Frank, Gerald M. Feldman, and Martha K. Cathcart. "Interleukin-13 Induction of 15-Lipoxygenase Gene Expression Requires p38 Mitogen-Activated Protein Kinase-Mediated Serine 727 Phosphorylation of Stat1 and Stat3." Molecular and Cellular Biology 23, no. 11 (June 1, 2003): 3918–28. http://dx.doi.org/10.1128/mcb.23.11.3918-3928.2003.
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ABSTRACT Interleukin-13 (IL-13) is a cytokine secreted by Th2 lymphocytes that is capable of inducing expression of 15-lipoxygenase (15-LO) in primary human monocytes. We recently demonstrated that induction of 15-LO requires the activation of Jak2 and Tyk2 kinases and Stats 1, 3, 5, and 6. Since IL-13-induced 15-LO expression was inhibited by H7 (a serine-threonine kinase inhibitor), we predicted that Stat serine phosphorylation may also be crucial for 15-LO expression. In this study, we present evidence indicating that IL-13-induced 15-LO mRNA expression was detectable as early as 1 h by real-time reverse transcription-PCR. We found that IL-13 induced a time-dependent serine phosphorylation of both Stat1 and Stat3, detectable at 15 min after IL-13 treatment. In addition, the activation of p38 mitogen-activated protein kinase (MAPK) was detected in a time-dependent fashion, with peak phosphorylation at 15 min after IL-13 treatment. SB202190, a p38 MAPK-specific inhibitor, markedly inhibited IL-13-induced Stat1 and Stat3 serine phosphorylation as well as DNA binding. Furthermore, treatment of cells with Stat1 or Stat3 decoys significantly impaired IL-13-induced 15-LO expression. Taken together, our results provide the first evidence that IL-13 induces p38 MAPK phosphorylation/activation, which regulates Stat1 and Stat3 serine 727 phosphorylation. Both of these events are important steps in IL-13-induced 15-LO expression in human monocytes.
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He, Jianying, Isao Usui, Ken Ishizuka, Yukiko Kanatani, Kazuyuki Hiratani, Minoru Iwata, Agussalim Bukhari, Tetsuro Haruta, Toshiyasu Sasaoka, and Masashi Kobayashi. "Interleukin-1α Inhibits Insulin Signaling with Phosphorylating Insulin Receptor Substrate-1 on Serine Residues in 3T3-L1 Adipocytes." Molecular Endocrinology 20, no. 1 (January 1, 2006): 114–24. http://dx.doi.org/10.1210/me.2005-0107.
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Abstract Proinflammatory cytokines are recently reported to inhibit insulin signaling causing insulin resistance. IL-1α is also one of the proinflammatory cytokines; however, it has not been clarified whether IL-1α may also cause insulin resistance. Here, we investigated the effects of IL-1α treatment on insulin signaling in 3T3-L1 adipocytes. IL-1α treatment up to 4 h did not alter insulin-stimulated insulin receptor tyrosine phosphorylation, whereas tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and the association with phosphatidylinositol 3-kinase were partially inhibited with the maximal inhibition in around 15 min. IRS-1 was transiently phosphorylated on some serine residues around 15 min after IL-1α stimulation, when several serine kinases, IκB kinase, c-Jun-N-terminal kinase, ERK, and p70S6K were activated. Chemical inhibitors for these kinases inhibited IL-1α-induced serine phosphorylation of IRS-1. Tyrosine phosphorylation of IRS-1 was recovered only by the IKK inhibitor or JNK inhibitor, suggesting specific involvement of these two kinases. Insulin-stimulated Akt phosphorylation and 2-deoxyglucose uptake were not inhibited only by IL-1α. Interestingly, Akt phosphorylation was synergistically inhibited by IL-1α in the presence of IL-6. Taken together, short-term IL-1α treatment transiently causes insulin resistance at IRS-1 level with its serine phosphorylation. IL-1α may suppress insulin signaling downstream of IRS-1 in the presence of other cytokines, such as IL-6.
6
Ju, Wei, Meili Zhang, Jian-kang Jiang, Craig J. Thomas, Unsong Oh, Bonita R. Bryant, Jing Chen, et al. "CP-690,550, a therapeutic agent, inhibits cytokine-mediated Jak3 activation and proliferation of T cells from patients with ATL and HAM/TSP." Blood 117, no. 6 (February 10, 2011): 1938–46. http://dx.doi.org/10.1182/blood-2010-09-305425.
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Abstract The retrovirus, human T-cell–lymphotrophic virus-1 (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL) and the neurological disorder HTLV-I–associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-I–encoded protein tax constitutively activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems that in turn activate the Jak3 (Janus kinase 3)/STAT5 (signal transducers and activators of transcription 5) pathway, suggesting a therapeutic strategy that involves targeting Jak3. We evaluated the action of the Jak3 inhibitor CP-690,550 on cytokine dependent ex vivo proliferation that is characteristic of peripheral blood mononuclear cells (PBMCs) from select patients with smoldering or chronic subtypes of ATL, or from those with HAM/TSP whose PBMCs are associated with autocrine/paracrine pathways that involve the production of IL-2, IL-9, IL-15, and their receptors. CP-690,550 at 50nM inhibited the 6-day ex vivo spontaneous proliferation of PBMCs from ATL and HAM/TSP patients by 67.1% and 86.4%, respectively. Furthermore, CP-690,550 inhibited STAT5 phosphorylation in isolated ATL T cells ex vivo. Finally, in an in vivo test of biological activity, CP-690,550 treatment of mice with a CD8 T-cell IL-15–transgenic leukemia that manifests an autocrine IL-15/IL-15Rα pathway prolonged the survival duration of these tumor-bearing mice. These studies support further evaluation of the Jak3 inhibitor CP-690,550 in the treatment of select patients with HTLV-I–associated ATL and HAM/TSP.
7
Yamada, Yasuaki, Kazuyuki Sugawara, Tomoko Hata, Kazuto Tsuruta, Ryozo Moriuchi, Takahiro Maeda, Sunao Atogami, et al. "Interleukin-15 (IL-15) Can Replace the IL-2 Signal in IL-2–Dependent Adult T-Cell Leukemia (ATL) Cell Lines: Expression of IL-15 Receptor α on ATL Cells." Blood 91, no. 11 (June 1, 1998): 4265–72. http://dx.doi.org/10.1182/blood.v91.11.4265.
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Abstract Interleukin-15 receptor (IL-15R) and IL-2R have the same β and γ chains, but IL-15R has a specific α chain distinct from that of IL-2Rα, which is indispensable for the high affinity binding of IL-15. In the present study, we examined four IL-2-dependent adult T-cell leukemia (ATL) cell lines for their IL-15R expression. All cell lines bound IL-15, which was not inhibited by a 100-fold excess amount of IL-2, proliferated in response to IL-15 to the same degree as to the stimulation with IL-2, and were maintained without IL-2. The responses to 1L-15 were inhibited by the antibodies against IL-2R β or γ chains but was not by the IL-2R α chain antibody. [125I]–IL-15 exhibited a single high-affinity binding with an apparent kd of 0.17 nmol/L. Reverse transcription–coupled polymerase chain reaction (RT-PCR) showed that the cell lines had the mRNA of IL-15R α. The cell lines also had IL-15 mRNA. Despite the presence of IL-15 mRNA, the cell lines did not secrete IL-15, and the culture supernatants of fresh ATL cells and plasma from the patients did not contain a detectable amount of IL-15 with a few exceptional cases, although fresh ATL cells also responded to IL-15. These results suggest that ATL cells have the complete form of IL-15R and respond to IL-15. Such an IL-15–dependent cell proliferation mechanism might be used in the development of ATL and for the invasion and proliferation of ATL cells in the visceral organs.
8
Yamada, Yasuaki, Kazuyuki Sugawara, Tomoko Hata, Kazuto Tsuruta, Ryozo Moriuchi, Takahiro Maeda, Sunao Atogami, et al. "Interleukin-15 (IL-15) Can Replace the IL-2 Signal in IL-2–Dependent Adult T-Cell Leukemia (ATL) Cell Lines: Expression of IL-15 Receptor α on ATL Cells." Blood 91, no. 11 (June 1, 1998): 4265–72. http://dx.doi.org/10.1182/blood.v91.11.4265.411k06_4265_4272.
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Interleukin-15 receptor (IL-15R) and IL-2R have the same β and γ chains, but IL-15R has a specific α chain distinct from that of IL-2Rα, which is indispensable for the high affinity binding of IL-15. In the present study, we examined four IL-2-dependent adult T-cell leukemia (ATL) cell lines for their IL-15R expression. All cell lines bound IL-15, which was not inhibited by a 100-fold excess amount of IL-2, proliferated in response to IL-15 to the same degree as to the stimulation with IL-2, and were maintained without IL-2. The responses to 1L-15 were inhibited by the antibodies against IL-2R β or γ chains but was not by the IL-2R α chain antibody. [125I]–IL-15 exhibited a single high-affinity binding with an apparent kd of 0.17 nmol/L. Reverse transcription–coupled polymerase chain reaction (RT-PCR) showed that the cell lines had the mRNA of IL-15R α. The cell lines also had IL-15 mRNA. Despite the presence of IL-15 mRNA, the cell lines did not secrete IL-15, and the culture supernatants of fresh ATL cells and plasma from the patients did not contain a detectable amount of IL-15 with a few exceptional cases, although fresh ATL cells also responded to IL-15. These results suggest that ATL cells have the complete form of IL-15R and respond to IL-15. Such an IL-15–dependent cell proliferation mechanism might be used in the development of ATL and for the invasion and proliferation of ATL cells in the visceral organs.
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Badolato, Raffaele, Alessandro Negro Ponzi, Maura Millesimo, Luigi D. Notarangelo, and Tiziana Musso. "Interleukin-15 (IL-15) Induces IL-8 and Monocyte Chemotactic Protein 1 Production in Human Monocytes." Blood 90, no. 7 (October 1, 1997): 2804–9. http://dx.doi.org/10.1182/blood.v90.7.2804.
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Abstract Interleukin-15 (IL-15) is a recently characterized cytokine that shares many biological activities with IL-2 and interacts with the β and γ components of the IL-2 receptor. Unlike IL-2, which is secreted only by T cells, IL-15 is expressed preferentially by nonlymphoid tissues, epithelial, and fibroblast cell lines and by activated monocytes/macrophages. High concentrations of IL-15 have been shown in inflamed joints of rheumatoid arthritis patients, suggesting a role for IL-15 in inflammatory diseases where there is recruitment of leukocytes. Although monocytes have been shown to bind IL-15, its effects on these cells are not defined. In this report we show that supernatants of monocytes treated with IL-15–contained chemotactic activity for neutrophils and monocytes which was neutralized by anti-IL-8 or by anti-monocyte chemotactic protein 1 (MCP-1) antibodies, respectively. Secretion of IL-8 and MCP-1 proteins is detectable by enzyme-linked immunosorbent assay as early as 6 hours after stimulation with IL-15. Production of the two chemokines is correlated with induction by IL-15 of mRNA expression in monocytes. In addition, IL-8 and MCP-1 induction by IL-15 is differently regulated by interferon-γ (IFN-γ) and IL-4. IFN-γ inhibited IL-15–induced IL-8 secretion, but synergized with IL-15 in MCP-1 induction; whereas IL-4 inhibited both IL-8 and MCP-1 induction by IL-15. These results show that IL-15 can stimulate monocytes to produce chemokines that cause inflammatory cell accumulation. Thus, IL-15 locally produced at sites of inflammation may play a pivotal role in the regulation of the leukocyte infiltrate.
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Badolato, Raffaele, Alessandro Negro Ponzi, Maura Millesimo, Luigi D. Notarangelo, and Tiziana Musso. "Interleukin-15 (IL-15) Induces IL-8 and Monocyte Chemotactic Protein 1 Production in Human Monocytes." Blood 90, no. 7 (October 1, 1997): 2804–9. http://dx.doi.org/10.1182/blood.v90.7.2804.2804_2804_2809.
