Journal articles on the topic 'Beta-cell protection'
To see the other types of publications on this topic, follow the link: Beta-cell protection.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Beta-cell protection.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
MANDRUP-POULSEN, THOMAS. "Beta Cell Death and Protection." Annals of the New York Academy of Sciences 1005, no. 1 (November 2003): 32–42. http://dx.doi.org/10.1196/annals.1288.005.
2
Hosseini, Azar, Reza Shafiee-Nick, and Ahmad Ghorbani. "Pancreatic beta cell protection/regeneration with phytotherapy." Brazilian Journal of Pharmaceutical Sciences 51, no. 1 (March 2015): 1–16. http://dx.doi.org/10.1590/s1984-82502015000100001.
Abstract:
Although currently available drugs are useful in controlling early onset complications of diabetes, serious late onset complications appear in a large number of patients. Considering the physiopathology of diabetes, preventing beta cell degeneration and stimulating the endogenous regeneration of islets will be essential approaches for the treatment of insulin-dependent diabetes mellitus. The current review focused on phytochemicals, the antidiabetic effect of which has been proved by pancreatic beta cell protection/regeneration. Among the hundreds of plants that have been investigated for diabetes, a small fraction has shown the regenerative property and was described in this paper. Processes of pancreatic beta cell degeneration and regeneration were described. Also, the proposed mechanisms for the protective/regenerative effects of such phytochemicals and their potential side effects were discussed.
3
Ljunggren, H. G., K. Sturmhöfel, E. Wolpert, G. J. Hämmerling, and K. Kärre. "Transfection of beta 2-microglobulin restores IFN-mediated protection from natural killer cell lysis in YAC-1 lymphoma variants." Journal of Immunology 145, no. 1 (July 1, 1990): 380–86. http://dx.doi.org/10.4049/jimmunol.145.1.380.
Abstract:
Abstract A beta 2-microglobulin (beta 2m)-deficient variant of YAC-1, A.H-2-, was transfected with a genomic beta 2m clone. Transfected cells were used to investigate the role of beta 2m in IFN-induced protection from NK cell lysis. IFN-gamma treatment of the NK-sensitive murine YAC-1 lymphoma results in reduced sensitivity to NK cell-mediated lysis in parallel with increased expression of its constitutively low MHC class I expression. It was previously shown that the A.H-2- variant had lost both these capacities, although it retained other responses to IFN-gamma. Here beta 2m transfection restored the YAC-1 phenotype with respect to an inducible expression of MHC class I molecules and a concomitant protection from NK cell lysis after treatment with IFN-gamma. In the absence of IFN-gamma the NK sensitivity of the transfectants did not differ significantly from A.H-2-. A similar protection from NK cell lysis, in parallel with enhanced MHC class I expression, was observed for in vivo-passaged beta 2m transfectants whereas no protection was found for in vivo-passaged A.H-2- cells. The present study provides evidence that the IFN-gamma-mediated protection from NK cell lysis is dependent on beta 2m expression in the YAC-1 lymphoma. Restoration of MHC class I assembly, transport, and concomitantly an IFN-gamma augmentable cell surface expression of MHC class I molecules is a possible explanation for the effect of beta 2m.
4
Asahara, Shun-ichiro, and Wataru Ogawa. "SGLT2 inhibitors and protection against pancreatic beta cell failure." Diabetology International 10, no. 1 (September 17, 2018): 1–2. http://dx.doi.org/10.1007/s13340-018-0374-y.
5
Hong, Su Hee, Jee-In Heo, Jeong-Hyeon Kim, Sang-Oh Kwon, Kyung-Mok Yeo, Anna M. Bakowska-Barczak, Paul Kolodziejczyk, et al. "Antidiabetic and Beta Cell-Protection Activities of Purple Corn Anthocyanins." Biomolecules and Therapeutics 21, no. 4 (July 31, 2013): 284–89. http://dx.doi.org/10.4062/biomolther.2013.016.
6
Costes, Safia, Gyslaine Bertrand, and Magalie A. Ravier. "Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies." International Journal of Molecular Sciences 22, no. 10 (May 18, 2021): 5303. http://dx.doi.org/10.3390/ijms22105303.
Abstract:
Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a decreased beta-cell mass was also reported to contribute to the pathophysiology of this metabolic disease. The decreased beta-cell mass in T2D is, at least in part, attributed to beta-cell apoptosis that is triggered by diabetogenic situations such as amyloid deposits, lipotoxicity and glucotoxicity. In this review, we discussed the molecular mechanisms involved in pancreatic beta-cell apoptosis under such diabetes-prone situations. Finally, we considered the molecular signaling pathways recruited by glucagon-like peptide-1-based therapies to potentially protect beta-cells from death under diabetogenic situations.
7
Hashim, G. A., H. Offner, R. Y. Wang, K. Shukla, E. Carvalho, W. J. Morrison, and A. A. Vandenbark. "Spontaneous development of protective anti-T cell receptor autoimmunity targeted against a natural EAE-regulatory idiotope located within the 39-59 region of the TCR-V beta 8.2 chain." Journal of Immunology 149, no. 8 (October 15, 1992): 2803–9. http://dx.doi.org/10.4049/jimmunol.149.8.2803.
Abstract:
Abstract The development of experimental autoimmune encephalomyelitis (EAE) in Lewis rats is mediated by V beta 8.2+ T cells specific for myelin basic protein. One consequence of this biased expression of V beta 8.2 is the spontaneous development of regulatory T cells and antibodies against residues 39-59 of the V beta 8.2 sequence. Moreover, a synthetic V beta 8.2-39-59 peptide could induce protection against and speed recovery from EAE. T cells and antibodies specific for V beta 8.2-39-59 could transfer protection from EAE. Recently, we reported that the protective T cell epitope is subsumed within the V beta 8-44-54 sequence. We now report that protection induced by V beta 8-44-54 lasted at least 102 days and produced "split tolerance," enhancing anti-myelin basic protein antibody titers but reducing anti-myelin basic protein T cell frequency. The shorter V beta 8-44-54 peptide induced a distinct set of antibodies that did not cross-react with the longer V beta 8.2-39-59 peptide, although both specificities could stain V beta 8.2+ T cells and were equally protective against EAE. However, the V beta 8.2-39-59 peptide, but not the V beta 8-44-54 peptide, would appear to represent the natural idiotope: antibodies to V beta 8.2-39-59 that develop spontaneously during EAE could be boosted to higher titers only by the V beta 8.2-39-59, but not by other TCR peptides from the V beta 8.2 sequence, including V beta 8-44-54 that contains the functional T cell epitope. These results suggest that natural processing of the TCR V beta-chain favors the formation of a peptide that resembles the V beta 8.2-39-59 sequence. The B cell epitope present on the V beta 8-44-54 sequence was evident only in the absence of residues 39-43 and 55-59, suggesting that the two peptides possess distinct conformations. However, the V beta 8-44-54 B cell epitope is most likely expressed on the V beta 8.2+ T cells, either as a low affinity determinant on the intact TCR alpha/beta heterodimer or as a cryptic epitope bound in the cleft of surface MHC molecules.
8
Offner, H., M. Vainiene, D. P. Gold, W. J. Morrison, R. Y. Wang, G. A. Hashim, and A. A. Vandenbark. "Protection against experimental encephalomyelitis. Idiotypic autoregulation induced by a nonencephalitogenic T cell clone expressing a cross-reactive T cell receptor V gene." Journal of Immunology 146, no. 12 (June 15, 1991): 4165–72. http://dx.doi.org/10.4049/jimmunol.146.12.4165.
Abstract:
Abstract The recovery process in experimental autoimmune encephalomyelitis (EAE) in Lewis rats is characterized by an increasing diversity of T cell clones directed at secondary epitopes of myelin basic protein. Of particular interest, residues 55 to 69 of guinea pig basic protein could induce protection against EAE. A nonencephalitogenic T cell clone, C455-69, that was specific for this epitope transferred protection against both active and passive EAE. Clone C4 was found to express V beta 8.6 in its Ag receptor, and residues 39 to 59 of the TCR V beta 8.6 sequence were found to be highly crossreactive with the corresponding residues 39 to 59 of TCR V beta 8.2, which is known to induce protective anti-idiotypic T cells and antibodies. Like the TCR V beta 8.2 peptide, the V beta 8.6 sequence induced autoregulation and provided effective treatment of established EAE. Thus, the EAE-protective effect of the guinea pig basic protein 55-69 sequence was most likely mediated by T cell clones such as C4 that could efficiently induce anti-TCR immunity directed at a cross-reactive regulatory idiotope.
9
Chen, Qi, Zhida Shen, Yanjun Mao, Qinfeng Li, Yu Liu, Menghan Mei, Fuyu Qiu, and Meihui Wang. "Inhibition of microRNA-34a mediates protection of thymosin beta 4 in endothelial progenitor cells against advanced glycation endproducts by targeting B-cell lymphoma 2." Canadian Journal of Physiology and Pharmacology 97, no. 10 (October 2019): 945–51. http://dx.doi.org/10.1139/cjpp-2018-0743.
