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1
Powers, Nicholas E., Benjamin Swartzwelter, Carlo Marchetti, Dennis M. de Graaf, Alexandra Lerchner, Martin Schlapschy, Rajiv Datar, et al. "PASylation of IL-1 receptor antagonist (IL-1Ra) retains IL-1 blockade and extends its duration in mouse urate crystal-induced peritonitis." Journal of Biological Chemistry 295, no. 3 (December 9, 2019): 868–82. http://dx.doi.org/10.1074/jbc.ra119.010340.
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Interleukin-1 (IL-1) is a key mediator of inflammation and immunity. Naturally-occurring IL-1 receptor antagonist (IL-1Ra) binds and blocks the IL-1 receptor-1 (IL-1R1), preventing signaling. Anakinra, a recombinant form of IL-1Ra, is used to treat a spectrum of inflammatory diseases. However, anakinra is rapidly cleared from the body and requires daily administration. To create a longer-lasting alternative, PASylated IL-1Ra (PAS–IL-1Ra) has been generated by in-frame fusion of a long, defined-length, N-terminal Pro/Ala/Ser (PAS) random-coil polypeptide with IL-1Ra. Here, we compared the efficacy of two PAS–IL-1Ra molecules, PAS600–IL-1Ra and PAS800–IL-1Ra (carrying 600 and 800 PAS residues, respectively), with that of anakinra in mice. PAS600–IL-1Ra displayed markedly extended blood plasma levels 3 days post-administration, whereas anakinra was undetectable after 24 h. We also studied PAS600–IL-1Ra and PAS800–IL-1Ra for efficacy in monosodium urate (MSU) crystal-induced peritonitis. 5 days post-administration, PAS800–IL-1Ra significantly reduced leukocyte influx and inflammatory markers in MSU-induced peritonitis, whereas equimolar anakinra administered 24 h before MSU challenge was ineffective. The 6-h pretreatment with equimolar anakinra or PAS800–IL-1Ra before MSU challenge similarly reduced inflammatory markers. In cultured A549 lung carcinoma cells, anakinra, PAS600–IL-1Ra, and PAS800-IL-Ra reduced IL-1α–induced IL-6 and IL-8 levels with comparable potency. In human peripheral blood mononuclear cells, these molecules suppressed Candida albicans–induced production of the cancer-promoting cytokine IL-22. Surface plasmon resonance analyses revealed significant binding between PAS–IL-1Ra and IL-1R1, although with a slightly lower affinity than anakinra. These results validate PAS–IL-1Ra as an active IL-1 antagonist with marked in vivo potency and a significantly extended half-life compared with anakinra.
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Vannier, E., R. de Waal Malefyt, A. Salazar-Montes, JE de Vries, and CA Dinarello. "Interleukin-13 (IL-13) induces IL-1 receptor antagonist gene expression and protein synthesis in peripheral blood mononuclear cells: inhibition by an IL-4 mutant protein." Blood 87, no. 8 (April 15, 1996): 3307–15. http://dx.doi.org/10.1182/blood.v87.8.3307.bloodjournal8783307.
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Interleukin-13 (IL-13) belongs to the IL-4 gene family. Like IL-4, IL- 13 induces IL-1 receptor antagonist (IL-1Ra) synthesis with no effect on IL-1beta synthesis. We investigated whether IL-13 induces IL-1Ra synthesis via a pathway similar to IL-4. In human peripheral blood mononuclear cells, IL-13 (1 to 100 ng/mL alone induced IL-1Ra synthesis in a dose-dependent manner. A single amino acid mutant form of IL-4 (hIL4.Yl24D) induced IL-1Ra synthesis, acting as a partial agonist. However, hIL-4.Yl24D inhibited IL-1Ra synthesis induced by either IL-4 or IL-13. IL-13 alone induced accumulation of IL-1Ra mRNA. Furthermore, IL-13 reduced steady- state levels for IL-1beta mRNA but enhanced those for IL-1Ra mRNA in cells stimulated with lipopolysaccharide (LPS) or IL- 1alpha. Accordingly, IL-13 suppressed IL-1beta synthesis but enhanced IL-1Ra synthesis in these cells. IL-13 reduced the stability of IL- 1beta mRNA (2.9 v 1.7 hours) but failed to modify the stability of IL- 1Ra mRNA (2.7 v 2.5 hours). Moreover, IL-13 induced transcriptional activation of the IL-1Ra gene, but reduced IL-1beta gene transcription. Our results suggest that the commonality between IL-13 and IL-4 in inducing IL-1Ra synthesis results from the engagement of a subunit common to both receptors.