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Interleukin-15 (IL-15) is a recently characterized cytokine that shares many biological activities with IL-2 and interacts with the β and γ components of the IL-2 receptor. Unlike IL-2, which is secreted only by T cells, IL-15 is expressed preferentially by nonlymphoid tissues, epithelial, and fibroblast cell lines and by activated monocytes/macrophages. High concentrations of IL-15 have been shown in inflamed joints of rheumatoid arthritis patients, suggesting a role for IL-15 in inflammatory diseases where there is recruitment of leukocytes. Although monocytes have been shown to bind IL-15, its effects on these cells are not defined. In this report we show that supernatants of monocytes treated with IL-15–contained chemotactic activity for neutrophils and monocytes which was neutralized by anti-IL-8 or by anti-monocyte chemotactic protein 1 (MCP-1) antibodies, respectively. Secretion of IL-8 and MCP-1 proteins is detectable by enzyme-linked immunosorbent assay as early as 6 hours after stimulation with IL-15. Production of the two chemokines is correlated with induction by IL-15 of mRNA expression in monocytes. In addition, IL-8 and MCP-1 induction by IL-15 is differently regulated by interferon-γ (IFN-γ) and IL-4. IFN-γ inhibited IL-15–induced IL-8 secretion, but synergized with IL-15 in MCP-1 induction; whereas IL-4 inhibited both IL-8 and MCP-1 induction by IL-15. These results show that IL-15 can stimulate monocytes to produce chemokines that cause inflammatory cell accumulation. Thus, IL-15 locally produced at sites of inflammation may play a pivotal role in the regulation of the leukocyte infiltrate.
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Devocelle, Aurore, Lola Lecru, Hélène François, Christophe Desterke, Cindy Gallerne, Pierre Eid, Oberlin Estelle, Bruno Azzarone, and Julien Giron-Michel. "Inhibition of TGF-β1 Signaling by IL-15: A Novel Role for IL-15 in the Control of Renal Epithelial-Mesenchymal Transition: IL-15 Counteracts TGF-β1-Induced EMT in Renal Fibrosis." International Journal of Cell Biology 2019 (July 7, 2019): 1–15. http://dx.doi.org/10.1155/2019/9151394.
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Renal tubulointerstitial fibrosis is the final common pathway in end-stage renal disease and is characterized by aberrant accumulation of extracellular matrix (ECM) components secreted by myofibroblasts. Tubular type 2 EMT, induced by TGF-β, plays an important role in renal fibrosis, by participating directly or indirectly in myofibroblasts generation. TGF-β1-induced apoptosis and fibrosis in experimental chronic murine kidney diseases are concomitantly associated with an intrarenal decreased expression of the IL-15 survival factor. Since IL-15 counteracts TGF-β1 effects in different cell models, we analyzed whether (1) human chronic inflammatory nephropathies evolving towards fibrosis could be also characterized by a weak intrarenal IL-15 expression and (2) IL-15 could inhibit epithelial-mesenchymal transition (EMT) and excess matrix deposition in human renal proximal tubular epithelial cells (RPTEC). Our data show that different human chronic kidney diseases are characterized by a strong decreased expression of intrarenal IL-15, which is particularly relevant in diabetic nephropathy, in which type 2 tubular EMT plays an important role in fibrosis. Moreover, primary epithelial tubular cultures deprived of growth supplements rapidly produce active TGF-β1 inducing a “spontaneous” EMT process characterized by the loss of membrane-bound IL-15 (mbIL-15) expression. Both “spontaneous” EMT and recombinant human (rh) TGF-β1-induced EMT models can be inhibited by treating RPTEC and HK2 cells with rhIL-15. Through a long-lasting phospho-c-jun activation, IL-15 inhibits rhTGF-β1-induced Snail1 expression, the master inducer of EMT, and blocks TGF-β1-induced tubular EMT and downstream collagen synthesis. In conclusion, our data suggest that intrarenal IL-15 could be a natural inhibitor of TGF-β in human kidney able to guarantee epithelial homeostasis and to prevent EMT process. Thus, both in vivo and in vitro an unbalance in intrarenal IL-15 and TGF-β1 levels could render RPTEC cells more prone to undergo EMT process. Exogenous IL-15 treatment could be beneficial in some human nephropathies such as diabetic nephropathy.
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Barlic, Jana, Joan M. Sechler, and Philip M. Murphy. "IL-15 and IL-2 oppositely regulate expression of the chemokine receptor CX3CR1." Blood 102, no. 10 (November 15, 2003): 3494–503. http://dx.doi.org/10.1182/blood-2003-03-0946.
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AbstractThe chemokine receptor CX3CR1 (CX3C chemokine receptor 1) is expressed in mouse blood on natural killer (NK) cells and on monocytes. Because interleukin-15 (IL-15) is an essential cytokine for NK cell development and maintenance, we hypothesized that it may induce CX3CR1 expression on this cell type. In contrast, we found that in primary mouse bone marrow-derived NK cells IL-15 specifically inhibited CX3CR1 protein and mRNA accumulation, whereas the related cytokine IL-2 did not inhibit but instead increased CX3CR1 expression. Consistent with this finding, intravenous injection of a single dose of recombinant IL-15 into C57BL/6 mice decreased steady-state CX3CR1 levels 24 hours after injection in freshly isolated peripheral blood mononuclear cells (PBMCs), splenocytes, and bone marrow cells, and treatment of mouse PBMCs with IL-15 in vitro inhibited CX3CL1 (ligand for CX3CR1)-induced chemotaxis. These data suggest that IL-15 may be a negative regulator of innate immunity by inhibiting CX3CR1 expression. These data also suggest that IL-15 inhibition of CX3CR1 may subvert potential cell immunotherapy strategies in which IL-15 is used to expand NK cell populations in vivo or ex vivo. Finally, our results provide additional evidence for differential signaling by IL-2 and IL-15, despite usage of common βγc receptor chains. (Blood. 2003;102:3494-3503)
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Marks-Konczalik, J., S. Dubois, J. M. Losi, H. Sabzevari, N. Yamada, L. Feigenbaum, T. A. Waldmann, and Y. Tagaya. "IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice." Proceedings of the National Academy of Sciences 97, no. 21 (October 3, 2000): 11445–50. http://dx.doi.org/10.1073/pnas.200363097.
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Park, Il-Kyoo, Chiara Giovenzana, Tiffany L. Hughes, Jianhua Yu, Rossana Trotta, and Michael A. Caligiuri. "The Axl/Gas6 Pathway Is Required for Human Natural Killer Cell Development." Blood 110, no. 11 (November 16, 2007): 2305. http://dx.doi.org/10.1182/blood.v110.11.2305.2305.
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Abstract Natural killer (NK) cells play an important role in host defense against microbial infection and tumors. Previous studies showed that IL-15 is essential for NK cell differentiation in vitro and in vivo. However the molecular mechanisms by which IL-15 is able to drive NK differentiation remain poorly understood. Here we show that blocking interaction between the receptor tyrosine kinase Axl and its ligands (Gas6 and protein S) by either soluble Axl/immunoglobulin Fc fusion protein (Axl-Fc) or warfarin, a vitamin K inhibitor, diminished the number and percentage of CD3−CD56+ NK cells differentiated from CD34+ human hematopoietic progenitors (HPCs) in blood and secondary lymphoid tissues in the presence of IL-15. Axl-Fc or warfarin increased HPC apoptosis, reduced the frequency of NK precursors, and resulted in impaired IFN-γ production. Mechanistically, in human CD34+ HPCs, Axl-Fc significantly inhibited IL-15-induced signaling events, such as phosphorylation of STAT5 and ERK. Taken together, our results suggest that the Axl/Gas6 pathway is important for IL-15-induced differentiation of NK cells from human CD34+ HPCs.
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Zhu, Siyu, Chen Zhang, Qian Sun, Yang Wang, Wenwen Yu, Feng Wei, and Xiubao Ren. "Trained Immunity of IL-12-, IL-15-, and IL-18-Induced CD3+CD56+ NKT-Like Cells." Journal of Oncology 2022 (June 23, 2022): 1–14. http://dx.doi.org/10.1155/2022/8724933.
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CD3+CD56+ natural killer T (NKT)-like cells have an immune function of T cells and NK cells, which play an important role in antitumor and antiviral immune responses. This study aims to establish a CD3+CD56+ NKT-like cell model by simulating the memory NK effect induced by cytokines IL-12, IL-15, and IL-18 (IL-12/15/18) and explore the formation mechanism. Our study found that the IL-12/15/18 preactivated CD3+CD56+ NKT-like cells exhibited enhanced IFN-γ production in response to restimulation with IL-12/15/18 for 6h on day 7. The intrinsic potential of these trained cells was significantly improved, showing an increase in IFN-γ, TNF-α, and cell proliferation potential. The IFN-γ release, granzyme B level, and proliferation ability significantly increased when stimulated by NK-cell-sensitive K562 tumor cells. Among these cytokines, the combination of IL-12/15/18 was particularly effective. After the preactivation of IL-12/15/18, some cell surface proteins related to function and differentiation, such as CD11b, CD62 L, NKp46, NKG2A, and CD127, showed an evident and consistent change trend. The CDK4/6 inhibitor can effectively weaken this effect, and the expression of cyclin D1, Rb protein phosphorylation, and E2F-1 decreased significantly. Our work revealed that cytokine IL-12/15/18 can induce CD3+CD56+ NKT-like cells to obtain enhanced training immunity, which was a memory-like phenomenon.
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Gurjar, Milind V., Jason Deleon, Ram V. Sharma, and Ramesh C. Bhalla. "Role of reactive oxygen species in IL-1β-stimulated sustained ERK activation and MMP-9 induction." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 6 (December 1, 2001): H2568—H2574. http://dx.doi.org/10.1152/ajpheart.2001.281.6.h2568.
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We have recently demonstrated that interleukin-1β (IL-1β) stimulates matrix metalloproteinase-9 (MMP-9) induction. In this study we have investigated the roles of superoxide and extracellular signal-regulated kinase (ERK) activation in MMP-9 induction following exposure to IL-1β. IL-1β stimulated biphasic ERK activation in vascular smooth muscle (VSM) cells, a transient activation that reached a maximum at 15 min and declined to baseline levels within 1 h, and a second phase of sustained ERK activation lasting up to 8 h. To determine the role of ERK in IL-1β-stimulated MMP-9 induction, we treated cells with the specific ERK pathway inhibitor PD-98059 at different time intervals after IL-1β stimulation. Addition of PD-98059 up to 4 h after IL-1β stimulation significantly inhibited MMP-9 induction, suggesting a role for sustained ERK activation in MMP-9 induction. IL-1β treatment stimulated superoxide production in VSM cells that was inhibited by pretreatment of cells with the superoxide scavenger N-acetyl-l-cysteine (NAC) and also by overexpression of the human manganese superoxide dismutase (MnSOD) gene. Treatment of VSM cells with NAC selectively inhibited the sustained phase of ERK activation without influencing the transient phase, suggesting a role for reactive oxygen species in sustained ERK activation. In addition, both NAC treatment and MnSOD overexpression significantly inhibited IL-1β-stimulated MMP-9 induction ( P < 0.05). The results demonstrate that IL-1β-dependent MMP-9 induction is mediated by superoxide-stimulated ERK activation.
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Kubota, Takeshi, Richard A. Brown, Jidong Fang, and James M. Krueger. "Interleukin-15 and interleukin-2 enhance non-REM sleep in rabbits." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 281, no. 3 (September 1, 2001): R1004—R1012. http://dx.doi.org/10.1152/ajpregu.2001.281.3.r1004.
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Interleukin (IL)-15 and -2 share receptor- and signal-transduction pathway (Jak-STAT pathway) components. IL-2 is somnogenic in rats but has not been tested in other species. Furthermore, the effects of IL-15 on sleep have not heretofore been described. We investigated the somnogenic actions of IL-15 in rabbits and compared them with those of IL-2. Three doses of IL-15 or -2 (10, 100, and 500 ng) were injected intracerebroventriculary at the onset of the dark period. In addition, 500 ng of IL-15 and -2 were injected 3 h after the beginning of the light period. IL-15 dose dependently increased non-rapid eye movement sleep (NREMS) and induced fever. IL-15 inhibited rapid eye movement sleep (REMS) after its administration during the light period; however, all doses of IL-15 failed to affect REMS if given at dark onset. IL-2 also dose dependently increased NREMS and fever. IL-2 inhibited REMS, and this effect was observed only in the light period. IL-15 and -2 enhanced electroencephalographic (EEG) slow waves during the initial 9-h postinjection period, then, during hours 10–23postinjection, reduced EEG slow-wave activity. Current data support the notion that the brain cytokine network is involved in the regulation of sleep.