Abstract:
The aim of our work was to test whether thymosin beta 4 protected endothelial progenitor cells against apoptosis induced by advanced glycation endproducts and investigate the underlying mechanism. Treatment with thymosin beta 4 or transfection with microRNA-34a inhibitor enhanced cell viability, reduced apoptosis, abated oxidative stress, and attenuated mitochondrial dysfunction in endothelial progenitor cells exposed to advanced glycation endproducts. Incubation with advanced glycation endproducts led to increased levels of microRNA-34a, which was attenuated by treatment with thymosin beta 4. Transfection with microRNA-34a reversed the beneficial effect of thymosin beta 4 against injuries induced by advanced glycation endproducts. The microRNA-34a could directly bind to the 3′UTRs of the mRNA of B-cell lymphoma 2, and thymosin beta 4 treatment upregulated B-cell lymphoma 2 expression in endothelial progenitor cells exposed to advanced glycation endproducts. More importantly, knockdown of B-cell lymphoma 2 abolished the protection of thymosin beta 4 and microRNA-34a inhibitor against advanced glycation endproducts. In conclusion, inhibition of microRNA-34a mediated protection of thymosin beta 4 in endothelial progenitor cells against advanced glycation endproducts by targeting B-cell lymphoma 2, which was helpful for understanding the therapeutic potential of thymosin beta 4 for diabetic patients.
10
Fu, Y. X., C. E. Roark, K. Kelly, D. Drevets, P. Campbell, R. O'Brien, and W. Born. "Immune protection and control of inflammatory tissue necrosis by gamma delta T cells." Journal of Immunology 153, no. 7 (October 1, 1994): 3101–15. http://dx.doi.org/10.4049/jimmunol.153.7.3101.
Abstract:
Abstract Host defenses against experimental listeriosis in mice involve neutrophils, macrophages, NK cells, and alpha beta T cells. Recently gamma delta T cells have also been implicated in antilisterial resistance. However, their specific role has remained unclear. Here we show that efficient resistance to infection by this bacterium depends on the functions of both alpha beta and gamma delta T cells in both primary and secondary responses. We also present evidence that these functions are complementary. In the livers of alpha beta T cell-depleted mice, bacteria grow to large numbers within hepatocytes but are infrequently found extracellularly. Granulomatous lesions are more frequent and somewhat larger than in normal controls, but remain focal. Neutrophils are absent from liver lesions in these mice. In contrast, the livers of gamma delta T cell-depleted mice contain many extracellular bacteria, but do not show hepatocytes containing large numbers of Listeria. Liver lesions in gamma delta T cell-depleted mice are far more extensive than in normal controls or in alpha beta T cell-depleted mice, and contain large numbers of neutrophils. Particularly in secondary listeriosis, gamma delta T cell-depleted mice show vast coalescent areas of necrotic liver parenchyma within 48 h after infection. Because the bacterial numbers in gamma delta T cell-depleted mice remain lower than in alpha beta T cell-depleted mice, increased mortality in the former may be in part caused by liver failure. We conclude that gamma delta T cells are required to control inflammatory reactivity and to prevent excessive liver damage during the immune response to Listeria monocytogenes.
11
Ajmal, Nida, Maislin C. Bogart, Palwasha Khan, Ibiagbani M. Max-Harry, and Craig S. Nunemaker. "Emerging Anti-Diabetic Drugs for Beta-Cell Protection in Type 1 Diabetes." Cells 12, no. 11 (May 25, 2023): 1472. http://dx.doi.org/10.3390/cells12111472.
Abstract:
Type 1 diabetes (T1D) is a chronic autoimmune disorder that damages beta cells in the pancreatic islets of Langerhans and results in hyperglycemia due to the loss of insulin. Exogenous insulin therapy can save lives but does not halt disease progression. Thus, an effective therapy may require beta-cell restoration and suppression of the autoimmune response. However, currently, there are no treatment options available that can halt T1D. Within the National Clinical Trial (NCT) database, a vast majority of over 3000 trials to treat T1D are devoted to insulin therapy. This review focuses on non-insulin pharmacological therapies. Many investigational new drugs fall under the category of immunomodulators, such as the recently FDA-approved CD-3 monoclonal antibody teplizumab. Four intriguing candidate drugs fall outside the category of immunomodulators, which are the focus of this review. Specifically, we discuss several non-immunomodulators that may have more direct action on beta cells, such as verapamil (a voltage-dependent calcium channel blocker), gamma aminobutyric acid (GABA, a major neurotransmitter with effects on beta cells), tauroursodeoxycholic acid (TUDCA, an endoplasmic reticulum chaperone), and volagidemab (a glucagon receptor antagonist). These emerging anti-diabetic drugs are expected to provide promising results in both beta-cell restoration and in suppressing cytokine-derived inflammation.
12
Song, Imane, Sarah Roels, Geert A. Martens, and Luc Bouwens. "Circulating microRNA-375 as biomarker of pancreatic beta cell death and protection of beta cell mass by cytoprotective compounds." PLOS ONE 12, no. 10 (October 17, 2017): e0186480. http://dx.doi.org/10.1371/journal.pone.0186480.
13
Rich, S., N. Van Nood, and H. M. Lee. "Role of alpha 5 beta 1 integrin in TGF-beta 1-costimulated CD8+ T cell growth and apoptosis." Journal of Immunology 157, no. 7 (October 1, 1996): 2916–23. http://dx.doi.org/10.4049/jimmunol.157.7.2916.
Abstract:
Abstract TGF-beta 1 regulates cell growth, differentiation, and adhesion and is a potent immunosuppressant, in part through its well-recognized growth-inhibitory effects. However, certain T cell subsets, particularly of naive phenotype, can instead be costimulated to proliferate by TGF-beta 1. We have previously demonstrated that naive murine CD8+ T cells, TCR activated by platebound anti-CD3 Ab or SEB superantigen, are growth stimulated by TGF-beta 1, acquire a memory phenotype, express elevated IL-10 and TGF-beta 1, and cause T cell growth inhibition as effector CD8+ T cells. TGF-beta 1 causes growth among certain nonlymphoid cells in part by inducing or mimicking integrin activation. The present studies thus addressed mediation of TGF-beta 1-dependent growth and survival of anti-CD3-triggered CD8+ T cells via beta 1 integrins. TGF-beta 1 reduced anti-CD3-activated alpha 4 beta 1 integrin expression and constitutive adhesion to fibronectin, while initial alpha 5 beta 1 expression was heightened and adhesive function sustained. Fibronectin-based RGD peptides that bind alpha 5 beta 1 integrins and alpha 5 or beta 1 integrin chain-specific Abs blocked TGF-beta 1-dependent proliferation, while connecting segment-1 peptide that binds alpha 4 beta 1 integrin and alpha 4 chain-specific Abs had no effect. Cross-linked alpha 5- but not alpha 4-specific Ab mimicked TGF-beta 1 function by costimulating CD8+ T cell growth. TGF-beta 1 also caused RGD peptide-sensitive CD8+ T cell aggregation. Additionally, TGF-beta 1-costimulated proliferation correlated with TGF-beta 1 protection of CD8+ T cells from anti-CD3-induced apoptosis. RGD peptides and alpha 5 integrin-specific Ab abolished TGF-beta 1 prevention of activation-induced apoptosis. Therefore, TGF-beta 1 costimulates CD8+ T cell growth via activation of the alpha 5 beta 1 integrin and/or its ligand and supports sustained growth at least in part by alpha 5 beta 1-mediated protection from activation-induced apoptosis.
14
Liu, Shuainan, Yue Wang, Quan Liu, Rongcui Li, Yi Huan, and Zhufang Shen. "Mitochondrial SIRT5 contributed to beta cell protection under glucolipotoxicity-induced apoptosis." Proceedings for Annual Meeting of The Japanese Pharmacological Society WCP2018 (2018): OR28–2. http://dx.doi.org/10.1254/jpssuppl.wcp2018.0_or28-2.
15
van Raalte, Daniël H., and C. Bruce Verchere. "Glucagon-Like Peptide-1 Receptor Agonists: Beta-Cell Protection or Exhaustion?" Trends in Endocrinology & Metabolism 27, no. 7 (July 2016): 442–45. http://dx.doi.org/10.1016/j.tem.2016.04.009.
16
Zaldumbide, Arnaud, Gonnie M. Alkemade, Joana R. F. Abreu, Francoise Carlotti, Eelco de Koning, Bart O. Roep, Emmanuel J. H. J. Wiertz, and Rob C. Hoeben. "PL - 91. Protection of transplanted human beta-cell by genetic manipulation." Nederlands Tijdschrift voor Diabetologie 9, no. 3 (November 2011): 154. http://dx.doi.org/10.1007/s12467-011-0116-2.
17
Wang, Jingjing, and Hongjun Wang. "Oxidative Stress in Pancreatic Beta Cell Regeneration." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/1930261.
Abstract:
Pancreatic β cell neogenesis and proliferation during the neonatal period are critical for the generation of sufficient pancreatic β cell mass/reserve and have a profound impact on long-term protection against type 2 diabetes (T2D). Oxidative stress plays an important role in β cell neogenesis, proliferation, and survival under both physiological and pathophysiological conditions. Pancreatic β cells are extremely susceptible to oxidative stress due to a high endogenous production of reactive oxygen species (ROS) and a low expression of antioxidative enzymes. In this review, we summarize studies describing the critical roles and the mechanisms of how oxidative stress impacts β cell neogenesis and proliferation. In addition, the effects of antioxidant supplements on reduction of oxidative stress and increase of β cell proliferation are discussed. Exploring the roles and the potential therapeutic effects of antioxidants in the process of β cell regeneration would provide novel perspectives to preserve and/or expand pancreatic β cell mass for the treatment of T2D.
18
Paliwal, V., W. Ptak, J. Sperl, E. Braswell, and P. W. Askenase. "Recombinant soluble alphabeta T cell receptors protect T cells from immune suppression: requirement for aggregated multimeric, disulfide-linked alphabeta heterodimers." Journal of Immunology 159, no. 4 (August 15, 1997): 1718–27. http://dx.doi.org/10.4049/jimmunol.159.4.1718.