3
Jordan, M., I. G. Otterness, R. Ng, A. Gessner, M. Röllinghoff, and H. U. Beuscher. "Neutralization of endogenous IL-6 suppresses induction of IL-1 receptor antagonist." Journal of Immunology 154, no. 8 (April 15, 1995): 4081–90. http://dx.doi.org/10.4049/jimmunol.154.8.4081.
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Abstract IL-1 is a potent cytokine that promotes host defense and inflammation. These processes may be modulated by an IL-1 receptor antagonist (IL-1Ra) that binds to and blocks IL-1 receptors. The objective of this study was to define the cellular origin and regulation of IL-1Ra production during bacterial infection. Oral infection of mice with Yersinia enterocolitica resulted in expression of IL-1Ra mRNA and synthesis of IL-1Ra in Peyer's patches (PP), the local site of infection, as well as in noninfected organs such as spleens. By immunostaining, recruited circulating neutrophils were identified to be the primary source of IL-1Ra in tissues. Only approximately 20% of the IL-1Ra-staining cells were accounted for by inflammatory macrophages. Strikingly, neutralization of IL-6 by anti-IL-6 antiserum caused a suppression of both IL-1Ra mRNA in PP and synthesis of IL-1Ra in circulating neutrophils. Confirmatory evidence that IL-6 participates in the generation of IL-1Ra was obtained when rIL-6 induced, and anti-IL-6 antiserum blocked, IL-1Ra expression in cultures of macrophage and polymorphonuclear leukocytes (PMN). These findings suggest that IL-6 induced induction of IL-1Ra may provide a negative feedback loop, facilitating resolution of the inflammatory response locally and presumably at remote sites of infection.
4
Levine, S. J., T. Wu, and J. H. Shelhamer. "Extracellular release of the type I intracellular IL-1 receptor antagonist from human airway epithelial cells: differential effects of IL-4, IL-13, IFN-gamma, and corticosteroids." Journal of Immunology 158, no. 12 (June 15, 1997): 5949–57. http://dx.doi.org/10.4049/jimmunol.158.12.5949.
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Abstract Three IL-1R antagonists (IL-1Ra) exist: secreted IL-1Ra and intracellular IL-1Ra (icIL-1Ra) types I and II. We have previously reported that human airway epithelial cells (HAEC) express icIL-1Ra type I, which can be up-regulated by corticosteroids. This study assessed whether cytokines and corticosteroids differentially effect icIL-1Ra type I protein release from HAEC to the extracellular compartment. We report that icIL-1Ra type I mRNA and intracellular protein are up-regulated in NCI-H292 cells, a human pulmonary mucoepidermoid carcinoma cell line, in response to IL-4, IL-13, IFN-gamma, and dexamethasone. The icIL-1Ra type I protein was detected in concentrated cell culture supernatants from NCI-H292 cells and normal human bronchial epithelial cells. The release of biologically relevant concentrations of active IL-1Ra from normal human bronchial epithelial cells was demonstrated by the ability of a neutralizing anti-IL-1Ra Ab to augment IL-1beta-mediated IL-8 secretion. IL-4, IL-13, and IFN-gamma induced immunoreactive IL-1Ra release into supernatants from NCI-H292 cells. Dexamethasone inhibited constitutive and cytokine-induced release of immunoreactive IL-1Ra. The release of icIL-1Ra type I protein was not related to cytotoxicity, as measured by lactate dehydrogenase. We propose that icIL-1Ra type I release from HAEC represents a novel mechanism by which IL-1 bioactivity in the airway microenvironment may be modulated. Cytokine-mediated icIL-1Ra type I synthesis may increase both intracellular protein and release to the extracellular space, where cell surface IL-1R can be antagonized. In contrast, corticosteroid-induced increases in icIL-1Ra type I synthesis and inhibition of extracellular protein release promote accumulation of icIL-1Ra type I protein within the intracellular compartment.