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Chiossone, Laura, Chiara Vitale, Francesca Cottalasso, Sara Moretti, Bruno Azzarone, Lorenzo Moretta, and Maria Cristina Mingari. "Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2– versus IL-15–activated NK cells." Blood 109, no. 9 (January 18, 2007): 3767–75. http://dx.doi.org/10.1182/blood-2006-07-037846.
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Abstract Steroids have been shown to inhibit the function of fresh or IL-2–activated natural killer (NK) cells. Since IL-15 plays a key role in NK-cell development and function, we comparatively analyzed the effects of methylprednisolone on IL-2– or IL-15–cultured NK cells. Methylprednisolone inhibited the surface expression of the major activating receptors NKp30 and NKp44 in both conditions, whereas NK-cell proliferation and survival were sharply impaired only in IL-2–cultured NK cells. Accordingly, methylprednisolone inhibited Tyr phosphorylation of STAT1, STAT3, and STAT5 in IL-2–cultured NK cells but only marginally in IL-15–cultured NK cells, whereas JAK3 was inhibited under both conditions. Also, the NK cytotoxicity was similarly impaired in IL-2– or IL-15–cultured NK cells. This effect strictly correlated with the inhibition of ERK1/2 Tyr phosphorylation, perforin release, and cytotoxicity in a redirected killing assay against the FcRγ+ P815 target cells upon cross-linking of NKp46, NKG2D, or 2B4 receptors. In contrast, in the case of CD16, inhibition of ERK1/2 Tyr phosphorylation, perforin release, and cytotoxicity were not impaired. Our study suggests a different ability of IL-15–cultured NK cells to survive to steroid treatment, thus offering interesting clues for a correct NK-cell cytokine conditioning in adoptive immunotherapy.
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Kim, Hyung-Yong, and Yasuko Rikihisa. "Roles of p38 Mitogen-Activated Protein Kinase, NF-κB, and Protein Kinase C in Proinflammatory Cytokine mRNA Expression by Human Peripheral Blood Leukocytes, Monocytes, and Neutrophils in Response to Anaplasma phagocytophila." Infection and Immunity 70, no. 8 (August 2002): 4132–41. http://dx.doi.org/10.1128/iai.70.8.4132-4141.2002.
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ABSTRACT Anaplasma phagocytophila, an obligately intracellular bacterium of granulocytes, causes human granulocytic ehrlichiosis. Within 2 h after addition of A. phagocytophila, interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and IL-6 mRNAs are induced in human peripheral blood leukocytes (PBLs) or monocytes in vitro. However, neutrophils generate only IL-1β mRNA. In the present study, signaling pathways for induction of these three cytokines were examined. TNF-α and IL-6 mRNA expression by PBLs was inhibited with SB 203580 (a p38 mitogen-activated protein kinase [MAPK] inhibitor), MG-132 (a proteasome inhibitor), and SN-50 (an NF-κB inhibitor). Activation of p38 MAPK and NF-κB mRNAs in monocytes was detectable within 15 to 30 min after addition of A. phagocytophila. Expression of these two cytokine mRNAs in PBLs and monocytes was also dependent on protein kinase C (PKC), protein kinase A (PKA), and protein tyrosine kinase (PTK). IL-1β mRNA expression by neutrophils was not dependent on p38 MAPK, and p38 MAPK was not activated in neutrophils incubated with A. phagocytophila. IL-1β mRNA induction by PBLs, monocytes, and neutrophils was dependent on PKC and PKA. Neutrophil expression of IL-1β mRNA was dependent on transglutaminase, phospholipase C, and PTK, all of which are also required for internalization of A. phagocytophila. However, monocyte expression of IL-1β mRNA was less dependent on these enzymes. These results suggest that A. phagocytophila transduces different signals between its host neutrophils and monocytes for proinflammatory cytokine generation.
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Ramírez-Pérez, Sergio, Luis Alexis Hernández-Palma, Edith Oregon-Romero, Brian Uriel Anaya-Macías, Samuel García-Arellano, Guillermo González-Estevez, and José Francisco Muñoz-Valle. "Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor." Molecules 25, no. 18 (September 21, 2020): 4322. http://dx.doi.org/10.3390/molecules25184322.
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The inflammatory process implicates homeostasis disruption and increased production of inflammatory mediators. Myeloid differentiation primary response 88 (MyD88) is an essential protein recruited after lipopolysaccharide (LPS) and interleukin (IL)-1β stimulation, a process that converges in nuclear factor kappa B (NF-κB) activation, as well as a transcription of several genes of both pro- and anti-inflammatory cytokines. The inhibition of MyD88 has shown efficacy by decrease inflammatory response, and has demonstrated potential application as a therapeutic target in chronic diseases. In this study, we investigate the effect of MyD88 dimerisation inhibitor ST2825 on cytokine production from rhIL-1β and LPS-stimulated peripheral blood mononuclear cells (PBMC) from healthy blood donors (HBD). ST2825 significantly downregulates the production of IFN-γ, IL-6, IL-12, IL-2, IL-15, IL-7, VEGF, IL-1Ra, IL-4, IL-5, IL-13 and IL-9 (p < 0.05) in LPS-stimulated PBMC. Moreover, ST2825 had a relatively low impact on IL-1β signalling pathway inhibition, showing that only a few specific cytokines, such as IFN-γ and IL-1Ra, are inhibited in rhIL-1β-stimulated PBMC (p < 0.01). In conclusion, MyD88 dimerisation inhibitor ST2825 showed high efficacy by inhibiting pro- and anti-inflammatory cytokine production in LPS-stimulated PBMC. Moreover, although rhIL-1β induced a sustained cytokine production (p < 0.05), ST2825 did not show a significant effect in the secretion of neither pro- nor anti-inflammatory cytokines in rhIL-1β-stimulated PBMC.
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Yajima, Toshiki, Hitoshi Nishimura, Kimika Saito, Hiroyuki Kuwano, and Yasunobu Yoshikai. "Overexpression of Interleukin-15 Increases Susceptibility to Lipopolysaccharide-Induced Liver Injury in Mice Primed with Mycobacterium bovis Bacillus Calmette-Guérin." Infection and Immunity 72, no. 7 (July 2004): 3855–62. http://dx.doi.org/10.1128/iai.72.7.3855-3862.2004.
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ABSTRACT Mice primed with Mycobacterium bovis bacillus Calmette-Guérin (BCG) are highly sensitive to lipopolysaccharide (LPS)-induced liver injury and lethality. We found that interleukin-15 (IL-15) transgenic (Tg) mice primed with BCG were more susceptible to LPS-induced liver injury than non-Tg mice. The numbers of CD44+ CD8+ T cells expressing intracellular gamma interferon (IFN-γ) significantly increased in the livers of BCG-primed IL-15 Tg mice after LPS injection, and the depletion of CD8+ T cells from BCG-primed IL-15 Tg mice completely abolished the susceptibility to LPS-induced lethality. Liver T cells from BCG-primed IL-15 Tg mice produced IFN-γ in vitro in response to LPS, which was inhibited by the addition of anti-IL-12 monoclonal antibody (MAb). In vivo treatment with anti-IL-12 MAb inhibited the appearance of CD44+ CD8+ T cells expressing intracellular IFN-γ after LPS injection. These results suggest that the overexpression of IL-15 increases susceptibility to LPS-induced liver injury in BCG-primed mice via bystander activation of CD8+ T cells.
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Carson, W. E., J. G. Giri, M. J. Lindemann, M. L. Linett, M. Ahdieh, R. Paxton, D. Anderson, J. Eisenmann, K. Grabstein, and M. A. Caligiuri. "Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor." Journal of Experimental Medicine 180, no. 4 (October 1, 1994): 1395–403. http://dx.doi.org/10.1084/jem.180.4.1395.
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Interleukin 15 (IL-15) is a novel cytokine that has recently been cloned and expressed. Whereas it has no sequence homology with IL-2, IL-15 interacts with components of the IL-2 receptor (IL-2R). In the present study we performed a functional analysis of recombinant IL-15 on phenotypically and functionally distinct populations of highly purified human natural killer (NK) cells. The CD56bright subset of human NK cells constitutively expresses the high affinity IL-2R and exhibits a brisk proliferative response after the binding of picomolar amounts of IL-2. Using a proliferation assay, IL-15 demonstrated a very steep dose-response curve that was distinct from the dose-response curve for IL-2. The proliferative effects of IL-15 could be abrogated by anti-IL-2R beta (p75), but not by anti-IL-2R alpha (p55). The proliferative effects of IL-2 on CD56bright NK cells could be inhibited by both antibodies. CD56dim NK cells express the intermediate affinity IL-2R in the absence of the high affinity IL-2R. Activation of CD56dim NK cells by IL-15 was similar to that of IL-2 as measured by enhanced NK cytotoxic activity, antibody-dependent cellular cytotoxicity, and NK cell production of interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-15-enhanced NK cytotoxic activity could be completely blocked by anti-IL-2R beta monoclonal antibody. The binding of radiolabeled IL-2 and IL-15 to CD56dim NK cells was inhibited in the presence of anti-IL-2R beta. Scatchard analysis of radiolabeled IL-15 and IL-2 binding to NK-enriched human lymphocytes revealed the presence of high and intermediate affinity receptors for both ligands. IL-15 is a ligand that activates human NK cells through components of the IL-2R in a pattern that is similar but not identical to that of IL-2. Unlike IL-2, IL-15 is produced by activated monocytes/macrophages. The discovery of IL-15 may increase our understanding of how monocytes/macrophages participate in the regulation of NK cell function.
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Rafei, Moutih, Jian Hui Wu, Borhane Annabi, Laurence Lejeune, Moïra François, and Jacques Galipeau. "A GMCSF and IL-15 fusokine leads to paradoxical immunosuppression in vivo via asymmetrical JAK/STAT signaling through the IL-15 receptor complex." Blood 109, no. 5 (November 2, 2006): 2234–42. http://dx.doi.org/10.1182/blood-2006-07-037473.
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Abstract We hypothesized that a granulocyte macrophage colony-stimulating factor (GMCSF) and interleukin 15 (IL-15) fusokine (GIFT15) would possess greater immune-stimulatory properties than their combined use. Unexpectedly, tumor cells engineered to secrete GIFT15 protein led to suppression of natural killer (NK) and NKT-cell recruitment in vivo, suggesting an unanticipated immune-suppressive effect. We found GIFT15 to have pleiotropic effects on an array of immune-competent cells. Among these, macrophages treated with GIFT15 secrete de novo the tissue inhibitor of metalloproteinase-2 (TIMP-2); activated matrix metalloproteinase-2 (MMP-2); transforming growth factor-β (TGF-β); as well as vascular endothelial growth factor (VEGF). We show that the GIFT15 fusokine has increased affinity for the α chain component of the IL-15R, leading to aberrant signaling through the β chain manifested by the hyperphosphorylation of STAT3 both in macrophages and splenocytes. Suppression of common γ chain–mediated STAT5 phosphorylation and blockade of the IL-15–dependent IFN-γ response in mouse splenocytes were also observed. We tested GIFT15 as an immunosuppressor and demonstrated that it allowed engraftment of allogeneic B16F0 and human xenograft U87GM glioma cells in immunocompetent mice. Thus, GIFT15 defines a new class of fusokine that mediates proangiogenic and immunosuppressive effects via aberrant signaling by the IL-15R in lymphomyeloid cells.
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Barner, Erica L., and Shelly L. Gray. "Donepezil Use in Alzheimer Disease." Annals of Pharmacotherapy 32, no. 1 (January 1998): 70–77. http://dx.doi.org/10.1345/aph.17150.