Abstract:
Abstract Recombinant soluble T cell receptors (sTCR) protected contact sensitivity (CS) effector T cells from down-regulation or immunosuppression. CS-protecting sTCR were released enzymatically from the surface of thymoma cells transfected with cDNAs encoding TCR-alpha and -beta extracellular domains that were expressed with a phosphatidylinositol linkage. sTCR affinity purified on anti-TCR-alpha and anti-TCR-beta mAb columns had identical CS-protective activity, as did sTCR from a CD4+ Th2 clone or from a CD8+ cytotoxic clone. Reduced sTCR alpha- and beta-chains had no CS-protective activity, but this was restored when the TCR chains were rejoined into disulfide-linked alphabeta heterodimers. sTCR CS protection was Ag nonspecific, MHC unrestricted, and not influenced by the relevant synthetic peptide specific for the TCR complexed with appropriate MHC. CS protection may have resided in the sTCR constant region. When heated at 62 degrees C for 30 min, sTCR formed a CS-protecting aggregate, with a molecular mass of 481 +/- 37 kDa, corresponding to an alphabeta TCR pentamer. HPLC gel filtration essentially confirmed the molecular mass at 516 kDa for the multimer, while the monomer, which was an alphabeta TCR heterodimer, had an expected molecular mass of approximately 104 kDa and no bioactivity. In summary, the pentameric sTCR may bind to and activate lymphoid cells, perhaps via constant domains, resulting in protection of CS effector T cells from down-regulation. The ability of sTCR to protect CS effector T cells from down-regulation/suppression, if generalized, could overcome immunosuppression accompanying infectious diseases, particularly AIDS, or in tumors.
19
Goudy, Kevin, Li Li, and Roland Tisch. "Expansion of GAD65–Specific Immunoregulatory Effector Cells by Biolistic-Mediated Gene Delivery Prevents Autoimmune Diabetes in NOD Mice (131.14)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S240. http://dx.doi.org/10.4049/jimmunol.178.supp.131.14.
Abstract:
Abstract Intramuscular (i.m.) vaccination with plasmid DNA (pDNA) encoding beta cell autoantigens such as glutamic acid decarboxylase 65 (GAD65) is an approach to suppress ongoing Type 1 diabetes (T1D) in NOD mice. However, protection is dependent on co-treatment with pDNAs encoding IL-4 and/or IL-10, and the subsequent induction of type 2 CD4+ T effectors. To enhance the therapeutic efficacy of pDNA vaccination, we explored epidermal delivery of pDNA via “gene gun”. Notably, reports have shown induction of a preferential type 2-like CD4+ T cell response when pDNA encoding antigen-only is delivered to the epidermis via gene gun. We hypothesized that biolistic delivery of pDNA would preferentially induce type 2 CD4+ T effectors and suppress established beta cell autoimmunity in NOD mice. Groups of 10 wk-old NOD female mice were treated four times with pDNA encoding GAD65-Ig (pGAD65) administered i.m. or delivered by gene gun on 1.6 uM gold particles. Whereas i.m. injection of pGAD65 resulted in preferential induction of GAD65-specific CD4+ Th1 cells and no protection against T1D, the majority of NOD mice treated with gene gun delivered pGAD65 remained diabetes-free and protection correlated with increased GAD65-specific IL-4 secreting CD4+ T cells. These results demonstrate that gene-gun delivered pDNA encoding beta cell autoantigen-only is an effective strategy to induce immunoregulatory CD4+ T cells and suppress T1D.
20
Adachi, M., M. Sekiya, T. Torigoe, S. Takayama, JC Reed, T. Miyazaki, Y. Minami, T. Taniguchi, and K. Imai. "Interleukin-2 (IL-2) upregulates BAG-1 gene expression through serine- rich region within IL-2 receptor beta c chain." Blood 88, no. 11 (December 1, 1996): 4118–23. http://dx.doi.org/10.1182/blood.v88.11.4118.4118.
Abstract:
Abstract BAG-1 is a Bci-2-binding protein which functions in protection from apoptotic cell death. Here we provide evidence for interleukin-2 (IL-2)-mediated upregulation of BAG-1 expression. In hematopoietic cell line BAF-B03 F7 cells, gene transfer mediated expression of the IL-2R beta c chain is sufficient to confer proliferation and cell survival responses to IL-2. In these IL-2R beta c-expressing cells, BAG-1 mRNA was dramatically induced by IL-2. The IL-2-mediated induction of BAG-1 expression required the activation of tyrosine kinase(s) and was sensitive to rapamycin as the induction of bcl-2 expression was. Analysis of the transfectants which express mutant IL-2R beta c chains or mutant Janus family protein tyrosine kinase Jak3 lacking the kinase domain showed that the IL-2-mediated BAG-1 gene expression required the serinerich region within the IL-2R beta c chain, but Jak3 activation was dispensable. The signaling pathway for BAG-1 gene expression thus highly resembles that for bcl-2 gene expression, strongly suggesting that their induction shares the same signaling pathway. In addition, deletion of the serine-rich region led to loss of IL-2-mediated protection from apoptotic cell death. Taken together, these studies demonstrate that the serine-rich region of the IL-2R beta c chain mediates the coordinated expression of bcl-2 and BAG-1 genes, thereby contributing to suppression of apoptosis.
21
Adachi, M., M. Sekiya, T. Torigoe, S. Takayama, JC Reed, T. Miyazaki, Y. Minami, T. Taniguchi, and K. Imai. "Interleukin-2 (IL-2) upregulates BAG-1 gene expression through serine- rich region within IL-2 receptor beta c chain." Blood 88, no. 11 (December 1, 1996): 4118–23. http://dx.doi.org/10.1182/blood.v88.11.4118.bloodjournal88114118.
Abstract:
BAG-1 is a Bci-2-binding protein which functions in protection from apoptotic cell death. Here we provide evidence for interleukin-2 (IL-2)-mediated upregulation of BAG-1 expression. In hematopoietic cell line BAF-B03 F7 cells, gene transfer mediated expression of the IL-2R beta c chain is sufficient to confer proliferation and cell survival responses to IL-2. In these IL-2R beta c-expressing cells, BAG-1 mRNA was dramatically induced by IL-2. The IL-2-mediated induction of BAG-1 expression required the activation of tyrosine kinase(s) and was sensitive to rapamycin as the induction of bcl-2 expression was. Analysis of the transfectants which express mutant IL-2R beta c chains or mutant Janus family protein tyrosine kinase Jak3 lacking the kinase domain showed that the IL-2-mediated BAG-1 gene expression required the serinerich region within the IL-2R beta c chain, but Jak3 activation was dispensable. The signaling pathway for BAG-1 gene expression thus highly resembles that for bcl-2 gene expression, strongly suggesting that their induction shares the same signaling pathway. In addition, deletion of the serine-rich region led to loss of IL-2-mediated protection from apoptotic cell death. Taken together, these studies demonstrate that the serine-rich region of the IL-2R beta c chain mediates the coordinated expression of bcl-2 and BAG-1 genes, thereby contributing to suppression of apoptosis.
22
Wileman, T., LP Kane, J. Young, GR Carson, and C. Terhorst. "Associations between subunit ectodomains promote T cell antigen receptor assembly and protect against degradation in the ER." Journal of Cell Biology 122, no. 1 (July 1, 1993): 67–78. http://dx.doi.org/10.1083/jcb.122.1.67.
Abstract:
The T cell antigen receptor (TCR) is an oligomeric protein complex made from at least six different integral membrane proteins (alpha beta gamma delta epsilon and zeta). The TCR is assembled in the ER of T cells, and correct assembly is required for transport to the cell surface. Single subunits and partial receptor complexes are retained in the ER where TCR alpha, beta, and CD3 delta chains are degraded selectively. The information required for the ER degradation of the TCR beta chain is confined to the membrane anchor of the protein (Wileman et al., 1990c; Bonifacino et al., 1990b). In this study we show that the rapid degradation of the TCR beta chain is inhibited when it assembles with single CD3 gamma, delta, or epsilon subunits in the ER, and have started to define the role played by transmembrane anchors, and receptor ectodomains, in the masking proteolytic targeting information. Acidic residues within the membrane spanning domains of CD3 subunits were essential for binding to the TCR beta chain. TCR beta chains and CD3 subunits therefore interact via transmembrane domains. However, when sites of binding were restricted to the membrane anchor of the TCR beta chain, stabilization by CD3 subunits was markedly reduced. Interactions between membrane spanning domains were not, therefore, sufficient for the protection of the beta chain from ER proteolysis. The presence of the C beta domain, containing the first 150 amino acids of the TCR ectodomain, greatly increased the stability of complexes formed in the ER. For assembly with CD3 epsilon, stability was further enhanced by the V beta amino acids. The results showed that the efficient neutralization of transmembrane proteolytic targeting information required associations between membrane spanning domains and the presence of receptor ectodomains. Interactions between receptor ectodomains may slow the dissociation of CD3 subunits from the beta chain and prolong the masking of transmembrane targeting information. In addition, the close proximity of TCR and CD3 ectodomains within the ER may provide steric protection from the action of proteases within the ER lumen.
23
Shear, HL, EF Jr Roth, ME Fabry, FD Costantini, A. Pachnis, A. Hood, and RL Nagel. "Transgenic mice expressing human sickle hemoglobin are partially resistant to rodent malaria." Blood 81, no. 1 (January 1, 1993): 222–26. http://dx.doi.org/10.1182/blood.v81.1.222.222.