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Poutsiaka, DD, BD Clark, E. Vannier, and CA Dinarello. "Production of interleukin-1 receptor antagonist and interleukin-1 beta by peripheral blood mononuclear cells is differentially regulated." Blood 78, no. 5 (September 1, 1991): 1275–81. http://dx.doi.org/10.1182/blood.v78.5.1275.1275.
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Abstract We studied the relationship between the production of the 23-Kd interleukin-1 receptor antagonist (IL-1ra) and IL-1 beta in cultures of human peripheral blood mononuclear cells (PBMC) using a specific radioimmunoassay for IL-1ra that had a sensitivity of 166 +/- 11 pg/mL. PBMC cultured without human serum made little IL-1ra or IL-1 beta. In the presence of 1% AB serum, there was no increase in IL-1 beta (0.25 +/- 0.13 ng/mL) but IL-1ra production increased sevenfold to 3.4 +/- 0.5 ng/mL. IgG (2.5 to 100 micrograms/mL IgG) or granulocyte-macrophage colony-stimulating factor (GM-CSF) (1 to 100 ng/mL) had no significant effect on IL-1 beta production but increased IL-1ra production up to 18- fold (18.2 +/- 3.9 ng/mL). Using endotoxin as a stimulant, 82% +/- 2% of IL-1ra was secreted in comparison with 52% +/- 9% of IL-1 beta. Culture conditions of PBMC influenced the production of IL-1ra but not IL-1 beta. Rocking endotoxin-stimulated PBMC produced 75% less IL-1ra but the same amount of IL-1 beta when compared with PBMC cultured in stationary plastic tubes. Rocking IgG-or GM-CSF-stimulated PBMC also produced 75% to 80% less IL-1ra. GM-CSF or IL-1 beta at concentrations that elicited submaximal production of IL-1ra potentiated IgG-induced IL-1ra production. The production of IL-1ra and IL-1 beta are under differential regulation because serum, IgG, and GM-CSF were potent stimuli for the production of IL-1ra but not IL-1 beta, and the prevention of cell-cell contact of PBMC reduced IL-1ra but not IL-1 beta production.
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Poutsiaka, DD, BD Clark, E. Vannier, and CA Dinarello. "Production of interleukin-1 receptor antagonist and interleukin-1 beta by peripheral blood mononuclear cells is differentially regulated." Blood 78, no. 5 (September 1, 1991): 1275–81. http://dx.doi.org/10.1182/blood.v78.5.1275.bloodjournal7851275.
Full textAbstract:
We studied the relationship between the production of the 23-Kd interleukin-1 receptor antagonist (IL-1ra) and IL-1 beta in cultures of human peripheral blood mononuclear cells (PBMC) using a specific radioimmunoassay for IL-1ra that had a sensitivity of 166 +/- 11 pg/mL. PBMC cultured without human serum made little IL-1ra or IL-1 beta. In the presence of 1% AB serum, there was no increase in IL-1 beta (0.25 +/- 0.13 ng/mL) but IL-1ra production increased sevenfold to 3.4 +/- 0.5 ng/mL. IgG (2.5 to 100 micrograms/mL IgG) or granulocyte-macrophage colony-stimulating factor (GM-CSF) (1 to 100 ng/mL) had no significant effect on IL-1 beta production but increased IL-1ra production up to 18- fold (18.2 +/- 3.9 ng/mL). Using endotoxin as a stimulant, 82% +/- 2% of IL-1ra was secreted in comparison with 52% +/- 9% of IL-1 beta. Culture conditions of PBMC influenced the production of IL-1ra but not IL-1 beta. Rocking endotoxin-stimulated PBMC produced 75% less IL-1ra but the same amount of IL-1 beta when compared with PBMC cultured in stationary plastic tubes. Rocking IgG-or GM-CSF-stimulated PBMC also produced 75% to 80% less IL-1ra. GM-CSF or IL-1 beta at concentrations that elicited submaximal production of IL-1ra potentiated IgG-induced IL-1ra production. The production of IL-1ra and IL-1 beta are under differential regulation because serum, IgG, and GM-CSF were potent stimuli for the production of IL-1ra but not IL-1 beta, and the prevention of cell-cell contact of PBMC reduced IL-1ra but not IL-1 beta production.