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OBJECTIVE To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug–drug interactions, and the therapeutic issues concerning the use of donepezil in patients with Alzheimer disease. DATA SOURCES Published articles and abstracts in English were identified by MEDLINE (January 1985–July 1997) searches using the search terms donepezil, E2020, treatment of Alzheimer's disease, and cholinesterase inhibitors. Additional articles were identified from the bibliographies of the retrieved articles. Data were also obtained from approved product labeling. DATA EXTRACTION The literature was assessed for adequate description of patients, methodology, and outcomes. DATA SYNTHESIS: Donepezil is a cholinesterase inhibitor that is selective and specific for acetylcholinesterase. It is metabolized by hepatic isoenzymes CYP2D6 and CYP3A4 and undergoes glucuronidation. Information about drug interactions is limited, but a potential for drug–drug interactions does exist, given the route of elimination. Donepezil has a relative bioavailability of 100% following oral administration and is not affected by the presence of food. In 15- and 30-week trials, donepezil was effective in patients with mild-to-moderate Alzheimer disease as shown by improvements on standard assessment instruments (i.e., the Alzheimer's Disease Assessment Scale–Cognitive Subscale, the Clinical Interview-Based Impression of Change with Caregiver Input). Adverse effects were comparable with those of placebo, and monitoring of liver function tests is not required. CONCLUSIONS Donepezil is an effective symptomatic treatment for some patients with mild-to-moderate Alzheimer disease. Although no comparative trials have been reported, donepezil appears to be a safe alternative for tacrine, given its convenient once-daily dosing, minimal adverse effects, and lower total cost. OBJETIVO Ofrecer un resumen de la farmacología, farmacocinética, eficacia clínica, efectos adversos, interacciones, y cuestiones terapeúticas relacionadas con el uso de donepezil en pacientes con la enfermedad de Alzheimer. FUENTES DE INFORMACIÓN Artículos y extractos en inglés fueron identificados a través de MEDLINE utilizando los términos donepezil, E2020, tratamiento de Alzheimer, e inhibidores de colinesterasa. Artículos adicionales fueron seleccionados a partir de la bibliografía de la literatura identificada. También se obtuvo información a partir de la marcación aprobada del producto. SELECCIÓN DE ESTUDIOS Los estudios fueron evaluados en cuanto a descripción adecuada de los pacientes, metodología, y resultados. SÍNTESIS Donepezil es un inhibidor selectivo de la colinesterasa y específico para la acetilcolinesterasa. Es metabolizado por las enzimas hepáticas CYP2D6 y CYP3A4 y experimenta glucuronidación. Aunque hay poca información acerca de interacciones con otras drogas, la potencial para estas interacciones existe, dada la ruta de eliminación. Después de administración oral, la biodisponibilidad relativa de donepezil es 100% y no es afectada por la presencia de comida. En estudios clínicos de 15 a 30 semanas de duración, pacientes con síntomas categorizadas como leve o moderados que recibieron donepezil demostraron mejoramientos en cuanto a resultados en pruebas estadardizadas. Efectos adversos fueron comparables con placebo y el uso de donepezil no requiere el monitoreo de pruebas de función hepática. CONCLUSIONES Donepezil es un tratamiento sintomático efectivo para algunos pacientes con la enfermedad de Alzheimer. Aunque no se han reportado estudios comparativos con tacrine, donepezil es un alternativo que ofrece dosificación una vez diariamente, un costo más bajo, efectos adversos mínimos y ningunos reportes de hepatotoxicidad. OBJECTIF Revoir la pharmacologie, la pharmacocinétique, l'efficacité clinique, les effets indésirables, les interactions médicamenteuses, et les buts thérapeutiques du donépézil chez les personnes avec de la maladie d'Alzheimer. REVUE DE LITTÉRATURE Les articles publiés et les RÉSUMÉs de langue anglaise ont été identifiés par une recherche dans la banque informatisee MEDLINE (1985–1997) sous les termes donépézil, E2020, traitement de la maladie d'Alzheimer, et inhibiteurs de la cholinestérase. D'autres articles ont été identifiés à partir des articles déjà identifiés par cette recherche. Des données ont aussi été extraites de la monographie du produit. SÉLECTION DE LINFORMATION: Les articles ont été comparés quant à la description adéquate des patients, la méthodologie, et les résultats attendus. RÉSUMÉ Le donépézil est un inhibiteur sélectif de la cholinestérase spécifique pour l'acétylcholinestérase. Il est métabolisé par les enzymes hépatiques CYP2D6 et CYP3A4 et subit la glucuronidation. L'information sur les interactions médicamenteuses est limitée, mais des interactions médicamenteuses sont possibles compte tenu de la voie d'élimination de ce produit. La biodisponibilité du donépézil est complet 100% par la voie orale et n'est pas modifiée en présence d'aliments. Dans des essais cliniques de 15 et 30 semaines, le donépézil est efficace chez les personnes avec de la maladie d'Alzheimer l'égère à modérée, tel que montré par des améliorations sur des échelles d'évaluation (ADAS-C, CIBIC). Les effets indésirables du donépézil dans ces études sont comparables à ceux du placébo et des tests de la fonction hépatique ne sont pas requis comme avec la tacrine. CONCLUSIONS Le donépézil est un traitement symptomatique efficace chez quelques personnes avec de la maladie d'Alzheimer légère à modérée. Même s'il n'existe pas d'études comparatives, le donépézil semble une alternative sécuritaire à la tacrine, compte tenu de sa prise uniquotidienne, de ses effets indésirables minimes et de son faible coût.
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di M’balu Joachim, Umba, Masimango N. Thaddée, and Mvumbi Lelo. "Inhibition du développement de l’Aspergillus flavus par l’acide acétique: Analyse de trois expériences réalisées à Kinshasa- RD Congo." Journal of Animal & Plant Sciences 45, no. 1 (July 31, 2020): 7809–21. http://dx.doi.org/10.35759/janmplsci.v45-1.5.
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L’Aspergillus flavus est un champignon cosmopolite, très répandu dans la nature et susceptible de contaminer plusieurs aliments. C’est un champignon qui fait beaucoup parler de lui depuis qu’on a découvert qu’il secrète de métabolites hautement toxiques, les aflatoxines, cancérigènes et exerçant d’autres effets nuisibles sur la santé des hommes et des animaux. En effet, les aflatoxines sont de métabolites toxiques secondaires biosynthétisés par certaines souches de micromycètes, notamment Aspergillus flavus. (En fait le terme est un moyen mnémotechnique pour dire : toxines d’Aspergillus flavus).Elles sont produites lorsque les champignons se trouvent dans des conditions de forte humidité relative (80-90%) conjointement à une température élevée (20-30°C).Les dégâts imputables aux aflatoxines sont nombreux aussi bien sur le plan de la santé (humaine et animale) que sur l’économie. En considérant que les mycotoxines ne peuvent jamais être complètement absentes ou éliminées des denrées alimentaires, divers moyens de lutte biologique, chimique ou physique empêchant le développement du champignon produisant l’Aspergillus flavus ont été essayés. L’objectif de ce travail est de faire connaître trois expériences de lutte des aflatoxines par l’acide acétique et de comparer si les résultats obtenus avec les extraits de caieux d’Allium sativum et d’écorces racinaires de Diospyros heterosictricha utilisé comme biopesticides pour inhiber la croissance mycélienne d’Aspergillus flavus. Il ressort des analyses que l’acide acétique exerce effectivement un pouvoir inhibiteur à des pourcentages différents sur le développement de l’Aspergillus flavus. La dose minimale efficace varie d’un auteur à un autre même lorsque les essais sont effectués dans de conditions comparables mais surtout en fonction de dilution. La dose minimale efficace d’inhibition d’Aspergillus flavus est située à 400 ppm (0,04%) estiment certains auteurs. Par contre, d’autres pensent qu’elle est comprise entre 0,02 ml à 15 ml. ABSTRACT Aspergillus flavus is a cosmopolitan fungus, widely distributed in nature and capable of contaminating several foods. It is a mushroom that has been talked about a lot since it was discovered that it secretes highly toxic metabolites, the aflatoxins, carcinogens and having other harmful effects on the health of humans and animals. Aflatoxins are secondary toxic Umba et al., 2020 Journal of Animal & Plant Sciences (J.Anim.Plant Sci. ISSN 2071-7024) Vol.45 (1): 7809-7821 https://doi.org/10.35759/JAnmPlSci.v45-1.5 7810 metabolites biosynthesized by certain strains of micromycetes, notably Aspergillus flavus. (In fact the term is a mnemonic means to say: toxins of Aspergillus flavus). They are produced when the mushrooms are in conditions of high relative humidity (80-90%) together with a high temperature (20-30°C). The damage attributable to aflatoxins is numerous both in terms of health (human and animal) and in terms of the economy. Considering that mycotoxins can never be completely absent or eliminated from food, various means of biological, chemical or physical control preventing the development of the fungus producing Aspergillus flavus have been tried. The objective of this work is to make known three experiences of aflatoxin control by acetic acid and to compare if the results obtained with the extracts of cloves of Allium sativum and root barks of Diospyros heterosictricha used as biopesticides to inhibit the mycelial growth of Aspergillus flavus. Analyses show that acetic acid effectively exerts inhibitory power at different percentages on the development of Aspergillus flavus. The minimum effective dose varies from one author to another even when the tests are carried out under comparable conditions but especially according to dilution. The minimum effective inhibition dose of Aspergillus flavus is located at 400 ppm (0.04%) believe some authors. On the other hand, others think that it is between 0.02 ml to 15 ml.
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Tai, Yueh-Hua, Ru-Yin Tsai, Shinn-Long Lin, Chun-Chang Yeh, Jhi-Joung Wang, Pao-Luh Tao, and Chih-Shung Wong. "Amitriptyline Suppresses Neuroinflammation-dependent Interleukin-10-p38 Mitogen-activated Protein Kinase-Heme Oxygenase-1 Signaling Pathway in Chronic Morphine-infused Rats." Anesthesiology 110, no. 6 (June 1, 2009): 1379–89. http://dx.doi.org/10.1097/aln.0b013e31819fccd5.
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Background This study explores the underlying mechanism of the antiinflammatory effect of amitriptyline in chronic morphine-infused rats. Methods Male Wistar rats were implanted with two intrathecal catheters. One catheter was for the continuous infusion of saline, amitriptyline (15 microg/h), morphine (15 microg/h), p38 mitogen-activated protein kinase inhibitor SB203580 (0.5 microg/h), morphine plus amitriptyline, or morphine plus amitriptyline plus SB203580 for 5 days. The other catheter was used for daily intrathecal injection of anti-interleukin-10 (IL-10) antibody or heme oxygenase-1 inhibitor zinc protoporphyrin for 5 days. Results Amitriptyline/morphine coinfusion upregulated IL-10 protein expression in microglia; this was not observed in morphine-infused rats. Anti-IL-10 antibody effectively neutralized the amitriptyline-induced IL-10 expression in chronic morphine-infused rats. In addition, coinfusion of amitriptyline restored the antinociceptive effect of morphine (a 4.8-fold right-shift of the morphine dose-response curve compared to a 77.8-fold right-shift in its absence), and the injection of anti-IL-10 antibody or coinfusion of SB203580 partially reversed the effect of amitriptyline on the antinociceptive effect of morphine in morphine-infused rats (a 17.9-fold and 15.1-fold right-shift in morphine dose-response curves). Anti-IL-10 antibody and SB203580 significantly inhibited the amitriptyline-induced p38 mitogen-activated protein kinase and heme oxygenase-1 expression and the associated antiinflammatory effect of amitriptyline. Daily injection of zinc protoporphyrin also demonstrated that it reverses the effect of amitriptyline in morphine's antinociception and antiinflammation in chronic morphine-infused rats. Conclusions These results suggest that the antiinflammatory effect of amitriptyline on morphine tolerance, probably acting by increasing IL-10 expression, is mediated by p38 mitogen-activated protein kinase heme oxygenase-1 signal transduction cascade.
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Saper, Vivian E., Michael J. Ombrello, Adriana H. Tremoulet, Gonzalo Montero-Martin, Sampath Prahalad, Scott Canna, Chisato Shimizu, et al. "Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles." Annals of the Rheumatic Diseases 81, no. 3 (November 17, 2021): 406–15. http://dx.doi.org/10.1136/annrheumdis-2021-220578.