Abstract:
Abstract The polymorphic frequency of the gene for beta s-globin involved in the generation of sickle trait and sickle cell anemia in the human population is caused by the enhanced resistance of sickle trait individuals to Plasmodium falciparum malaria, as supported by epidemiologic and in vitro studies. However, the mechanism for the protective effect of sickle hemoglobin in vivo has not been fully defined. The generation of transgenic mice expressing high levels of human beta s- and alpha-chains has allowed us to study this phenomenon in vivo in an experimental model. We infected the transgenic beta s mice with two species of rodent malaria and found a diminished and delayed increase in parasitemia as compared with controls. This is in contrast to our previous studies involving the introduction of a beta A transgene, which does not alter the infection. The use of this model allowed us to address the question of the mechanism of protection against malaria in mice expressing sickle hemoglobin. We find that splenectomy of transgenic mice completely reverses the protection against Plasmodium chabaudi adami infection. The results reported have shown a relationship between the presence of the beta s gene product and partial resistance to malaria in an experimental model in vivo and shows that the spleen plays an important role in this protection.
24
Shear, HL, EF Jr Roth, ME Fabry, FD Costantini, A. Pachnis, A. Hood, and RL Nagel. "Transgenic mice expressing human sickle hemoglobin are partially resistant to rodent malaria." Blood 81, no. 1 (January 1, 1993): 222–26. http://dx.doi.org/10.1182/blood.v81.1.222.bloodjournal811222.
Abstract:
The polymorphic frequency of the gene for beta s-globin involved in the generation of sickle trait and sickle cell anemia in the human population is caused by the enhanced resistance of sickle trait individuals to Plasmodium falciparum malaria, as supported by epidemiologic and in vitro studies. However, the mechanism for the protective effect of sickle hemoglobin in vivo has not been fully defined. The generation of transgenic mice expressing high levels of human beta s- and alpha-chains has allowed us to study this phenomenon in vivo in an experimental model. We infected the transgenic beta s mice with two species of rodent malaria and found a diminished and delayed increase in parasitemia as compared with controls. This is in contrast to our previous studies involving the introduction of a beta A transgene, which does not alter the infection. The use of this model allowed us to address the question of the mechanism of protection against malaria in mice expressing sickle hemoglobin. We find that splenectomy of transgenic mice completely reverses the protection against Plasmodium chabaudi adami infection. The results reported have shown a relationship between the presence of the beta s gene product and partial resistance to malaria in an experimental model in vivo and shows that the spleen plays an important role in this protection.
25
Gomes, Vinícius M., Rosangela A. M. Wailemann, Gabriel S. Arini, Talita C. Oliveira, Daria R. Q. Almeida, Ancély F. dos Santos, Letícia F. Terra, Stephan Lortz, and Leticia Labriola. "HSPB1 Is Essential for Inducing Resistance to Proteotoxic Stress in Beta-Cells." Cells 10, no. 9 (August 24, 2021): 2178. http://dx.doi.org/10.3390/cells10092178.
Abstract:
During type 1 diabetes mellitus (T1DM) development, beta-cells undergo intense endoplasmic reticulum (ER) stress that could result in apoptosis through the failure of adaptation to the unfolded protein response (UPR). Islet transplantation is considered an attractive alternative among beta-cell replacement therapies for T1DM. To avoid the loss of beta-cells that will jeopardize the transplant’s outcome, several strategies are being studied. We have previously shown that prolactin induces protection against proinflammatory cytokines and redox imbalance-induced beta-cell death by increasing heat-shock protein B1 (HSPB1) levels. Since the role of HSPB1 in beta cells has not been deeply studied, we investigated the mechanisms involved in unbalanced protein homeostasis caused by intense ER stress and overload of the proteasomal protein degradation pathway. We tested whether HSPB1-mediated cytoprotective effects involved UPR modulation and improvement of protein degradation via the ubiquitin-proteasome system. We demonstrated that increased levels of HSPB1 attenuated levels of pro-apoptotic proteins such as CHOP and BIM, as well as increased protein ubiquitination and the speed of proteasomal protein degradation. Our data showed that HSPB1 induced resistance to proteotoxic stress and, thus, enhanced cell survival via an increase in beta-cell proteolytic capacity. These results could contribute to generate strategies aimed at the optimization of beta-cell replacement therapies.
26
Heinrich, MC, DC Dooley, and WW Keeble. "Transforming growth factor beta 1 inhibits expression of the gene products for steel factor and its receptor (c-kit)." Blood 85, no. 7 (April 1, 1995): 1769–80. http://dx.doi.org/10.1182/blood.v85.7.1769.bloodjournal8571769.
Abstract:
Transforming growth factor beta 1 (TGF-beta 1), a product of marrow stromal cells, inhibits the proliferation and differentiation of hematopoietic progenitor cells within the hematopoietic microenvironment. Steel factor (SF), also a product of marrow stromal cells, is an essential positive regulator of hematopoiesis in vivo. TGF- beta 1 has been shown to repress human and murine leukemic cell and murine lin-bone marrow mononuclear cell expression of the receptor for SF (c-kit). We speculated that TGF-beta 1 might exert its inhibitory effect on hematopoiesis in part by decreasing SF/c-kit interactions. Therefore, we tested the hypothesis that TGF-beta 1 inhibits both stromal cell expression of SF and hematopoietic progenitor cell expression of c-kit. We measured stromal cell expression of SF protein and hematopoietic progenitor cell expression of membrane-bound c-kit before and after exposure to recombinant human TGF-beta 1. Both stromal cell expression of SF protein and hematopoietic progenitor cell expression of c-kit protein were inhibited 50% to 80% by TGF-beta 1. Using Northern blot and ribonuclease protection assays, we determined that TGF-beta 1 repressed stromal cell SF mRNA, but did not alter SF transcript stability. TGF-beta 1 was also found to repress c-kit mRNA in human leukemic myeloblasts as well as in normal lin-hematopoietic progenitor cells. In contrast with its effect on SF mRNA, TGF-beta 1 accelerated the degradation of c-kit mRNA. We conclude that TGF-beta 1 inhibits stromal cell production of SF by repression of SF gene transcription and represses hematopoietic progenitor cell expression of c-kit by decreasing the stability of c-kit transcripts. Taking into account the importance of SF and c-kit in maintaining steady-state hematopoiesis in vivo, the dual effect of TGF-beta 1 on both SF and c-kit gene expression is likely to be one of the major mechanisms by which TGF-beta 1 inhibits hematopoiesis in vivo.
27
Liu, Chongxiao, Jianhua Zhou, Yanhong Xu, Sa Gong, Yi Zhu, Hongli Zhang, Yan Dong, Bingxia Zhao, and Xiaohua Li. "Irisin Ameliorates Oxidative Stress-Induced Injury in Pancreatic Beta-Cells by Inhibiting Txnip and Inducing Stat3-Trx2 Pathway Activation." Oxidative Medicine and Cellular Longevity 2022 (September 6, 2022): 1–13. http://dx.doi.org/10.1155/2022/4674215.
Abstract:
Lipotoxicity can lead to beta-cell dysfunction and apoptosis because it induces oxidative stress. Recent studies have found that Irisin prevents pancreatic beta-cell dysfunction induced by palmitic acid (PA). However, an association between the protection against oxidative stress conferred by Irisin and beta-cell dysfunction has not been fully elucidated. In this study, we observed that Irisin treatment prevented INS-1 cell apoptosis induced by PA treatment and preserved the insulin-secreting function of INS-1 cells in vitro. These effects probably resulted from the Irisin-induced decrease in intracellular ROS levels triggered by PA treatment. In addition, PA treatment induced oxidative stress partially by inhibiting the activation of thioredoxin 2 (Trx2) through its increase of thioredoxin-interacting protein (Txnip) expression. However, Irisin administration blocked the increase in Txnip expression, which reversed the PA-induced inactivation of Trx2. Irisin also increased the nuclear translocation of Stat3, and the inhibition of Stat3 by siRNAs blocked Irisin-induced Trx2 expression, indicating that both Txnip and Stat3 are involved in Irisin-induced activation of Trx2. Furthermore, blockade of Stat3 by siRNAs led to the decreased gene expression of MafA and Ins and to cessation of glucose-induced insulin secretion that had been enhanced by Irisin. In vivo, HFD treatment led to reduced glucose tolerance and an increase in the level of the oxidative marker malondialdehyde (MDA) compared to that in the control group. However, these effects were ameliorated by Irisin injection due to the inhibition of beta-cell apoptosis and the activation of Trx2, probably through Txnip inhibition and Stat3 activation. In conclusion, our results reveal a possible mechanism for Irisin-induced beta-cell protection, which is mediated through Txnip inhibition and activation of the Stat3-Trx2 pathway.
28
Schafer, D. A., Y. O. Korshunova, T. A. Schroer, and J. A. Cooper. "Differential localization and sequence analysis of capping protein beta-subunit isoforms of vertebrates." Journal of Cell Biology 127, no. 2 (October 15, 1994): 453–65. http://dx.doi.org/10.1083/jcb.127.2.453.
Abstract:
Capping protein nucleates the assembly of actin filaments and stabilizes actin filaments by binding to their barbed ends. We describe here a novel isoform of the beta subunit of chicken capping protein, the beta 2 isoform, which arises by alternative splicing. The chicken beta 1 isoform and the beta 2 isoform are identical in their amino acid sequence except for a short region at the COOH terminus; this region of the beta subunit has been implicated in binding actin. Human and mouse cDNAs of the beta 1 and beta 2 isoforms also were isolated and among these vertebrates, the COOH-terminal region of each isoform is highly conserved. In contrast, comparison of the sequences of the vertebrate beta subunit COOH-termini to those of lower eukaryotes shows no similarities. The beta 2 isoform is the predominant isoform of nonmuscle tissues and the beta 1 isoform, which was first characterized in studies of capping protein from chicken muscle, is the predominant isoform of muscle tissues, as shown by immunoblots probed with isoform-specific antibodies and by RNAse protection analysis of mRNAs. The beta 2 isoform also is a component of dynactin complex from brain, which contains the actin-related protein Arp1. Both beta-subunit isoforms are expressed in cardiac muscle but they have non-overlapping subcellular distributions. The beta 1 isoform is at Z-discs of myofibrils, and the beta 2 isoform is enriched at intercalated discs; in cardiac myocytes grown in culture, the beta 2 isoform also is a component of cell-cell junctions and at sites where myofibrils contact the sarcolemma. The biochemical basis for the differential distribution of capping protein isoforms is likely due to interaction with specific proteins at Z-discs and cell-cell junctions, or to preferential association with different actin isoforms. Thus, vertebrates have developed isoforms of capping protein that associate with distinct actin-filament arrays.