7
Watson, J. M., A. K. Lofquist, C. A. Rinehart, J. C. Olsen, S. S. Makarov, D. G. Kaufman, and J. S. Haskill. "The intracellular IL-1 receptor antagonist alters IL-1-inducible gene expression without blocking exogenous signaling by IL-1 beta." Journal of Immunology 155, no. 9 (November 1, 1995): 4467–75. http://dx.doi.org/10.4049/jimmunol.155.9.4467.
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Abstract The epithelium-associated tissue distribution of the intracellular IL-1R antagonist (icIL-1Ra) suggests that it functions as a novel regulatory molecule for IL-1 in somatic tissues. We examined the role of the icIL-1Ra in IL-1 beta-induced responses in human ovarian cancer cells because ovarian surface epithelium expresses transcripts for the icIL-1Ra, and the majority of ovarian cancers arise from these cells. Several human ovarian and cervical cancer cell lines spontaneously express the icIL-1Ra. icIL-1Ra-expressing cells did not have altered growth characteristics or altered short term responses to IL-1 compared with icIL-1Ra-nonexpressing cells. While a 90-min exposure to IL-1 beta resulted in increased steady state cytokine mRNA levels in all cells, icIL-1Ra-positive cells were incapable of maintaining IL-1-beta-induced expression of GRO mRNA. This did not result from decreased transcriptional activity of the GRO gene, but reflected differences in mRNA stability and/or degradation. To determine whether the icIL-1Ra altered mRNA stability, we used a retroviral expression vector to express the icIL-1Ra in an icIL-1Ra-negative cell line. The resulting cells displayed a profile of IL-1 beta-induced genes analogous to that found in cells spontaneously expressing icIL-1Ra. These data show for the first time an intrinsic biologic activity for the icIL-1Ra. The capacity to selectively alter IL-1-induced gene expression suggests that this version of the IL-1Ra is a unique intracellular inhibitor that attenuates IL-1 responses at a point downstream of the initial IL-1/IL-1 receptor interaction.
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Chomarat, P., E. Vannier, J. Dechanet, M. C. Rissoan, J. Banchereau, C. A. Dinarello, and P. Miossec. "Balance of IL-1 receptor antagonist/IL-1 beta in rheumatoid synovium and its regulation by IL-4 and IL-10." Journal of Immunology 154, no. 3 (February 1, 1995): 1432–39. http://dx.doi.org/10.4049/jimmunol.154.3.1432.
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Abstract The spontaneous production of IL-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1Ra) by rheumatoid arthritis (RA) synovium, and the regulation of their production by IL-4 and IL-10, were studied. Supernatants from cultured synovium pieces from 19 RA patients were assayed for IL-1 beta and IL-1Ra production using ELISA and RIA, respectively. After 10 days of culture, spontaneous production of IL-1Ra was 1.42 +/- 0.43 ng/ml/100 mg of synovium whereas spontaneous production of IL-1 beta was 4.03 +/- 0.90 ng/ml/100 mg of synovium (n = 19). The addition of IL-4 reduced IL-1 beta production by 2.3-fold (p = 0.001) and increased that of IL-1Ra by 2.8-fold (p = 0.003). IL-10 had no significant effect on IL-1Ra production and suppressed IL-1 beta production (primarily in samples producing high levels of IL-1 beta). However, IL-10 was less potent than IL-4 in suppressing IL-1 beta production. IL-1Ra was mainly produced by rheumatoid synovial monocytes/macrophages. IL-4 was more potent than IL-10 in inducing IL-1Ra production by monocytes/macrophages purified from RA synovium, as well as from RA blood. Thus, RA synovium is characterized by an imbalance between IL-1Ra and IL-1 beta production, in favor of the latter. IL-4, and to a lesser extent IL-10, shift this balance in favor of an anti-inflammatory situation.