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ObjectivesDrug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still’s disease with atypical lung disease. We sought to characterise features of patients with Still’s disease with DRESS compared with drug-tolerant Still’s controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort.MethodsIn a case/control study, we collected a multicentre series of patients with Still’s disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still’s controls (n=65). We retrospectively analysed clinical data from all Still’s subjects and typed 94/131 for HLA. European Still’s-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still’s cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still’s-DRESS cases (n=64) compared with drug-tolerant Still’s controls (n=30). KD subjects (n=19) were similarly studied.ResultsStill’s-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still’s-DRESS (64%) versus drug-tolerant Still’s (3%; p=1.2×10−14). We found striking enrichment for HLA-DRB1*15 haplotypes in Still’s-DRESS cases versus INCHARGE Still’s controls (p=7.5×10-13) and versus self-identified, ancestry-matched Still’s controls (p=6.3×10−10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.ConclusionsDRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.
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Wilkinson, P. C., and F. Y. Liew. "Chemoattraction of human blood T lymphocytes by interleukin-15." Journal of Experimental Medicine 181, no. 3 (March 1, 1995): 1255–59. http://dx.doi.org/10.1084/jem.181.3.1255.
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Recombinant interleukin (IL)-15, derived from a simian kidney epithelial cell line, is a chemoattractant for human blood T lymphocytes judged by its ability to increase the proportion of cells in polarized morphology, to stimulate invasion of collagen gels containing IL-15, and to increase the proportion of locomotor cells observed by time-lapse videorecording. The ability of lymphocytes to respond was partly, but not completely, inhibited by pretreatment with anti-IL-2 receptor beta-chain. The activity of IL-15 was completely abolished by preincubation with aIL-15 but unaffected by preincubation with aIL-2. No response of monocytes, neutrophils, or B lymphocytes to IL-15 was observed.
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Medeiros, Alexandra I., Anderson Sá-Nunes, Edson G. Soares, Camila M. Peres, Célio L. Silva, and Lúcia H. Faccioli. "Blockade of Endogenous Leukotrienes Exacerbates Pulmonary Histoplasmosis." Infection and Immunity 72, no. 3 (March 2004): 1637–44. http://dx.doi.org/10.1128/iai.72.3.1637-1644.2004.
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ABSTRACT Leukotrienes are classical mediators of inflammatory response. New aspects of leukotriene function have recently been described. We examine here the previously unreported role that leukotrienes play in the regulation of cytokines in a murine model of histoplasmosis. We demonstrate that administration of MK 886, a leukotriene synthesis inhibitor, caused Histoplasma capsulatum-infected mice to die by the day 15 of infection, whereas the correlating death rate in untreated infected mice was 0%. Treating infected animals with MK 886 inhibited leukotriene synthesis but increased leukocyte recruitment to the lungs. Subsequent to this phenomenon, levels of tumor necrosis factor alpha, interleukin-1 (IL-1), IL-6, and KC chemoattractant cytokines and fungi in the lung parenchyma increased, as did inflammatory response. In contrast, IL-2, IL-5, IL-12, and gamma interferon cytokine levels actually decreased. Thus, murine response to pulmonary histoplasmosis may be leukotriene modulated. This finding may enable us to alter the course of the immune response and inflammation caused by histoplasmosis. The data from the present study suggest an important new strategy for immunologic or drug intervention in human patients.
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Trotta, Rossana, Jessica Dal Col, Jeffrey Allard, Paolo Neviani, Ramasamy Santhanam, Hsiaoyin Mao, Brian Becknell, et al. "In Vitro and In Vivo Evidence That the PP2A Inhibitor SET Regulates IFN-γ Production in Monokine-Stimulated Natural Killer Cells." Blood 108, no. 11 (November 16, 2006): 928. http://dx.doi.org/10.1182/blood.v108.11.928.928.
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Abstract Monokines (i.e. IL-12, IL-18 and IL-15) induce natural killer (NK) cells to produce interferon-γ (IFN-γ), which is critical for monocyte clearance of infectious pathogens and tumor surveillance. To identify new regulators of IFN-γ production we performed oligonucleotide array analysis of unstimulated and IL-12- and IL-18-stimulated NK92 cells. Among the subset of mRNAs differentially regulated in monokine-stimulated cells, we found SET, a potent inhibitor of the protein phosphatase type 2A (PP2A). SET mRNA and/or protein levels were upregulated in IL-12/IL-18- and IL-12/IL-15-stimulated primary human NK cells. Interestingly, the SET protein is also selectively increased in the resting CD56bright NK subset, which is a potent producer of IFN-γ relative to the CD56dim NK subset. To determine whether SET positively regulates IFN-γ production by inhibiting PP2A activity, we employed RNAi and interfered with SET expression in NK92 cells. SET downregulation inhibited IFN-γ secretion by IL-12/IL-18, IL-12/IL-15- or IL-15/IL-18-stimulated NK92 cells. By contrast, ectopic SET expression increased IFN-γ production in monokine-stimulated NK92 and primary human NK cells. Because downregulation of SET augmented PP2A activity in NK92 cells, we sought to investigate whether pharmacologic activation of PP2A inhibits the ability of NK cells to produce IFN-γ. Indeed, suppression of IFN-γ expression and secretion was also observed upon treatment of NK92 and primary NK cells with 1,9-dideoxy-forskolin, a known inducer of PP2A activity. Accordingly, NK cells from mice treated with 1.9-dideoxy-forskolin produced less IFN-γ in response to in vivo monokine stimulation than did NK cells from vehicle-treated mice. Mechanistically, activation of PP2A by SET knock-down or 1,9-dideoxy-forskolin treatment leads to inhibition of ERK1/2, p65RelA and STAT5 activity in monokine-stimulated NK cells. Because these signaling molecules are important for IFN-γ production by monokine-stimulated NK cells, our results strongly suggest that monokine induction of SET expression in NK cells is essential for limiting PP2A activity that, otherwise, would negatively impact the ability of NK cells to produce and release optimal levels of IFN-γ.
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Burger, Renate, Steven Legouill, Yu-Tzu Tai, Reshma Shringarpure, Klaus Podar, Laurence Catley, Pierfrancesco Tassone, et al. "The JAK Inhibitor INCB20 Induces Antiproliferative and Apoptotic Effects in Human Myeloma Cells In Vitro and In Vivo." Blood 106, no. 11 (November 16, 2005): 3357. http://dx.doi.org/10.1182/blood.v106.11.3357.3357.
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Abstract In multiple myeloma (MM), IL-6 plays an important role for tumor cell growth, survival, and drug resistance. Janus kinases (JAKs) are protein tyrosine kinases and constitutively associated with the gp130 chain of the IL-6 receptor complex. Their activation is one of the first steps in cytokine receptor-mediated signaling and critical for virtually all subsequent downstream signaling cascades. INCB20 is a small-molecule synthetic compound which, in biochemical assays, potently inhibited all four JAKs with IC50 values between 0.3 nM and 1.2 nM (for comparison, IC50 of AG490, another JAK inhibitor, was >50 μM). Consistent with the central role of JAKs in gp130-mediated signaling, INCB20 inhibited IL-6 induced phosphorylation of SHP-2, STAT1, STAT3, ERK1/2, and AKT in MM1.S cells. In contrast, AKT phosphorylation induced by IGF-1 remained unchanged. Evaluation of the cellular efficacy of INCB20 was performed using the IL-6 dependent INA -6 cell line. Growth of INA-6 cells was inhibited in a dose-dependent manner with an IC50 of approx. 0.5 μM, as measured by [3H]-thymidine uptake and an MTS-based assay (for comparison, the cellular IC50 of AG490 was 15–20 μM). This correlated with an increase in the percentage of apoptotic cells, as evaluated by Apo2.7 staining after 48 hours. Importantly, INA-6 growth was inhibited in the presence of bone marrow stromal cells accompanied by a decrease in phospho-STAT3 levels. Furthermore, in a subcutaneous INA-6-SCID model, INCB20 inhibited tumor growth (and phosphorylated STAT3) in a dose-dependent manner. Our studies provide the conceptual basis for the use of JAK inhibitors as a therapeutic approach in MM.
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Chen, Hongjin, Yuchen Jiang, Rongdiao Liu, Jie Deng, Qinbo Chen, Lingfeng Chen, Guang Liang, Xiong Chen, and Zheng Xu. "Curcumin Derivative C66 Suppresses Pancreatic Cancer Progression through the Inhibition of JNK-Mediated Inflammation." Molecules 27, no. 10 (May 11, 2022): 3076. http://dx.doi.org/10.3390/molecules27103076.
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Pancreatic adenocarcinoma is by far the deadliest type of cancer. Inflammation is one of the important risk factors in tumor development. However, it is not yet clear whether deterioration in pancreatic cancer patients is related to inflammation, as well as the underlying mechanism. In addition, JNK is abnormally activated in pancreatic cancer cells and the JNK inhibitor C66 reduces the inflammatory microenvironment in the tumor. Therefore, the aim of this study was to evaluate the role of C66 in the proliferation and migration of pancreatic cancer. Our results showed that various inflammatory cytokines, such as IL-1β, IL-6, IL-8, and IL-15, were more expressed in pancreatic cancer than in the matching normal tissue. Furthermore, C66, a curcumin analogue with good anti-inflammatory activity, inhibited the proliferation and migration of pancreatic cancer cells in a dose-dependent manner, and effectively inhibited the expression of the above inflammatory factors. Our previous research demonstrated that C66 prevents the inflammatory response by targeting JNK. Therefore, in this study, JNK activity in pancreatic cancer cells was investigated, revealing that JNK was highly activated, and the treatment with C66 inhibited the phosphorylation of JNK. Next, shJNK was used to knockdown JNK expression in pancreatic cancer cells to further confirm the role of JNK in the proliferation and migration of this tumor, as well as in the inflammatory tumor microenvironment (TME). The results demonstrated that JNK knockdown could significantly inhibit the proliferation and migration of pancreatic cancer. Moreover, the low JNK expression in pancreatic cancer cells significantly inhibited the expression of various inflammatory factors. These results indicated that C66 inhibited the progression of pancreatic cancer through the inhibition of JNK-mediated inflammation.
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Tong, Min, and Hsin-Hsiung Tai. "Synergistic Induction of the Nicotinamide Adenine Dinucleotide-Linked 15-Hydroxyprostaglandin Dehydrogenase by an Androgen and Interleukin-6 or Forskolin in Human Prostate Cancer Cells." Endocrinology 145, no. 5 (May 1, 2004): 2141–47. http://dx.doi.org/10.1210/en.2003-1229.
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Abstract The nicotinamide adenine dinucleotide-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of 15 (S)-hydroxyl group of prostaglandins and lipoxins and participates along with cyclooxygenases and lipoxygenases in controlling the cellular levels of prostaglandins and lipoxins. 15-PGDH could be induced by IL-6 and forskolin in addition to androgens in a time- and dose-dependent manner but not by other cytokines and growth factors in LNCaP cells. Concurrent addition of IL-6 and forskolin showed additive effect in the induction of 15-PGDH activity. However, combined addition of dihydrotestosterone (DHT) and IL-6 or DHT plus forskolin exhibited synergistic induction of 15-PGDH activity. The increase in enzyme activity was correlated with the expression of the enzyme protein as shown by Western blot analysis. The induction by DHT or IL-6 or forskolin or their combinations was inhibited by antiandrogen, casodex, in a dose-dependent manner, indicating that a functional androgen receptor was required for the action of any of these three agents. The induction by forskolin plus DHT or by either agent or by IL-6 alone was greatly inhibited by H-89, indicating the involvement of protein kinase A in the actions of forskolin, DHT, and IL-6. The induction of 15-PGDH by IL-6 was also blocked by some other protein kinase inhibitors, indicating the participation of MAPK, MAPK/ERK kinase, and STAT3 in the signaling pathway of IL-6. These results indicate that the induction of 15-PGDH by DHT, IL-6, and forskolin in LNCaP cells may involve a functional androgen receptor and phosphorylation-dependent multiple signaling pathways.