29
Ngamjariyawat, Anongnad, Jing Cen, Xuan Wang, and Nils Welsh. "GDF15 Protects Insulin-Producing Beta Cells against Pro-Inflammatory Cytokines and Metabolic Stress via Increased Deamination of Intracellular Adenosine." International Journal of Molecular Sciences 25, no. 2 (January 8, 2024): 801. http://dx.doi.org/10.3390/ijms25020801.
Abstract:
It has been proposed that antidiabetic drugs, such as metformin and imatinib, at least in part, promote improved glucose tolerance in type 2 diabetic patients via increased production of the inflammatory cytokine GDF15. This is supported by studies, performed in rodent cell lines and mouse models, in which the addition or production of GDF15 improved beta-cell function and survival. The aim of the present study was to determine whether human beta cells produce GDF15 in response to antidiabetic drugs and, if so, to further elucidate the mechanisms by which GDF15 modulates the function and survival of such cells. The effects and expression of GDF15 were analyzed in human insulin-producing EndoC-betaH1 cells and human islets. We observed that alpha and beta cells exhibit considerable heterogeneity in GDF15 immuno-positivity. The predominant form of GDF15 present in islet and EndoC-betaH1 cells was pro-GDF15. Imatinib, but not metformin, increased pro-GDF15 levels in EndoC-betaH1 cells. Under basal conditions, exogenous GDF15 increased human islet oxygen consumption rates. In EndoC-betaH1 cells and human islets, exogenous GDF15 partially ameliorated cytokine- or palmitate + high-glucose-induced loss of function and viability. GDF15-induced cell survival was paralleled by increased inosine levels, suggesting a more efficient disposal of intracellular adenosine. Knockdown of adenosine deaminase, the enzyme that converts adenosine to inosine, resulted in lowered inosine levels and loss of protection against cytokine- or palmitate + high-glucose-induced cell death. It is concluded that imatinib-induced GDF15 production may protect human beta cells partially against inflammatory and metabolic stress. Furthermore, it is possible that the GDF15-mediated activation of adenosine deaminase and the increased disposal of intracellular adenosine participate in protection against beta-cell death.
30
Tarlton, Jamie M. R., Richard J. Lightbody, Steven Patterson, and Annette Graham. "Protection against Glucolipotoxicity by High Density Lipoprotein in Human PANC-1 Hybrid 1.1B4 Pancreatic Beta Cells: The Role of microRNA." Biology 10, no. 3 (March 13, 2021): 218. http://dx.doi.org/10.3390/biology10030218.
Abstract:
High-density lipoproteins provide protection against the damaging effects of glucolipotoxicity in beta cells, a factor which sustains insulin secretion and staves off onset of type 2 diabetes mellitus. This study examines epigenetic changes in small non-coding microRNA sequences induced by high density lipoproteins in a human hybrid beta cell model, and tests the impact of delivery of a single sequence in protecting against glucolipotoxicity. Human PANC-1.1B4 cells were used to establish Bmax and Kd for [3H]cholesterol efflux to high density lipoprotein, and minimum concentrations required to protect cell viability and reduce apoptosis to 30mM glucose and 0.25 mM palmitic acid. Microchip array identified the microRNA signature associated with high density lipoprotein treatment, and one sequence, hsa-miR-21-5p, modulated via delivery of a mimic and inhibitor. The results confirm that low concentrations of high-density lipoprotein can protect against glucolipotoxicity, and report the global microRNA profile associated with this lipoprotein; delivery of miR-21-5p mimic altered gene targets, similar to high density lipoprotein, but could not provide sufficient protection against glucolipotoxicity. We conclude that the complex profile of microRNA changes due to HDL treatment may be difficult to replicate using a single microRNA, findings which may inform current drug strategies focused on this approach.
31
Magisson, Jordan, Aladin Sassi, Daela Xhema, Aram Kobalyan, Pierre Gianello, Brice Mourer, Nguyen Tran, Charles-Thibault Burcez, Richard Bou Aoun, and Séverine Sigrist. "Safety and function of a new pre-vascularized bioartificial pancreas in an allogeneic rat model." Journal of Tissue Engineering 11 (January 2020): 204173142092481. http://dx.doi.org/10.1177/2041731420924818.
Abstract:
Cell encapsulation could overcome limitations of free islets transplantation but is currently limited by inefficient cells immune protection and hypoxia. As a response to these challenges, we tested in vitro and in vivo the safety and efficacy of a new macroencapsulation device named MailPan®. Membranes of MailPan® device were tested in vitro in static conditions. Its bio-integration and level of oxygenation was assessed after implantation in non-diabetic rats. Immune protection properties were also assessed in rat with injection in the device of allogeneic islets with incompatible Major Histocompatibility Complex. Finally, function was assessed in diabetic rats with a Beta cell line injected in MailPan®. In vitro, membranes of the device showed high permeability to glucose, insulin, and rejected IgG. In rat, the device displayed good bio-integration, efficient vascularization, and satisfactory oxygenation (>5%), while positron emission tomography (PET)-scan and angiography also highlighted rapid exchanges between blood circulation and the MailPan®. The device showed its immune protection properties by preventing formation, by the rat recipient, of antibodies against encapsulated allogenic islets. Injection of a rat beta cell line into the device normalized fasting glycemia of diabetic rat with retrieval of viable cell clusters after 2 months. These data suggest that MailPan® constitutes a promising encapsulation device for widespread use of cell therapy for type 1 diabetes.
32
Mathieu, Chantal, and Lut Overbergh. "The Story of NAIMIT – A Framework 7 Project on Type 1 Diabetes." European Endocrinology 10, no. 2 (2014): 100. http://dx.doi.org/10.17925/ee.2014.10.02.100.
Abstract:
NAIMIT (acronym for Natural Immune Modulation for Intervention in Type 1 Diabetes) is a large-scale collaborative programme of the 7th framework from the European Commission. The aim of the consortium is to bring together a group of leading European researchers spanning the field from genetics, through pancreatic beta-cell, dendritic cells and T-cell biology, towards clinical interventions. The ultimate goal is to develop novel and personalised interventional therapies in recent-onset type 1 diabetic patients, with minimal immune system interference, leading to beta-cell protection and restoration, based on a solid understanding of the disease pathogenesis, enabling experimental findings to be adopted for clinical applications.
33
White, K. L., H. L. Snyder, and U. Krzych. "MHC class I-dependent presentation of exoerythrocytic antigens to CD8+ T lymphocytes is required for protective immunity against Plasmodium berghei." Journal of Immunology 156, no. 9 (May 1, 1996): 3374–81. http://dx.doi.org/10.4049/jimmunol.156.9.3374.
Abstract:
Abstract T lymphocytes are believed to play a major role in protection against malaria. Previous experiments using in vivo depletion of CD8+ T cells, reconstitution with CD8+ T splenic cells, and adoptive transfer of CD8+ CTL clones demonstrated that protection against the exoerythrocytic stage of the murine strain, Plasmodium berghei malaria, was CD8+ T cell-dependent. Despite evidence for the critical role of CD8+ CTL, neither the cellular nor the molecular requirements for CD8+ T cell induction or for recognition of malaria Ags are known. In this study, we wished to define the role of CD8+ T cells and MHC class I molecules by using the P. berghei malaria attenuated sporozoites (SPZ) protection model in beta 2-microglobulin (beta 2m) knockout (-/-) mice. In contrast to observations that beta 2m-/- mice are resistant to many infectious diseases by compensatory mechanisms involving non-class I-restricted T cells, we found that beta 2m-/- mice failed to be protected against P. berghei SPZ, although immunization with attenuated SPZ induced production of IL-2, INF-gamma, anti-circumsporozoite protein IgG, and proliferative T cells. The lack of compensatory mechanisms involving non-CD8+ T cells was particularly evident in the failure to adoptively transfer protective immunity with wild-type SPZ-immune splenic T cells. From our data it can be concluded that CD8+ T cells induced during immunization with attenuated SPZ must recognize liver-expressed Ags presented by class I molecules to engage effectively in a response leading to destruction of the malaria parasites.
34
Cabello-Olmo, Miriam, Miriam Araña, Ilian Radichev, Paul Smith, Eduardo Huarte, and Miguel Barajas. "New Insights into Immunotherapy Strategies for Treating Autoimmune Diabetes." International Journal of Molecular Sciences 20, no. 19 (September 26, 2019): 4789. http://dx.doi.org/10.3390/ijms20194789.
Abstract:
Type 1 diabetes mellitus (T1D) is an autoimmune illness that affects millions of patients worldwide. The main characteristic of this disease is the destruction of pancreatic insulin-producing beta cells that occurs due to the aberrant activation of different immune effector cells. Currently, T1D is treated by lifelong administration of novel versions of insulin that have been developed recently; however, new approaches that could address the underlying mechanisms responsible for beta cell destruction have been extensively investigated. The strategies based on immunotherapies have recently been incorporated into a panel of existing treatments for T1D, in order to block T-cell responses against beta cell antigens that are very common during the onset and development of T1D. However, a complete preservation of beta cell mass as well as insulin independency is still elusive. As a result, there is no existing T1D targeted immunotherapy able to replace standard insulin administration. Presently, a number of novel therapy strategies are pursuing the goals of beta cell protection and normoglycemia. In the present review we explore the current state of immunotherapy in T1D by highlighting the most important studies in this field, and envision novel strategies that could be used to treat T1D in the future.