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Roberge, C. J., R. de Médicis, J. M. Dayer, M. Rola-Pleszczynski, P. H. Naccache, and P. E. Poubelle. "Crystal-induced neutrophil activation. V. Differential production of biologically active IL-1 and IL-1 receptor antagonist." Journal of Immunology 152, no. 11 (June 1, 1994): 5485–94. http://dx.doi.org/10.4049/jimmunol.152.11.5485.
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Abstract Neutrophils produce IL-1 when stimulated by monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals. Neutrophils also generate the IL-1R antagonist (IL-1Ra), especially when incubated with granulocyte-macrophage CSF (GM-CSF) or TNF-alpha. We studied the simultaneous expression of IL-1 and IL-1Ra by GM-CSF- or TNF-alpha-treated neutrophils activated by MSU or CPPD. Neutrophils incubated with GM-CSF or TNF-alpha produced approximately 300 or 200 times more IL-1Ra than IL-1, respectively. Suboptimal concentrations of MSU or CPPD induced low amounts of IL-1 without affecting IL-1Ra. Interaction of GM-CSF- and TNF-alpha-treated neutrophils with MSU or CPPD up-regulated IL-1 while simultaneously down-regulating IL-1Ra. As a result, the bioactivity of IL-1 secreted was enhanced. Synergistic increases of IL-1 (but not IL-1Ra) mRNA levels were noted in GM-CSF- or TNF-alpha-treated neutrophils exposed to CPPD. Treatment of neutrophils with colchicine before incubation with GM-CSF or TNF alpha, inhibited crystal-induced IL-1 by 50 to 55%, but failed to significantly affect IL-1Ra. The IL-1Ra to IL-1 ratio was significantly increased by 185 to 220%. These results demonstrate that IL-1 and IL-1Ra production by human neutrophils are differentially regulated, that the combined presence of GM-CSF or TNF-alpha and microcrystals favor the production of biologically active IL-1 over that of IL-1Ra, and that colchicine selectively inhibits IL-1 without affecting IL-1Ra production.
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Yoon, Ho Joo, Zhou Zhu, Jack M. Gwaltney, and Jack A. Elias. "Rhinovirus Regulation of IL-1 Receptor Antagonist In Vivo and In Vitro: A Potential Mechanism of Symptom Resolution." Journal of Immunology 162, no. 12 (June 15, 1999): 7461–69. http://dx.doi.org/10.4049/jimmunol.162.12.7461.
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Abstract Rhinovirus (RV) upper respiratory tract infections are prototypic transient inflammatory responses. To address the mechanism of disease resolution in these infections, we determined if RV stimulated the production of the IL-1 receptor antagonist (IL-1ra) in vivo and in vitro. In contrast to IL-1α and IL-1β, immunoreactive IL-1ra was readily detected in the nasal washings of normal human volunteers. Symptomatic RV infection caused a small increase in IL-1α, a modest increase in IL-1β, and an impressive increase in IL-1ra. Maximal induction of IL-1α and IL-1β was transiently noted 48 h after RV infection. In contrast, maximal induction of IL-1ra was prolonged appearing 48–72 h after RV infection. These time points corresponded to the periods of peak symptomatology and the onset of symptom resolution, respectively. Western analysis of nasal washings demonstrated that RV stimulated the accumulation of intracellular IL-1ra type I in all and secreted IL-1ra in a subset of volunteers. Unstimulated normal respiratory epithelial cells contained intracellular IL-1ra type I mRNA and protein. RV infection increased the intracellular levels and extracellular transport of this IL-1ra moiety without causing significant changes in the levels of IL-1ra mRNA. IL-1ra may play an important role in the resolution of RV respiratory infections. RV stimulates epithelial cell IL-1ra elaboration, at least in part, via a novel translational and/or posttranslational mechanism.