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Ehrlich, Lori A., Masahiro Ito, Sun Jin Choi, and G. D. Roodman. "IL-3 Inhibits Osteoblast Formation in Multiple Myeloma Via CD45+ Cells." Blood 104, no. 11 (November 16, 2004): 2347. http://dx.doi.org/10.1182/blood.v104.11.2347.2347.
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Abstract Normally, osteoclast activation is coupled to an increase in osteoblast activity. In Multiple Myeloma (MM), bone remodeling is uncoupled, and bone destruction occurs both by markedly increased osteoclastic bone destruction and severely impaired osteoblastic bone formation. Although several reports have shown that conditioned media from MM cell lines suppress osteoblast (OBL) differentiation, the identity of the OBL inhibitor(s) is unknown. A recent report by Tian et al (NEJM 2003) has identified DKK1, an inhibitor of the WNT signaling pathway, as a putative OBL inhibitor in MM. However, it is likely that other inhibitors of OBL differentiation are present in the myeloma microenvironment, just as there are several potent stimulators of osteoclast formation produced or induced by myeloma cells. We recently reported that IL-3 levels in bone marrow plasma of patients with MM are increased compared to normal controls and that IL-3 in MM marrow plasma stimulates osteoclast formation. We also demonstrated that IL-3 is produced by primary myeloma cells and that it increased MM cell growth in vitro. However, the effects of IL-3 on OBL are unknown. Therefore, to determine if IL-3 could affect OBL growth and differentiation, we tested the effects of IL-3 on OBL differentiation in primary mouse marrow stromal cells. We found that murine marrow stromal cells and OBL-like cell lines expressed IL-3 receptor alpha (IL-3R) by RT-PCR. Staining for IL-3R in marrow stromal cell cultures after treatment with IL-3 confirmed that the IL-3R was present on thirty percent of the cells. Importantly, treatment of primary murine stromal cell cultures with IL-3 (0.01–10 ng/mL) inhibited basal and BMP-2 stimulated osteoblast formation in a dose dependent manner, without affecting cell growth. At 10 ng/mL IL-3 inhibited OBL differentiation by 80%. Time course studies demonstrated that IL-3 affected the later stages of osteoblast differentiation. Further, the inhibitory effects of IL-3 were not due to induction of TNFalpha, a known OBL inhibitor. TNFalpha levels were very low (0–20pg/ml) in the conditioned media of these cultures, and treating the cultures with anti-mouse TNFalpha did not block the IL-3 effect. IL-3 did not inhibit alkaline phosphatase activity in the osteoblast-like cell lines, MC3T3-E1 and C2C12 suggesting that IL-3 may act indirectly through another cell type in the mixed cell population in the primary mouse osteoblast culture system. Since IL-3 acts primarily on hematopoietic cells, we determined if IL-3 was acting indirectly by increasing CD45+ cells in the cultures. IL-3 increased the number of CD45+ hematopoietic cells in the primary culture from approximately 15% to 30%. Further, depletion of the CD45+ cells abolished the inhibitory effects of IL-3 but not TNFalpha on osteoblasts, and adding back CD45+ cells to the stromal cell cultures restores the inhibitory effects of IL-3. This data suggests that IL-3 is an important mediator of bone destruction in MM by both inducing osteoclast formation and indirectly inhibiting osteoblast formation.
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Kozak, W., J. J. Klir, C. A. Conn, and M. J. Kluger. "Attenuation of lipopolysaccharide fever in rats by protein kinase C inhibitors." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 273, no. 3 (September 1, 1997): R873—R879. http://dx.doi.org/10.1152/ajpregu.1997.273.3.r873.
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The purpose of this study was to assess the effects of inhibitors of protein kinase C (PKC) on lipopolysaccharide (LPS)-induced fever and changes in circulating interleukin-6 (IL-6) levels in freely moving biotelemetered rats. We used PKC inhibitors with different inhibition constants (Ki): H-7 (Ki = 6 microM) and chelerythrine (Chel; Ki = 0.66 microM; a more potent PKC inhibitor). Rats were injected subcutaneously with either 3 or 15 microM/kg of these inhibitors and then 1 h later were injected intraperitoneally with LPS (50 micrograms/kg). Blood samples for IL-6 bioassay were collected 4 h after LPS injection. H-7 at lower doses did not significantly affect fever and LPS-induced elevation of circulating IL-6, whereas at a higher dose (15 microM/kg) H-7 reduced both fever and the increase of IL-6 (analysis of variance, Scheffe's test, P < 0.05). Chel (3 and 15 microM/kg) significantly reduced fever and almost completely inhibited the LPS-induced elevation of plasma IL-6. In separate experiments, we studied the effect of H-7 on antipyresis due to dexamethasone (Dex). Dex at a dose of 0.6 microM/kg given subcutaneously 1 h before LPS partially prevented fever (approximately 55% inhibition) and attenuated the increase of IL-6 (P < 0.05). Simultaneous pretreatment of the rats with Dex and H-7 (3 microM/kg; a dose that did not affect fever and IL-6 elevation) led to a potentiation of the antipyretic effect of Dex, resulting in no fever. H-7 did not potentiate, however, the inhibitory effect of Dex on LPS-induced elevation of circulating IL-6. We conclude that PKC is involved in the regulation of LPS fever and constitutes a rate-limiting factor in modulation of the fever by glucocorticoids.
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Ahmed, Tamer A., Mark D. Buzzelli, Charles H. Lang, John B. Capen, Margaret L. Shumate, Maithili Navaratnarajah, Murali Nagarajan, and Robert N. Cooney. "Interleukin-6 inhibits growth hormone-mediated gene expression in hepatocytes." American Journal of Physiology-Gastrointestinal and Liver Physiology 292, no. 6 (June 2007): G1793—G1803. http://dx.doi.org/10.1152/ajpgi.00547.2006.
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During systemic inflammation, the liver becomes unresponsive to growth hormone (GH), resulting in decreased plasma insulin-like growth factor-I (IGF-I) with concomitant reductions in lean body mass. Transgenic mice that overexpress IL-6 also demonstrate impaired growth and decreased IGF-I. To determine whether IL-6 directly inhibits GH-inducible gene expression, CWSV-1 hepatocytes were incubated with IL-6 (10 ng/ml), then stimulated with recombinant human GH (500 ng/ml, 18 h). The increase in IGF-I and serine protease inhibitor 2.1 (Spi 2.1) mRNA in GH-treated cells was inhibited by treatment with IL-6 for 24 h. To investigate potential mechanisms, we examined the effects of IL-6 on GH receptor (GHR) expression and GH signaling via the JAK/signal transducer and activator of transcription (STAT) and MAP kinase pathways. Incubation of cells with IL-6 (10 ng/ml, 24 h) had no effect on GHR abundance or signaling proteins JAK2, STAT5b, and ERK1/2. Although GH transiently increased (2- to 5-fold) the tyrosine phosphorylation of GHR, JAK2, STAT5b, and ERK1/2, IL-6 did not alter these phosphorylation events. However, nuclear protein from IL-6-treated cells demonstrated reduced STAT5 DNA binding (by EMSA) at 15 min (−20%) and 60 min (−43%) after GH stimulation. To determine whether IL-6 inhibits GH-inducible promoter activity, CWSV-1 cells were transfected with Spi 2.1 or prolactin receptor promoter luciferase vectors, incubated with or without IL-6, then stimulated with GH. The induction of both Spi 2.1 (7.5-fold) and prolactin receptor (4-fold) promoter activity by GH was inhibited by IL-6. In summary, IL-6 mediates hepatic GH resistance by a time-dependent inhibition of GH-inducible promoter activity that is associated with reductions in STAT5 DNA binding.
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Kohnken, Rebecca, Jing Wen, Max Yano, Alex Hartlage, Leah Grinshpun, Michael A. Caligiuri, Pierluigi Porcu, and Anjali Mishra. "Targeting BRD4 Disables IL-15 Oncogenic Signaling in Cutaneous T-Cell Lymphoma Via Down Regulation of IL-15 Receptor Complex." Blood 128, no. 22 (December 2, 2016): 1097. http://dx.doi.org/10.1182/blood.v128.22.1097.1097.
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Abstract Targeting the epigenome is a promising strategy in the treatment of advanced stage cutaneous T-cell lymphoma (CTCL). CTCL is a malignancy of mature CD4+ T-cells which initially involves the skin but may progress to involve blood and visceral organs. There is no curative treatment, and drug resistance is a common problem. A hallmark feature in the development and progression of CTCL is global dysregulation of the epigenome resulting in aberrant gene expression, increased expression of oncogenes, and silencing of tumor suppressors. Bromodomain 4 (BRD4) is a master epigenetic regulator of gene expression recently identified as a survival factor in many hematologic and solid malignancies. A member of the bromodomain and extra terminal (BET) protein family, BRD4 binds chromatin in super-enhancer regions to direct downstream gene expression through interaction with co-factors such as Mediator and p-TEFb. Recently, a small molecule specific inhibitor of BRD4, JQ1, has been investigated as an anti-tumor agent. The role of BRD4, and therefore the efficacy and mechanism of JQ1 in CTCL is not known. Our group recently reported the critical role of IL-15 signaling in the development and progression of CTCL (Mishra et al, Cancer Discovery, 2016). Utilizing CTCL-derived cell lines, patient samples, and the newly characterized IL-15 transgenic mouse model of CTCL, we describe the effects of IL-15 signaling on BRD4 expression, and demonstrate for the first time regulation of IL-15 receptor expression by BRD4. We also describe the efficacy of JQ1 as an anti-tumor agent in CTCL which acts by inducing cell cycle arrest in cell lines and preventing disease progression in IL-15 transgenic mice. IL-15 signaling through its heterotrimeric receptor is a driver of oncogenesis in CTCL. Treatment of primary CD4+ T-cells from healthy donors with IL-15 (100ng/ml) for 48 hours increases protein expression of BRD4 (Figure 1A). To evaluate the occupancy of BRD4 in regulatory regions of IL-15 receptor genes, we performed ChIP-sequencing for BRD4 binding in CD4+ T-cells from a healthy donor, fresh CTCL cells, and JQ1-treated CTCL cells. At the gene locus for IL-15Rα (Chromosome 10p14-p15), we observed increased BRD4 binding at the transcription start site. This occupancy is reversed upon treatment with JQ1, to a level comparable to that of healthy donor CD4+ T-cells. This pattern is recapitulated in regulatory regions for IL-15Rβ and IL-15Rγ loci. To determine if decreased BRD4 occupancy following JQ1 treatment results in decreased IL-15 receptors gene expression, immunoblotting was performed for each receptor subunit. Treatment of the CTCL cell line HuT78 cells, with JQ1 results in significant reduction in the expression of all three IL-15 receptor subunits compared to vehicle. IL-15Rα expression decreased 2.3-fold, IL-15Rβ by 17-fold, and IL-15Rγ by 122-fold (Figure 1A). To determine the efficacy of JQ1 as an anti-tumor agent, CTCL-derived cell lines were treated with increasing doses of JQ1 for 72 hours. Cell viability and cell cycle analysis was performed and IC50 values were calculated for each cell line. At 10µM dose, there were significant decreases in % cell viability for all 5 cell lines (MyLa 66±2.56; HuT102 37±1.39; HuT78 30±1.86; HH 19±2.15; SeAx 36±0.79; p<0.0001 for all of the above). IC50 for MyLa is 21µM, HuT102 0.445µM, SeAx 4.45µM, HuT78 0.167µM, and HH 0.461µM. Treatment of these cell lines with JQ1 also resulted in a dose-dependent increase of cells in sub-G0 phase of the cell cycle, corresponding with increased Annexin V staining. IL-15 transgenic mice universally develop CTCL by 3-4 weeks of age. We treated these mice with 50mg/kg JQ1 (n=8) or a vehicle control (n=5) beginning at 4 weeks of age for 4 weeks. Scoring of the morphology, and severity of skin lesions histologically (Figure 1B) demonstrated a significant difference between JQ1 treated animals and controls (Figure 1C,p=0.0041), with JQ1-treated animals having milder disease. We conclude that BRD4 binding at regulatory regions enhances IL-15 receptor expression in CTCL. Increased receptor expression may augment IL-15 signaling, a known oncogenic mechanism in this malignancy. Furthermore, JQ1 reverses the effects of BRD4 on IL-15 receptor expression, results in significant cytotoxicity in cell lines, and prevents development of severe disease in a mouse model of CTCL. BRD4 therefore represents a promising therapeutic target in CTCL. Disclosures Porcu: Innate Pharma: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; miRagen: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial.