35
Li, Li, Kevin Goudy, Alexander Pham, and Roland Tisch. "Suppression of autoimmune diabetes by peptide-MHC class II dimers (131.13)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S239—S240. http://dx.doi.org/10.4049/jimmunol.178.supp.131.13.
Abstract:
Abstract Type 1 diabetes (T1D) is an autoimmune disease mediated by pathogenic beta cell-specific T cells. The use of antigen-specific based immunotherapies has been one strategy to selectively target beta cell-specific T cells leaving the remainder of the immune system intact. Administration with peptides derived from beta cell autoantigens such as glutamic acid decarboxylase 65 (GAD65) to NOD mice prevents T1D. However, as beta cell autoimmunity progresses the conditions for peptide treatment to suppress T1D become highly stringent. To enhance the efficacy of peptide treatment, recombinant IAg7-immunoglobulin (Ig) dimers covalently linked to GAD65 peptides (217–236, 286–309) or the mimetic BDC2.5 epitope (sBDC) were tested. Twelve week-old NOD female mice with established beta cell autoimmunity received a short course of IAg7-Ig dimers intravenously. Surprisingly, treatment with IAg7-Ig:sBDC accelerated the onset of diabetes in NOD mice due to expansion of sBDC-specific CD4+ Th1 cells. In marked contrast, the majority of NOD mice treated with IAg7-Ig:GADp217 or IAg7-Ig:GADp286 remained diabetes-free. Protection correlated with an increased frequency of IL-10 secreting immunoregulatory CD4+ T cells that blocked diabetes in a co-adoptive transfer model. These results demonstrate that treatment with a short-course of IAg7-Ig-GAD65 peptide dimers is an effective approach to suppress T1D.
36
Keeton, Roanne, Marius B. Tincho, Amkele Ngomti, Richard Baguma, Ntombi Benede, Akiko Suzuki, Khadija Khan, et al. "T cell responses to SARS-CoV-2 spike cross-recognize Omicron." Nature 603, no. 7901 (January 31, 2022): 488–92. http://dx.doi.org/10.1038/s41586-022-04460-3.
Abstract:
AbstractThe SARS-CoV-2 Omicron variant (B.1.1.529) has multiple spike protein mutations1,2 that contribute to viral escape from antibody neutralization3–6 and reduce vaccine protection from infection7,8. The extent to which other components of the adaptive response such as T cells may still target Omicron and contribute to protection from severe outcomes is unknown. Here we assessed the ability of T cells to react to Omicron spike protein in participants who were vaccinated with Ad26.CoV2.S or BNT162b2, or unvaccinated convalescent COVID-19 patients (n = 70). Between 70% and 80% of the CD4+ and CD8+ T cell response to spike was maintained across study groups. Moreover, the magnitude of Omicron cross-reactive T cells was similar for Beta (B.1.351) and Delta (B.1.617.2) variants, despite Omicron harbouring considerably more mutations. In patients who were hospitalized with Omicron infections (n = 19), there were comparable T cell responses to ancestral spike, nucleocapsid and membrane proteins to those in patients hospitalized in previous waves dominated by the ancestral, Beta or Delta variants (n = 49). Thus, despite extensive mutations and reduced susceptibility to neutralizing antibodies of Omicron, the majority of T cell responses induced by vaccination or infection cross-recognize the variant. It remains to be determined whether well-preserved T cell immunity to Omicron contributes to protection from severe COVID-19 and is linked to early clinical observations from South Africa and elsewhere9–12.
37
Oshima, Masaya, Séverine Pechberty, Lara Bellini, Sven O. Göpel, Mélanie Campana, Claude Rouch, Julien Dairou, et al. "Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity." Diabetologia 63, no. 2 (December 3, 2019): 395–409. http://dx.doi.org/10.1007/s00125-019-05046-x.
Abstract:
Abstract Aims/hypothesis During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-βH1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment. Methods EndoC-βH1 cells were exposed to palmitate after knockdown of genes related to saturated NEFA metabolism. We analysed whether and how palmitate induces apoptosis, stress and inflammation and modulates beta cell identity. Results EndoC-βH1 cells were insensitive to the deleterious effects of saturated NEFA (palmitate and stearate) unless stearoyl CoA desaturase (SCD) was silenced. SCD was abundantly expressed in EndoC-βH1 cells, as well as in human islets and human induced pluripotent stem cell-derived beta cells. SCD silencing induced markers of inflammation and endoplasmic reticulum stress and also IAPP mRNA. Treatment with the SCD products oleate or palmitoleate reversed inflammation and endoplasmic reticulum stress. Upon SCD knockdown, palmitate induced expression of dedifferentiation markers such as SOX9, MYC and HES1. Interestingly, SCD knockdown by itself disrupted beta cell identity with a decrease in mature beta cell markers INS, MAFA and SLC30A8 and decreased insulin content and glucose-stimulated insulin secretion. Conclusions/interpretation The present study delineates an important role for SCD in the protection against lipotoxicity and in the maintenance of human beta cell identity. Data availability Microarray data and all experimental details that support the findings of this study have been deposited in in the GEO database with the GSE130208 accession code.
38
Dhounchak, Sarita, Sarah K. Popp, Debra J. Brown, D. Ross Laybutt, Trevor J. Biden, Stefan R. Bornstein, Christopher R. Parish, and Charmaine J. Simeonovic. "Heparan sulfate proteoglycans in beta cells provide a critical link between endoplasmic reticulum stress, oxidative stress and type 2 diabetes." PLOS ONE 16, no. 6 (June 4, 2021): e0252607. http://dx.doi.org/10.1371/journal.pone.0252607.
Abstract:
Heparan sulfate proteoglycans (HSPGs) consist of a core protein with side chains of the glycosaminoglycan heparan sulfate (HS). We have previously identified (i) the HSPGs syndecan-1 (SDC1), and collagen type XVIII (COL18) inside mouse and human islet beta cells, and (ii) a critical role for HS in beta cell survival and protection from reactive oxygen species (ROS). The objective of this study was to investigate whether endoplasmic reticulum (ER) stress contributes to oxidative stress and type 2 diabetes (T2D) by depleting beta cell HSPGs/HS. A rapid loss of intra-islet/beta cell HSPGs, HS and heparanase (HPSE, an HS-degrading enzyme) accompanied upregulation of islet ER stress gene expression in both young T2D-prone db/db and Akita Ins2WT/C96Y mice. In MIN6 beta cells, HSPGs, HS and HPSE were reduced following treatment with pharmacological inducers of ER stress (thapsigargin or tunicamycin). Treatment of young db/db mice with Tauroursodeoxycholic acid (TUDCA), a chemical protein folding chaperone that relieves ER stress, improved glycemic control and increased intra-islet HSPG/HS. In vitro, HS replacement with heparin (a highly sulfated HS analogue) significantly increased the survival of wild-type and db/db beta cells and restored their resistance to hydrogen peroxide-induced death. We conclude that ER stress inhibits the synthesis/maturation of HSPG core proteins which are essential for HS assembly, thereby exacerbating oxidative stress and promoting beta cell failure. Diminished intracellular HSPGs/HS represent a previously unrecognized critical link bridging ER stress, oxidative stress and beta cell failure in T2D.
39
Rassu, Giovanna, Silvia Fancello, Marta Roldo, Milo Malanga, Lajos Szente, Rossana Migheli, Elisabetta Gavini, and Paolo Giunchedi. "Investigation of Cytotoxicity and Cell Uptake of Cationic Beta-Cyclodextrins as Valid Tools in Nasal Delivery." Pharmaceutics 12, no. 7 (July 12, 2020): 658. http://dx.doi.org/10.3390/pharmaceutics12070658.
Abstract:
Cyclodextrin polymers have high applicability in pharmaceutical formulations due to better biocompatibility, solubility enhancement, loading capacity and controlled drug release than their parent, cyclodextrins. The cytotoxicity and cell uptake of new cationic beta-cyclodextrin monomers and polymers were evaluated as suitable materials for nasal formulations and their protective effects on cells exposed to hydrogen peroxide were studied. PC12 and CACO-2 cells were selected as the neuronal- and epithelial-type cells, respectively, to mimic the structure of respiratory and olfactory epithelia of the nasal cavity. All cationic beta-cyclodextrin polymers tested showed dose- and time-dependent toxicity; nevertheless, at 5 µM concentration and 60 min of exposure, the quaternary-ammonium-beta-cyclodextrin soluble polymer could be recognized as nontoxic. Based on these results, a fluorescently labelled quaternary-ammonium-beta-cyclodextrin monomer and polymer were selected for uptake studies in CACO-2 cells. The monomeric and polymeric beta-cyclodextrins were internalized in the cytoplasm of CACO-2 cells; the cationic monomer showed higher permeability than the hydroxypropyl-beta-cyclodextrin, employed as comparison. Therefore, these cationic beta-cyclodextrins showed potential as excipients able to improve the nasal absorption of drugs. Furthermore, amino-beta-cyclodextrin and beta-cyclodextrin soluble polymers were able to reduce oxidative damage in PC12 and CACO-2 cells and thus could be studied as bioactive carriers or potential drugs for cell protection against oxidative stress.
40
Buenafe, A. C., M. Vainiene, B. Celnik, A. A. Vandenbark, and H. Offner. "Analysis of V beta 8.2 CDR3 sequences from spinal cord T cells of Lewis rats vaccinated or treated with TCR V beta 8.2-39-59 peptide." Journal of Immunology 155, no. 3 (August 1, 1995): 1556–64. http://dx.doi.org/10.4049/jimmunol.155.3.1556.