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Wilkinson, Robert J., Punita Patel, Martin Llewelyn, Christina S. Hirsch, Geoffrey Pasvol, Georges Snounou, Robert N. Davidson, and Zahra Toossi. "Influence of Polymorphism in the Genes for the Interleukin (IL)-1 Receptor Antagonist and IL-1β on Tuberculosis." Journal of Experimental Medicine 189, no. 12 (June 21, 1999): 1863–74. http://dx.doi.org/10.1084/jem.189.12.1863.
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Several lines of evidence suggest that host genetic factors controlling the immune response influence infection by Mycobacterium tuberculosis. The proinflammatory cytokine interleukin (IL)-1β and its antagonist, IL-1Ra (IL-1 receptor agonist), are strongly induced by M. tuberculosis and are encoded by polymorphic genes. The induction of both IL-1Ra mRNA and secreted protein by M. tuberculosis in IL-1Ra allele A2–positive (IL-1Ra A2+) healthy subjects was 1.9-fold higher than in IL-1Ra A2− subjects. The M. tuberculosis–induced expression of mRNA for IL-1β was higher in subjects of the IL-1β (+3953) A1+ haplotype (P = 0.04). The molar ratio of IL-1Ra/IL-1β induced by M. tuberculosis was markedly higher in IL-1Ra A2+ individuals (P < 0.05), with minor overlap between the groups, reflecting linkage between the IL-1Ra A2 and IL-1β (+3953) A2 alleles. In M. tuberculosis–stimulated peripheral blood mononuclear cells, the addition of IL-4 increased IL-1Ra secretion, whereas interferon γ increased and IL-10 decreased IL-1β production, indicative of a differential influence on the IL-1Ra/IL-1β ratio by cytokines. In a study of 114 healthy purified protein derivative–reactive subjects and 89 patients with tuberculosis, the frequency of allelic variants at two positions (−511 and +3953) in the IL-1β and IL-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2−/IL-1β (+3953) A1+ haplotype was unevenly distributed, being more common in patients with tuberculous pleurisy (92%) in comparison with healthy M. tuberculosis–sensitized control subjects or patients with other disease forms (57%, P = 0.028 and 56%, P = 0.024, respectively). Furthermore, the IL-1Ra A2+ haplotype was associated with a reduced Mantoux response to purified protein derivative of M. tuberculosis: 60% of tuberculin-nonreactive patients were of this type. Thus, the polymorphism at the IL-1 locus influences the cytokine response and may be a determinant of delayed-type hypersensitivity and disease expression in human tuberculosis.
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Gabay, Cem, Brandon Porter, Denis Guenette, Bahri Billir, and William P. Arend. "Interleukin-4 (IL-4) and IL-13 Enhance the Effect of IL-1β on Production of IL-1 Receptor Antagonist by Human Primary Hepatocytes and Hepatoma HepG2 Cells: Differential Effect on C-Reactive Protein Production." Blood 93, no. 4 (February 15, 1999): 1299–307. http://dx.doi.org/10.1182/blood.v93.4.1299.
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Abstract Interleukin-1 receptor antagonist (IL-1Ra) is produced by hepatocytes with characteristics of an acute-phase protein. To examine the role of IL-4 and IL-13 in production of IL-1Ra, human primary hepatocytes and HepG2 human hepatoma cells were cultured in the presence of IL-4 or IL-13 in combination with IL-1β and/or IL-6. The results indicated that both IL-4 and IL-13 amplified the stimulatory effect of IL-1β on production of IL-1Ra protein and messenger RNA (mRNA) by both human primary hepatocytes and HepG2 cells. IL-1Ra refers to three different peptides, one secreted (sIL-1Ra) and two intracellular (icIL-1RaI and icIL-1RaII), derived from the same gene. sIL-1Ra and icIL-1RaI are the products of two different mRNA, whereas icIL-1RaII is synthesized by alternative translation initiation mainly from sIL-1Ra mRNA. Our results show that both sIL-1Ra and icIL-1RaII, but not icIL-1RaI, are produced by HepG2 cells and human hepatocytes. Transient transfection experiments as well as mRNA stability studies indicated that IL-4 stimulated sIL-1Ra production primarly at the level of transcription. Gel retardation assays showed that IL-4 induced the formation of a STAT6-DNA complex with a STAT6 binding element within the sIL-1Ra promoter, but had no effect on IL-1–induced NF-κB binding activity. In contrast to IL-1Ra, production of C-reactive protein by human primary hepatocytes was stimulated by IL-6 and decreased by the addition of IL-4.