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Brammer, Jonathan E., Anjali Mishra, Amy Boles, Anthony Mansour, Monique Mathe-Allainmat, Agnes Quemener, and Pierluigi Porcu. "79696 Reversible DNA Hypermethylation of the Interleukin-15 Promoter Induces IL-15 Expression, Drives the Pathogenesis of T-Cell Large Granular Lymphocytic Leukemia (T-LGLL) and Provides a Therapeutic Approach Using 5-Azacitidine." Journal of Clinical and Translational Science 5, s1 (March 2021): 92. http://dx.doi.org/10.1017/cts.2021.638.
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ABSTRACT IMPACT: This work describes, for the first time, the methylome in patients with T-LGLL, focusing on the IL-15 promoter, and clearly demonstrates that 5-azacytidine decreases IL-15 production leading to T-LGLL cell death. These results form the basis a translational clinical trial in T-LGLL that will begin accrual in 2021 OBJECTIVES/GOALS: T-LGLL is an incurable leukemia with few treatment options driven by overexpression of IL-15. Our objective is to characterize the methylation status of the IL-15 promoter in T-LGLL patients and evaluate the potential use of 5-azacytidine (5-aza) in a translational trial by studying the effect of 5-aza in vitro on IL-15 levels, and the IL-15 promoter. METHODS/STUDY POPULATION: We sorted T-LGLL patient (n=3) and normal donor (ND) samples (n=3) for CD3+/CD8+/CD5-/dim for T-LGLL immunophenotype. We analyzed DNA methylation and gene expression profiling using reduced representation bisulfite and RNA sequencing and determined differential methylation and gene expression using 1-way ANOVA analysis. To determine the functional significance of differential methylation, we evaluated MOTN-1 T-LGLL cell viability in vitro with 5-aza at increasing concentrations. Next, we evaluated IL-15 gene expression in MOTN-1 cells treated with 5-Aza versus MOTN-1 with control using western immunoblot. Finally, we exposed MOTN-1 cells to a novel IL-15 inhibitor, IBI-15, and compared cell viability against MOTN-1 cells exposed to an inactive control. RESULTS/ANTICIPATED RESULTS: There was significant differential methylation (P= 0.0178) and expression (P =0.0059) in T-LGLL patients vs ND. These data revealed significant differential hypermethylation of gene promoters, including an increase in DNA methylation of the IL-15 promoter in T-LGLL cells vs ND. In MOTN-1 cells treated in vitro with 5-Aza at 24 and 48 hours, a dose-dependent decrease in the viability of T-LGLL cells was observed, from 100% to 49.5%, p=0.037. Further, a marked decrease in IL-15 expression was observed at all concentrations of 5-aza compared to control (p=0.0001). Finally, a decrease in cell viability was observed utilizing the IL-15 inhibitor IBI-15 vs control. These results confirm that 5-aza leads to decreased transcription of the IL-15 gene, possibly due to hypomethylation of the IL-15 promoter. DISCUSSION/SIGNIFICANCE OF FINDINGS: Hypermethylation of the IL-15 promoter and subsequent increase in IL-15 is critical to the pathogenesis of T-LGLL. Inhibition of the IL-15 promoter by 5-aza leads to down-regulation of the IL-15 gene transcript, which is sufficient to induce T-LGLL cell death. Based on these results, a phase I trial will be conducted using CC-486 (oral 5-Aza) in T-LGLL.
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Devocelle, Aurore, Lola Lecru, Sophie Ferlicot, Thomas Bessede, Jean-Jacques Candelier, Julien Giron-Michel, and Hélène François. "IL-15 Prevents Renal Fibrosis by Inhibiting Collagen Synthesis: A New Pathway in Chronic Kidney Disease?" International Journal of Molecular Sciences 22, no. 21 (October 28, 2021): 11698. http://dx.doi.org/10.3390/ijms222111698.
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Chronic kidney disease (CKD), secondary to renal fibrogenesis, is a public health burden. The activation of interstitial myofibroblasts and excessive production of extracellular matrix (ECM) proteins are major events leading to end-stage kidney disease. Recently, interleukin-15 (IL-15) has been implicated in fibrosis protection in several organs, with little evidence in the kidney. Since endogenous IL-15 expression decreased in nephrectomized human allografts evolving toward fibrosis and kidneys in the unilateral ureteral obstruction (UUO) model, we explored IL-15’s renoprotective role by pharmologically delivering IL-15 coupled or not with its soluble receptor IL-15Rα. Despite the lack of effects on myofibroblast accumulation, both IL-15 treatments prevented tubulointerstitial fibrosis (TIF) in UUO as characterized by reduced collagen and fibronectin deposition. Moreover, IL-15 treatments inhibited collagen and fibronectin secretion by transforming growth factor-β (TGF-β)-treated primary myofibroblast cultures, demonstrating that the antifibrotic effect of IL-15 in UUO acts, in part, through a direct inhibition of ECM synthesis by myofibroblasts. In addition, IL-15 treatments resulted in decreased expression of monocyte chemoattractant protein 1 (MCP-1) and subsequent macrophage infiltration in UUO. Taken together, our study highlights a major role of IL-15 on myofibroblasts and macrophages, two main effector cells in renal fibrosis, demonstrating that IL-15 may represent a new therapeutic option for CKD.
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Vargaftig, B. Boris, and Monique Singer. "Leukotrienes, IL-13, and chemokines cooperate to induce BHR and mucus in allergic mouse lungs." American Journal of Physiology-Lung Cellular and Molecular Physiology 284, no. 2 (February 1, 2003): L260—L269. http://dx.doi.org/10.1152/ajplung.00226.2002.
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In mice, intratracheal challenges with antigen (ovalbumin) or recombinant murine interleukin-13 (IL-13) induce lung inflammation, bronchial hyperreactivity (BHR), and mucus accumulation as independent events (Singer M, Lefort J, and Vargaftig BB. Am J Respir Cell Mol Biol 26: 74–84, 2002), largely mediated by leukotrienes (LT). We previously showed that LTC4 was released 15 min after ovalbumin, and we show that it induces the expression of monocyte chemoattractant proteins 1 and 5 and KC in the lungs, as well as IL-13 mRNA. Instilled intratracheally, these chemokines induced BHR and mucus accumulation, which were inhibited by the 5-lipoxygenase inhibitor zileuton and by the cysteinyl-LT receptor antagonist MK-571, suggesting mediation by cysteinyl-LT. Because these chemokines also induced release of LT into the bronchoalveolar lavage fluid and IL-13 into the lungs, we hypothesize that LT- and chemokine-based loops for positive-feedback regulations cooperate to maintain and amplify BHR and lung mucus accumulation after allergic challenge and in situations where IL-13, LT, or chemokines are generated.
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Tefferi, Ayalew, Rakhee Vaidya, Domenica Caramazza, Christy Finke, Terra Lasho, and Animesh Pardanani. "Circulating Interleukin (IL)-8, IL-2R, IL-12, and IL-15 Levels Are Independently Prognostic in Primary Myelofibrosis: A Comprehensive Cytokine Profiling Study." Journal of Clinical Oncology 29, no. 10 (April 1, 2011): 1356–63. http://dx.doi.org/10.1200/jco.2010.32.9490.
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Purpose Abnormal cytokine expression accompanies myelofibrosis and might be a therapeutic target for Janus-associated kinase (JAK) inhibitor drugs. This study describes the spectrum of plasma cytokine abnormalities in primary myelofibrosis (PMF) and examines their phenotypic correlates and prognostic significance. Patients and Methods Patients included in this study were required to have archived plasma, bone marrow biopsy, and cytogenetic information available at the time of first referral to the Mayo Clinic. Multiplex biometric sandwich immunoassay was used to measure plasma levels of 30 cytokines. Results In total, 127 PMF patients were studied; comparison with normal controls (n = 35) revealed significantly increased interleukin-1β (IL-1β), IL-1RA, IL-2R, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, tumor necrosis factor α (TNF-α), granulocyte colony-stimulating factor (G-CSF), interferon alfa (IFN-α), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, hepatocyte growth factor (HGF), IFN-γ–inducible protein 10 (IP-10), monokine induced by IFN-γ (MIG), monocyte chemotactic protein 1 (MCP-1), and vascular endothelial growth factor (VEGF) levels and decreased IFN-γ levels. In treatment-naive patients (n = 90), increased levels of IL-8 (P < .001), IL-2R (P < .001), IL-12 (P < .001), IL-15 (P = .001), and IP-10 (P = .003) were independently predictive of inferior survival. A similar multivariable analysis that included all 127 study patients confirmed the prognostic value of these five cytokines, and IL-8, IL-2R, IL-12, and IL-15 remained significant when risk stratification, according to the recently revised Dynamic International Prognostic Scoring System (DIPSS plus), was added to the multivariable model. Leukemia-free survival was predicted by IL-8, which was also the only cytokine associated with ≥ 1% circulating blasts. Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP-10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1β, and JAK2V617F. A two-cytokine (IL-8/IL-2R) –based risk categorization delineated prognostically different groups within specific DIPSS plus risk categories. Conclusion This study signifies the presence of specific cytokine-phenotype associations in PMF and a prognostically relevant plasma cytokine signature that might prove useful as a laboratory tool for predicting and monitoring treatment response.
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Beales, I. L. P., and J. Calam. "Interleukin 1β and tumour necrosis factor α inhibit acid secretion in cultured rabbit parietal cells by multiple pathways." Gut 42, no. 2 (February 1, 1998): 227–34. http://dx.doi.org/10.1136/gut.42.2.227.
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Background—The cytokines interleukin 1β (IL-1β) and tumour necrosis factor α (TNF-α) are inhibitors of gastric acid secretion when administered systemically.Aims—To investigate the inhibitory effect of IL-1β and TNF-α on cultured, acid secreting parietal cells in order to determine the mechanism of this inhibition.Methods—Rabbit parietal cells were prepared by collagenase-EDTA digestion and counter flow elutriation. Acid secretory activity was assessed by aminopyrine accumulation.Results—IL-1β and TNF-α inhibited basal and stimulated acid secretion in a dose dependent manner; near maximal effects were seen with both at 10 ng/ml. Inhibition was maximal with 15 minutes pretreatment but seen with up to 18 hours of preincubation. Both cytokines inhibited histamine, carbachol, gastrin, forskolin, and A23187 stimulated acid secretion but had no effect on stimulation by dibutyryl-cAMP. Inhibition of acid secretion was not accompanied by a change in radioligand binding to histamine H2 or gastrin/CCKB receptors. Pertussis toxin abolished the inhibitory effects on histamine and forskolin stimulation. The tyrosine kinase inhibitor herbimycin reduced the inhibitory effects of TNF-α against all stimuli but only reduced the effects of IL-1β against histamine and forskolin stimulation.Conclusions—IL-1β and TNF-α seem to inhibit parietal cell acid secretion by multiple pathways; the inhibition occurs at postreceptor level and involves pertussis toxin and tyrosine kinase dependent and independent pathways. Mucosal production of cytokines may be important in the regulation of gastric acid secretion.
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Shi, Samuel X., Yu-Jing Li, Kaibin Shi, Kristofer Wood, Andrew F. Ducruet, and Qiang Liu. "IL (Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates Brain Injury Following Intracerebral Hemorrhage." Stroke 51, no. 3 (March 2020): 967–74. http://dx.doi.org/10.1161/strokeaha.119.028638.
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Background and Purpose— Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods— Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15 tg ). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results— In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15 tg mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15 tg mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1β, and TNF-α is markedly increased in GFAP-IL-15 tg mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15 tg mice. Conclusions— Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.
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Cui, Ke, Giamal N. Luheshi, and Patricia Boksa. "Effects of endogenous glucocorticoid secretion on the interleukin-6 response to bacterial endotoxin in pregnant and non-pregnant rats." Journal of Endocrinology 209, no. 1 (January 17, 2011): 95–103. http://dx.doi.org/10.1530/joe-10-0436.