Abstract:
Abstract Experimental autoimmune encephalomyelitis (EAE) in the Lewis rat can be induced with the administration of Gp-BP. This disease appears to be mediated at least in part by V beta 8.2+CD4+T cells, which specifically recognize the BP72-89 encephalitogenic peptide. Treatment or protection with V beta 8.2 CDR2 39-59 peptide can suppress or prevent clinical signs of EAE, presumably through the activation of regulatory T cells. Interestingly, V beta 8.2+ T cells continue to persist in the spinal cord of protected animals, although their appearance in the central nervous system (CNS) is delayed when compared with control animals with EAE. As part of our effort to elucidate the mechanism(s) of peptide protection and therapy, we sought to determine whether the V beta 8.2+ T cells in the spinal cord of protected or treated rats were truly representative of those found in rats with clinical EAE. Therefore, we examined the following CNS samples for the Asp96Ser97 motif, which has been identified previously in V beta 8.2+ BP-specific, encephalitogenic T cell clones: 1) rats protected with V beta 8.2-39-59 peptide, 2) rats treated with V beta 8.2-39-59 peptide, and 3) control rats with EAE. Our findings indicate that EAE-associated V beta 8.2+ sequences can still be found in both peptide-treated and peptide-protected rats. It appears that administration of V beta 8.2 CDR2 peptide does not prevent EAE-associated V beta 8.2+ T cells from infiltrating the CNS and that other mechanisms are at work to prevent the development of EAE.
41
Moreb, J., JR Zucali, and S. Rueth. "The effects of tumor necrosis factor-alpha on early human hematopoietic progenitor cells treated with 4-hydroperoxycyclophosphamide." Blood 76, no. 4 (August 15, 1990): 681–89. http://dx.doi.org/10.1182/blood.v76.4.681.681.
Abstract:
Abstract We have previously reported that 20 hours' preincubation of human bone marrow cells with interleukin-1 beta (IL-1) can protect early progenitor cells from 4-hydroperoxycyclophosphamide (4-HC) cytotoxicity. Since tumor necrosis factor-alpha (TNF alpha) shares many of the biologic properties of IL-1, we have compared the protective effects of TNF alpha with IL-1 against 4-HC. Incubation of human bone marrow mononuclear cells or an enriched progenitor population for 20 hours with either TNF alpha or IL-1 resulted in the survival of an increased number of single- and mixed-lineage colonies, including replatable blast cell colonies, while only rare colonies were seen in the control group. Antibodies to TNF alpha completely abolished the protection observed with IL-1, while antibodies to IL-1 alpha and IL-1 beta decreased but did not abolish the protection seen with TNF alpha. Combinations of low doses of TNF alpha and IL-1 showed synergy in their protective effects. Furthermore, no protection was observed by IL-1, IL- 1 bone-marrow-conditioned medium (IL-1-BMCM), or TNF alpha for HL-60, K562, KG1, KG1a, and DU.528 leukemic-cell lines or primary acute myelogenous leukemic (AML) blast cells from the lethal effects of 4-HC. In the case of HL-60 and KG1a cell lines, TNF alpha preincubation resulted in increased cytotoxicity. Furthermore, preincubation of a mixture of AML cells and normal bone-marrow cells with IL-1 + TNF alpha before 4-HC resulted in the protection of normal but not leukemic progenitors. These results suggest that TNF alpha is necessary for the protection of normal, early, human hematopoietic progenitors from 4-HC, while IL-1 is not mandatory but will synergize with TNF alpha to offer increased protection. In addition, no protection from 4-HC is observed by TNF alpha, IL-1, or IL-1-BMCM for primary leukemic blast cells or leukemic cell lines.
42
Moreb, J., JR Zucali, and S. Rueth. "The effects of tumor necrosis factor-alpha on early human hematopoietic progenitor cells treated with 4-hydroperoxycyclophosphamide." Blood 76, no. 4 (August 15, 1990): 681–89. http://dx.doi.org/10.1182/blood.v76.4.681.bloodjournal764681.
Abstract:
We have previously reported that 20 hours' preincubation of human bone marrow cells with interleukin-1 beta (IL-1) can protect early progenitor cells from 4-hydroperoxycyclophosphamide (4-HC) cytotoxicity. Since tumor necrosis factor-alpha (TNF alpha) shares many of the biologic properties of IL-1, we have compared the protective effects of TNF alpha with IL-1 against 4-HC. Incubation of human bone marrow mononuclear cells or an enriched progenitor population for 20 hours with either TNF alpha or IL-1 resulted in the survival of an increased number of single- and mixed-lineage colonies, including replatable blast cell colonies, while only rare colonies were seen in the control group. Antibodies to TNF alpha completely abolished the protection observed with IL-1, while antibodies to IL-1 alpha and IL-1 beta decreased but did not abolish the protection seen with TNF alpha. Combinations of low doses of TNF alpha and IL-1 showed synergy in their protective effects. Furthermore, no protection was observed by IL-1, IL- 1 bone-marrow-conditioned medium (IL-1-BMCM), or TNF alpha for HL-60, K562, KG1, KG1a, and DU.528 leukemic-cell lines or primary acute myelogenous leukemic (AML) blast cells from the lethal effects of 4-HC. In the case of HL-60 and KG1a cell lines, TNF alpha preincubation resulted in increased cytotoxicity. Furthermore, preincubation of a mixture of AML cells and normal bone-marrow cells with IL-1 + TNF alpha before 4-HC resulted in the protection of normal but not leukemic progenitors. These results suggest that TNF alpha is necessary for the protection of normal, early, human hematopoietic progenitors from 4-HC, while IL-1 is not mandatory but will synergize with TNF alpha to offer increased protection. In addition, no protection from 4-HC is observed by TNF alpha, IL-1, or IL-1-BMCM for primary leukemic blast cells or leukemic cell lines.
43
Weiss, W. R., J. A. Berzofsky, R. A. Houghten, M. Sedegah, M. Hollindale, and S. L. Hoffman. "A T cell clone directed at the circumsporozoite protein which protects mice against both Plasmodium yoelii and Plasmodium berghei." Journal of Immunology 149, no. 6 (September 15, 1992): 2103–9. http://dx.doi.org/10.4049/jimmunol.149.6.2103.
Abstract:
Abstract Clone B is a cytotoxic T cell clone induced by immunization with Plasmodium yoelii sporozoites which recognizes an epitope on both the P. yoelii and Plasmodium berghei circumsporozoite proteins. It is CD8, uses the V beta 8.1 TCR, and is Kd restricted. When adoptively transferred, it protects mice against infection by both species of malaria sporozoites, and this protection is dependent on IFN-gamma. Clone B cells are more broadly reactive and protective than previously described murine T cell clones against malaria. Clone B may be an important model for immune protection against the spectrum of variant parasites in nature.
44
De Paoli, Monica, Deep Shah, Alexander Zakharia, Zil Patel, Zinal Patel, Pakhi Pakhi, and Geoff H. Werstuck. "Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta Cells." International Journal of Molecular Sciences 25, no. 3 (February 2, 2024): 1816. http://dx.doi.org/10.3390/ijms25031816.
Abstract:
Diabetes mellitus is clinically defined by chronic hyperglycemia. Sex differences in the presentation and outcome of diabetes exist with premenopausal women having a reduced risk of developing diabetes, relative to men, or women after menopause. Accumulating evidence shows a protective role of estrogens, specifically 17-beta estradiol, in the maintenance of pancreatic beta cell health; however, the mechanisms underlying this protection are still unknown. To elucidate these potential mechanisms, we used a pancreatic beta cell line (BTC6) and a mouse model of hyperglycemia-induced atherosclerosis, the ApoE−/−:Ins2+/Akita mouse, exhibiting sexual dimorphism in glucose regulation. In this study we hypothesize that 17-beta estradiol protects pancreatic beta cells by modulating the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress. We observed that ovariectomized female and male ApoE−/−:Ins2+/Akita mice show significantly increased expression of apoptotic UPR markers. Sham operated female and ovariectomized female ApoE−/−:Ins2+/Akita mice supplemented with exogenous 17-beta estradiol increased the expression of adaptive UPR markers compared to non-supplemented ovariectomized female ApoE−/−:Ins2+/Akita mice. These findings were consistent to what was observed in cultured BTC6 cells, suggesting that 17-beta estradiol may protect pancreatic beta cells by repressing the apoptotic UPR and enhancing the adaptive UPR activation in response to pancreatic ER stress.
45
Zaller, D. M., G. Osman, O. Kanagawa, and L. Hood. "Prevention and treatment of murine experimental allergic encephalomyelitis with T cell receptor V beta-specific antibodies." Journal of Experimental Medicine 171, no. 6 (June 1, 1990): 1943–55. http://dx.doi.org/10.1084/jem.171.6.1943.
Abstract:
Experimental allergic encephalomyelitis (EAE) is a model system for T cell-mediated autoimmune disease. Symptoms of EAE are similar to those of multiple sclerosis (MS) in humans. EAE is induced in susceptible animal strains by immunization with myelin basic protein (MBP) and potent adjuvant. The major T cell response to MBP in B10.PL mice is directed towards an NH2-terminal epitope and involves T cells expressing either V beta 8.2 or V beta 13 gene segments. Animals treated with a TCR V beta 8-specific mAb have a reduced incidence of EAE. We report here that the in vivo administration of a combination of anti-V beta 8.2 and anti-V beta 13 mAbs results in a long-term elimination of T cells involved in the response to MBP. When given before MBP immunization, anti-TCR antibody treatment leads to nearly complete protection against EAE. Antibody treatment also results in a dramatic reversal of paralysis in diseased animals. Thus, treatment with a combination of V beta-specific antibodies is a very effective therapy for the prevention and treatment of EAE. It is hoped that the future characterization of TCR V gene usage in human autoimmune diseases may lead to similar strategies of immune intervention.