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Gabay, Cem, Brandon Porter, Denis Guenette, Bahri Billir, and William P. Arend. "Interleukin-4 (IL-4) and IL-13 Enhance the Effect of IL-1β on Production of IL-1 Receptor Antagonist by Human Primary Hepatocytes and Hepatoma HepG2 Cells: Differential Effect on C-Reactive Protein Production." Blood 93, no. 4 (February 15, 1999): 1299–307. http://dx.doi.org/10.1182/blood.v93.4.1299.404k26_1299_1307.
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Interleukin-1 receptor antagonist (IL-1Ra) is produced by hepatocytes with characteristics of an acute-phase protein. To examine the role of IL-4 and IL-13 in production of IL-1Ra, human primary hepatocytes and HepG2 human hepatoma cells were cultured in the presence of IL-4 or IL-13 in combination with IL-1β and/or IL-6. The results indicated that both IL-4 and IL-13 amplified the stimulatory effect of IL-1β on production of IL-1Ra protein and messenger RNA (mRNA) by both human primary hepatocytes and HepG2 cells. IL-1Ra refers to three different peptides, one secreted (sIL-1Ra) and two intracellular (icIL-1RaI and icIL-1RaII), derived from the same gene. sIL-1Ra and icIL-1RaI are the products of two different mRNA, whereas icIL-1RaII is synthesized by alternative translation initiation mainly from sIL-1Ra mRNA. Our results show that both sIL-1Ra and icIL-1RaII, but not icIL-1RaI, are produced by HepG2 cells and human hepatocytes. Transient transfection experiments as well as mRNA stability studies indicated that IL-4 stimulated sIL-1Ra production primarly at the level of transcription. Gel retardation assays showed that IL-4 induced the formation of a STAT6-DNA complex with a STAT6 binding element within the sIL-1Ra promoter, but had no effect on IL-1–induced NF-κB binding activity. In contrast to IL-1Ra, production of C-reactive protein by human primary hepatocytes was stimulated by IL-6 and decreased by the addition of IL-4.
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Malyak, Mark, Joel M. Guthridge, Kenneth R. Hance, Steven K. Dower, John H. Freed, and William P. Arend. "Characterization of a Low Molecular Weight Isoform of IL-1 Receptor Antagonist." Journal of Immunology 161, no. 4 (August 15, 1998): 1997–2003. http://dx.doi.org/10.4049/jimmunol.161.4.1997.
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Abstract IL-1R antagonist (IL-1Ra) exists in two well-characterized forms, 17-kDa secretory IL-1Ra (sIL-1Ra) and 18-kDa intracellular IL-1Ra (icIL-1Ra), that arise by alternative transcription of the same IL-1Ra gene. A third, lower molecular mass form (∼16 kDa) was detected by immunoblot within lysates of a variety of cells, including human monocytes and myelomonocytic cell lines. The 16-kDa isoform was designated icIL-1RaII, and the previously established 18-kDa form was designated icIL-1RaI. Intracellular IL-1RaII bound type I IL-1R up to fivefold less avidly than did sIL-1Ra and icIL-1RaI. Microsequencing of cyanogen bromide fragments of purified icIL-1RaII provided evidence consistent with initiation of protein translation at the second start site in either IL-1Ra mRNA. The results of site-directed mutation experiments established that icIL-1RaII could be derived by alternative translation initiation. In vitro transcription and translation of intact sIL-1Ra cDNA in rabbit reticulocyte lysates led to both pro-sIL-1Ra and icIL-1RaII proteins, whereas transcription and translation of icIL-1RaI cDNA produced both icIL-1RaI and icIL-1RaII proteins. Mutation of the first 5′ ATG in sIL-1Ra cDNA led to translation of only icIL-1RaII, while only sIL-1Ra was observed after mutation of the second ATG. These results indicate that icIL-1RaII is a third member of the IL-1Ra family and is a 16-kDa, 143-amino acid intracellular protein derived by alternative translation initiation from either sIL-1Ra mRNA or icIL-1Ra mRNA. The role in biology of either intracellular form of IL-1Ra remains unknown.