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Glucocorticoids (GCs) are released in response to immune activation by the bacterial endotoxin, lipopolysaccharide (LPS). However, GC secretion in response to immune activation and other stressors is attenuated at term of pregnancy. GCs are important modulators of the immune response, and both pro- and anti-inflammatory effects are described. Here, we examined whether GC secretion in response to LPS is maintained in earlier pregnancy before term, and investigated the role of endogenous GCs in modulating LPS-induced circulating cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), in pregnant compared to non-pregnant female rats. Plasma corticosterone (Cort) and ACTH responses to LPS were well maintained in pregnant rats at embryonic days 15/16 (E15/16) and E18/19 compared to non-pregnant rats. At E19, maternal LPS administration increased fetal plasma Cort and decreased testosterone in male fetuses. In non-pregnant animals, pretreatment with the GC synthesis inhibitor, metyrapone, inhibited the LPS-induced increase in IL-6, and the IL-6 response was restored by Cort replacement, indicating that LPS induction of IL-6 is Cort-dependent. In E15 pregnant animals, metyrapone had no effect on LPS-induced IL-6 levels, indicating that LPS-induction of IL-6 is not dependent on Cort. These contrasting patterns of IL-6 induction in non-pregnant and pregnant animals were reflected in levels of hypothalamic Socs3 mRNA, an indicator of IL-6 signaling pathway activation. In both non-pregnant and pregnant rats, LPS-induced plasma TNF-α responses were inhibited by metyrapone but not re-instated by Cort replacement. It is suggested that altered GC regulation of IL-6 may be required to sustain specialized functions of IL-6 during pregnancy.
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Watanabe, Ryo, Ryoko Wakizono Azuma, Jun-ichi Suzuki, Masahito Ogawa, Akiko Itai, Yasunobu Hirata, Issei Komuro, and Mitsuaki Isobe. "Inhibition of NF-κB activation by a novel IKK inhibitor reduces the severity of experimental autoimmune myocarditis via suppression of T-cell activation." American Journal of Physiology-Heart and Circulatory Physiology 305, no. 12 (December 15, 2013): H1761—H1771. http://dx.doi.org/10.1152/ajpheart.00159.2013.
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NF-κB, which is activated by the inhibitor of NF-κB kinase (IKK), is involved in the progression of inflammatory disease. However, the effect of IKK inhibition on the progression of myocarditis is unknown. We examined the effect of IKK inhibition on the progression of myocarditis. Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis (EAM). We administered the IKK inhibitor (IMD-0354; 15 mg·kg−1·day−1) or vehicle to EAM rats daily. Hearts were harvested 21 days after immunization. Although the untreated EAM group showed increased heart weight-to-body weight ratio, and severe myocardial damage, these changes were attenuated in the IKK inhibitor-treated group. Moreover, IKK inhibitor administration significantly reduced NF-κB activation and mRNA expression of IFN-γ, IL-2, and monocyte chemoattractant protein-1 in myocardium compared with vehicle administration. In vitro study showed that the IKK inhibitor treatment inhibited T-cell proliferation and Th1 cytokines production induced by myosin stimulation. The IKK inhibitor ameliorated EAM by suppressing inflammatory reactions via suppression of T-cell activation.
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Wermes, C., B. Eifrig, K. Holstein, H. Pollmann, B. Siegmund, W. Eberl, B. Kemkes-Matthes, et al. "Inhibitor-Immunology-Study." Hämostaseologie 31, S 01 (2011): S57—S60. http://dx.doi.org/10.1055/s-0037-1619751.
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SummaryThe development of inhibitors in haemophilia B is one of the most important complications of replacement therapy, affecting mortality and morbidity. Inhibitor development is based on complex immunological factors, and to date, only little is known about its underlying mechanisms. Here, we present first results of the haemophilia B group of our Inhibitor-Immunology study. Patients, methods So far we have analysed 15 patients with haemophilia B. Four of them developed a high titre inhibitor; the remaining 11 had no inhibitor. We evaluated 9 SNPs in 8 genes (CD40, CTLA-4, IL-1β, IL-10, TLR2, TLR4, TLR9, TNF-α). We compared the distribution of these alleles between inhibitor and non-inhibitor haemophilia B patients and between haemophilia B patients and a normal male control population. HLA typing was performed in all patients. Results, discussion There appears to be a trend towards a skewed distribution of TLR 9, IL-10 and CTLA4 alleles in haemophilia B patients. Due to the limited number these differences are, however, not statistically significant.The t-test of all patients with inhibitor versus without inhibitor was significant for HLA-A*03 and DPB1*0401 and borderline for DRB1*0201.
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Marzec, Michal, Xiaobin Liu, Monika Kasprzycka, Agnieszka Witkiewicz, Puthiyaveettil N. Raghunath, Mouna El-Salem, Erle Robertson, Niels Odum, and Mariusz A. Wasik. "IL-2– and IL-15–induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes." Blood 111, no. 4 (February 15, 2008): 2181–89. http://dx.doi.org/10.1182/blood-2007-06-095182.
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We examined functional status, activation mechanisms, and biologic role of the mTORC1 signaling pathway in malignant CD4+ T cells derived from the cutaneous T-cell lymphoma (CTCL). Whereas the spontaneously growing CTCL-derived cell lines displayed persistent activation of the TORC1 as well as the PI3K/Akt and MEK/ERK pathways, the IL-2–dependent cell lines activated the pathways in response to IL-2 and IL-15 but not IL-21. Activation of mTORC1 and MEK/ERK was nutrient dependent. The mTORC1, PI3K/Akt, and MEK/ERK pathways could also be activated by IL-2 in the primary leukemic, mitogen-preactivated CTCL cells. mTORC1 activation was also detected in the CTCL tissues in the lymphoma stage–dependent manner with the highest percentage of positive cells present in the cases with a large cell transformation. Rapamycin inhibited mTORC1 signaling and suppressed CTCL cell proliferation but showed little effect on their apoptotic rate when used as a single agent. Activation of the mTORC1, PI3K/Akt, and MEK/ERK pathways was strictly dependent on the Jak3 and Jak1 kinases. Finally, mTORC1 activation was transduced preferentially through the PI3K/Akt pathway. These findings document the selective γc-signaling cytokine-mediated activation of the mTORC1 pathway in the CTCL cells and suggest that the pathway represents a therapeutic target in CTCL and, possibly, other T-cell lymphomas.
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Manganaro, Lara, Patrick Hong, Matthew M. Hernandez, Dionne Argyle, Lubbertus C. F. Mulder, Uma Potla, Felipe Diaz-Griffero, Benhur Lee, Ana Fernandez-Sesma, and Viviana Simon. "IL-15 regulates susceptibility of CD4+ T cells to HIV infection." Proceedings of the National Academy of Sciences 115, no. 41 (September 26, 2018): E9659—E9667. http://dx.doi.org/10.1073/pnas.1806695115.
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HIV integrates into the host genome to create a persistent viral reservoir. Stimulation of CD4+ memory T lymphocytes with common γc-chain cytokines renders these cells more susceptible to HIV infection, making them a key component of the reservoir itself. IL-15 is up-regulated during primary HIV infection, a time when the HIV reservoir established. Therefore, we investigated the molecular and cellular impact of IL-15 on CD4+ T-cell infection. We found that IL-15 stimulation induces SAM domain and HD domain-containing protein 1 (SAMHD1) phosphorylation due to cell cycle entry, relieving an early block to infection. Perturbation of the pathways downstream of IL-15 receptor (IL-15R) indicated that SAMHD1 phosphorylation after IL-15 stimulation is JAK dependent. Treating CD4+ T cells with Ruxolitinib, an inhibitor of JAK1 and JAK2, effectively blocked IL-15–induced SAMHD1 phosphorylation and protected CD4+ T cells from HIV infection. Using high-resolution single-cell immune profiling using mass cytometry by TOF (CyTOF), we found that IL-15 stimulation altered the composition of CD4+ T-cell memory populations by increasing proliferation of memory CD4+ T cells, including CD4+ T memory stem cells (TSCM). IL-15–stimulated CD4+ TSCM, harboring phosphorylated SAMHD1, were preferentially infected. We propose that IL-15 plays a pivotal role in creating a self-renewing, persistent HIV reservoir by facilitating infection of CD4+ T cells with stem cell-like properties. Time-limited interventions with JAK1 inhibitors, such as Ruxolitinib, should prevent the inactivation of the endogenous restriction factor SAMHD1 and protect this long-lived CD4+ T-memory cell population from HIV infection.
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Widowati, Wahyu, Diana K Jasaputra, Sutiman B Sumitro, Mochammad A Widodo, Tjandrawati Mozef, Rizal Rizal, Hanna Sari W Kusuma, et al. "Effect of interleukins (IL-2, IL-15, IL-18) on receptors activation and cytotoxic activity of natural killer cells in breast cancer cell." African Health Sciences 20, no. 2 (July 22, 2020): 822–32. http://dx.doi.org/10.4314/ahs.v20i2.36.
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Introduction: Breast cancer is one of the leading cause of cancer deaths in women. Metastasis in BC is caused by immuno- surveillance deficiency, such NK cell maturation, low NK activity and decreasing cytotoxicity. This study was performed to improve activating receptors and cytotoxicity of NK cells using interleukins (ILs).
Methods: Human recombinant IL-2, -15, and -18 were used to induce NK cells. We measured the activating and inhibiting receptors, proliferation activity of NK cells, and the cytotoxicity of NK cells on BC cells (MCF7). The effects of ILs were tested on the NK cell receptors CD314, CD158a and CD107a with flowcytometry, proliferation at various incubation times with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and concen- trations of TNF-α and IFN-γ by NK cells with ELISA.
Results: ILs increased NK cell receptor levels (CD314, CD158a, and CD107a) at 24 hours of incubation. ILs increased NK cell viability, which increased with longer incubation. Moreover, ILs-induced NK cells inhibited proliferation in MCF7 cells, as well as increased TNF-α, IFN-γ, PRF1 and GzmB secretion.
Conclusion: IL-2, IL-15, and IL-18 improved activating receptors and proliferation of NK cells. IL-induced NK cells in- creased TNF-α, IFN-γ, PRF1 and GzmB secretion and cytotoxic activity on BC cells. High NK cell numbers increased BC cell growth inhibition.
Keywords: Activator; breast cancer; interleukins; natural killer; receptor.
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Banchereau, Jacques, LuAnn Thompson-Snipes, Sandra Zurawski, Jean-Philippe Blanck, Yanying Cao, Sandra Clayton, Jean-Pierre Gorvel, Gerard Zurawski, and Eynav Klechevsky. "The differential production of cytokines by human Langerhans cells and dermal CD14+ DCs controls CTL priming." Blood 119, no. 24 (June 14, 2012): 5742–49. http://dx.doi.org/10.1182/blood-2011-08-371245.
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Abstract We recently reported that human epidermal Langerhans cells (LCs) are more efficient than dermal CD14+ DCs at priming naive CD8+ T cells into potent CTLs. We hypothesized that distinctive dendritic cell (DC) cytokine expression profiles (ie, IL-15 produced by LCs and IL-10 expressed by dermal CD14+ DCs) might explain the observed functional difference. Blocking IL-15 during CD8+ T-cell priming reduced T-cell proliferation by ∼ 50%. These IL-15–deprived CD8+ T cells did not acquire the phenotype of effector memory cells. They secreted less IL-2 and IFN-γ and expressed only low amounts of CD107a, granzymes and perforin, and reduced levels of the antiapoptotic protein Bcl-2. Confocal microscopy analysis showed that IL-15 is localized at the immunologic synapse of LCs and naive CD8+ T cells. Conversely, blocking IL-10 during cocultures of dermal CD14+ DCs and naive CD8+ T cells enhanced the generation of effector CTLs, whereas addition of IL-10 to cultures of LCs and naive CD8+ T cells inhibited their induction. TGF-β1 that is transcribed by dermal CD14+ DCs further enhanced the inhibitory effect of IL-10. Thus, the respective production of IL-15 and IL-10 explains the contrasting effects of LCs and dermal CD14+ DCs on CD8+ T-cell priming.