46
Epstein, S. L., J. A. Misplon, C. M. Lawson, E. K. Subbarao, M. Connors, and B. R. Murphy. "Beta 2-microglobulin-deficient mice can be protected against influenza A infection by vaccination with vaccinia-influenza recombinants expressing hemagglutinin and neuraminidase." Journal of Immunology 150, no. 12 (June 15, 1993): 5484–93. http://dx.doi.org/10.4049/jimmunol.150.12.5484.
Abstract:
Abstract Immunity to viral infections includes both antibody and T cell components. The contributions of humoral and cell-mediated immune responses vary depending on virus and host factors. We have used an in vivo challenge system to examine protective immunity to influenza A(H1N1) virus infection in immunocompetent B6 (H-2b) mice, and in H-2b mice homozygous for disruption of the gene for beta 2-microglobulin, termed beta 2 mu(-/-) mice. The latter mice do not express conventional MHC class I complexes on cell surfaces and lack CD8+ class I-restricted T cells. Ten vaccinia virus recombinants, each expressing 1 of the 10 proteins of influenza virus, were used to immunize the mice. Normal mice were protected against challenge with influenza virus by vaccination with HA-VAC and NA-VAC, but not by any of the vaccinia vectors expressing one of the eight other influenza virus proteins nor by a mixture of all eight of the latter vectors. Similar results were observed in mice of H-2d or H-2k MHC haplotypes. The beta 2 mu(-/-) mice were also protected by immunization with HA-VAC and NA-VAC, demonstrating that classical CD8+ CTL responses were not required for protection. Depletion of CD4+ T cells in either normal or beta 2 mu(-/-) mice at the time of challenge had little or no effect on protection induced by HA-VAC or NA-VAC, suggesting that preformed antibody is the dominant mediator of protective immunity induced by these recombinants. Antibody responses to vaccinia virus Ag and expressed influenza virus Ag were lower in titer in beta 2 mu(-/-) mice than in normal B6 mice, suggesting an influence of MHC class I complexes, CD8+ T cells, or their products on antibody production.
47
Wu, S. P., D. Theodorescu, R. S. Kerbel, J. K. Willson, K. M. Mulder, L. E. Humphrey, and M. G. Brattain. "TGF-beta 1 is an autocrine-negative growth regulator of human colon carcinoma FET cells in vivo as revealed by transfection of an antisense expression vector." Journal of Cell Biology 116, no. 1 (January 1, 1992): 187–96. http://dx.doi.org/10.1083/jcb.116.1.187.
Abstract:
Transforming growth factor-beta 1 (TGF-beta 1) has previously been implicated as a potential negative autocrine or paracrine growth regulator of certain cell types (Arteaga, C. L., R. J. Coffey, Jr., T. C. Dugger, C. M. McCutchen, H. L. Moses, and R. M. Lyons. 1990. Cell Growth & Differ. 1:367-374; Hafez, M. M., D. Infante, S. Winawer, and E. Friedman. 1990. Cell Growth & Differ. 1:617-626; Glick, A. B., K. C. Flanders, D. Danielpour, S. H. Yuspa, and M. B. Sporn. 1989. Cell Regulation. 1:87-97). This is based mainly on experiments assessing the effects of exogenous TGF-beta 1 or neutralizing antibodies to TGF-beta 1 on normal or tumor cell proliferation in vitro. However, direct evidence demonstrating such a negative regulation of tumor cell growth in vivo is still lacking. To overcome this problem we have constructed and used an antisense expression vector for TGF-beta 1 as a means of regulating endogenous TGF-beta 1 expression in tumor cells. Antisense-transfected FET human colon carcinoma cells showed a fivefold reduction in TGF-beta 1 mRNA and 15-fold reduction in TGF-beta 1 secretion. Antisense mRNA was detected in transfected cells by an RNase protection assay. Compared to control cells, cultured antisense-transfected cells showed a reduction in lag phase time rather than a change in doubling time. Cloning efficiencies of transfected cells were four times greater than control cells in anchorage-independent assays. Control cells did not form tumors at 5 x 10(5) in athymic nude mice. Antisense-transfected cells formed tumors in 40% of animals injected. At higher inocula (1 x 10(6) cells) antisense-transfected cells formed tumors in 100% of animals injected, but control cells still failed to form tumors. These results show that TGF-beta 1 acts as a negative growth regulator of human colon carcinoma cells in vivo as well as in vitro. Acquisition of partial or full resistance to such inhibitory effects may therefore contribute to tumor development and progression.
48
Helqvist, Steffen, Pierre Bouchelouche, Henrik Ullits Andersen, and Jørn Nerup. "Modulation of calciumflux influences interleukin 1 β effects on insulin release from isolated islets of Langerhans." Acta Endocrinologica 121, no. 3 (September 1989): 447–55. http://dx.doi.org/10.1530/acta.0.1210447.
Abstract:
Abstract. The controlled flux of calcium across the cell membrane is intimately linked to the release of insulin from pancreatic beta-cells, but the uncontrolled influx of calcium is a common final denominator of cell death. Because interleukin 1 has been shown to be cytotoxic to beta-cells in isolated rat islets of Langerhans and since interleukin 1 has a calcium ionophore effect on other cell types, this study was designed to test whether alterations of the calcium flux across the beta-cell membrane would influence the effects of interleukin 1 on isolated rat and mouse islets. Further, the cytosolic free Ca2+ concentration was measured by the fura-2 method in rat islets during acute interleukin 1 exposure. Treatment with 10 μmol/l of verapamil (a potent blocker of the voltage-dependent calcium channel) tended to suppress the inhibitory effect of interleukin 1 on insulin release from rat islets, suggesting protection against cytotoxicity. Conversely, a stimulatory effect of interleukin 1 on mouse islets during 6 days of exposure to interleukin 1 was turned into inhibition by high extracellular calcium concentration. Interleukin 1 did not have any acute effect on cytosolic free Ca2+ concentration. In conclusion, interleukin 1 has no specific calcium ionophore effect on beta-cells, but alterations of the calcium flux across the beta-cell membrane influence the functional effects of interleukin 1, suggesting interference with cell function and toxicity, which would likely be accompanied by an uncontrolled influx of calcium.
49
Lotem, J., and L. Sachs. "Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells." Blood 80, no. 7 (October 1, 1992): 1750–57. http://dx.doi.org/10.1182/blood.v80.7.1750.1750.
Abstract:
Abstract Transforming growth factor-beta 1 (TGF-beta 1) induces cell death in myeloid leukemia by apoptosis. In the M1 myeloid leukemia, this induction of apoptosis was inhibited by granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6) and to a lesser extent by IL-1 alpha. IL-3 and stem cell factor/mast cell growth factor (SCF) showed only a marginal effect, and granulocyte-macrophage and macrophage CSFs (GM-CSF and M-CSF, respectively) were inactive. The induction of apoptosis by TGF-beta 1 in a different myeloid leukemia (7-M12) was inhibited by GM-CSF and IL-3 but not by the other cytokines. In the absence of TGF-beta 1, both M1 and 7-M12 leukemic cells were independent of hematopoietic cytokines for cell viability and growth. The cytotoxic compounds vincristine, vinblastine, adriamycin, cytosine arabinoside, cycloheximide, and sodium azide, some of which are used in cancer chemotherapy, induced cell death by apoptosis in both leukemias. As with TGF-beta 1, apoptosis induced by these cytotoxic compounds was inhibited by GM-CSF (7-M12 leukemia) and by G-CSF or IL-6 (M1 leukemia). Cyclosporine A decreased cell multiplication in M1 cells without inducing apoptosis, and G-CSF and IL-6 inhibited the cytostatic effect of cyclosporine A. It is suggested that the clinical use of cytokines to correct therapy-associated myelosuppression should be carefully timed to avoid protection of malignant cells from the cytotoxic action of the therapeutic compounds.
50
Lotem, J., and L. Sachs. "Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells." Blood 80, no. 7 (October 1, 1992): 1750–57. http://dx.doi.org/10.1182/blood.v80.7.1750.bloodjournal8071750.
Abstract:
Transforming growth factor-beta 1 (TGF-beta 1) induces cell death in myeloid leukemia by apoptosis. In the M1 myeloid leukemia, this induction of apoptosis was inhibited by granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6) and to a lesser extent by IL-1 alpha. IL-3 and stem cell factor/mast cell growth factor (SCF) showed only a marginal effect, and granulocyte-macrophage and macrophage CSFs (GM-CSF and M-CSF, respectively) were inactive. The induction of apoptosis by TGF-beta 1 in a different myeloid leukemia (7-M12) was inhibited by GM-CSF and IL-3 but not by the other cytokines. In the absence of TGF-beta 1, both M1 and 7-M12 leukemic cells were independent of hematopoietic cytokines for cell viability and growth. The cytotoxic compounds vincristine, vinblastine, adriamycin, cytosine arabinoside, cycloheximide, and sodium azide, some of which are used in cancer chemotherapy, induced cell death by apoptosis in both leukemias. As with TGF-beta 1, apoptosis induced by these cytotoxic compounds was inhibited by GM-CSF (7-M12 leukemia) and by G-CSF or IL-6 (M1 leukemia). Cyclosporine A decreased cell multiplication in M1 cells without inducing apoptosis, and G-CSF and IL-6 inhibited the cytostatic effect of cyclosporine A. It is suggested that the clinical use of cytokines to correct therapy-associated myelosuppression should be carefully timed to avoid protection of malignant cells from the cytotoxic action of the therapeutic compounds.