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Zhang, Zhong, Susan O’Brien, Michael Keating, Iman Jilani, Hagop Kantarjian, Zeev Estrov, Alessandra Ferrajoli, Francis Giles, and Maher Albitar. "Interleukin-1 Receptor Antagonist and Interleukin-1 beta: Different Roles in Patients with Chronic Lymphocytic Leukemia." Blood 108, no. 11 (November 16, 2006): 4948. http://dx.doi.org/10.1182/blood.v108.11.4948.4948.
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Abstract Interleukin-1 receptor antagonist (IL-1Ra) is a 23-KDa soluble glycoprotein that blocks the activity of IL-1α and IL-1β by competing with type I and type II IL-1 receptors without initiating signal transduction. IL-1Ra is anti-inflammatory, while IL-1β is a proinflammatory molecule. IL-1β enhances the immunological and hemopoietic systems and IL-1Ra acts as an inhibitor. IL-1β induces the cell surface expression of cytokine receptors on lymphoid and hemopoietic cells, whereas IL-1Ra suppresses this activity. IL-1β augments lymphoid and hemopoietic cell growth, whereas IL-1Ra suppresses this growth. We evaluated the clinical relevance of IL-1Ra and IL-1β levels in the plasma of 92 patients with chronic lymphocytic leukemia (CLL). IL-1Ra levels were significantly higher in CLL patients (median, 389, range 52–3667 pg/mL) than in 31 normal control subjects (median, 217; range, 94–868 pg/mL) (P <0.001). In contrast, IL-1B levels were significantly lower in CLL patients (median, 2.23; range, 1.89–12 pg/mL) than in normal controls (median, 2.68; range, 2.08–5.5) (P <0.01). Overall, neither IL-1Ra nor IL-1B correlated significantly with WBC count, β2-microglobulin (β2-M) level, Rai stage, platelet count, mutation status, or treatment history. Only age correlated with IL-1Ra (R = 0.39, P <0.001). Using a univariate Cox proportional hazards model, we found direct correlation with survival when IL-1Ra was used as a continuous variable (P <0.001). This association was independent of Rai stage, β-2M, and IgVH mutation status. However, in a multivariate analysis incorporating a combination of IgVH, β2-M, and IL-1Ra, IL-1Ra was no longer a predictor of survival. When patients were dichotomized according to the median IL-1Ra level, those with higher levels had longer survival (P = 0.057). In contrast, IL-1B did not correlate with survival (P = 0.14). These data suggest that IL-1Ra, but not IL-1B, plays a role in the biology of CLL and that the stronger the anti-inflammatory process in CLL, the more aggressive the disease.
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Sauter, Nadine S., Fabienne T. Schulthess, Ryan Galasso, Lawrence W. Castellani, and Kathrin Maedler. "The Antiinflammatory Cytokine Interleukin-1 Receptor Antagonist Protects from High-Fat Diet-Induced Hyperglycemia." Endocrinology 149, no. 5 (January 31, 2008): 2208–18. http://dx.doi.org/10.1210/en.2007-1059.
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Subclinical inflammation is a recently discovered phenomenon in type 2 diabetes. Elevated cytokines impair β-cell function and survival. A recent clinical trial shows that blocking IL-1β signaling by IL-1 receptor antagonist (IL-1Ra) improves β-cell secretory function in patients with type 2 diabetes. In the present study, we provide further mechanisms of the protective role of IL-1Ra on the β-cell. IL-1Ra prevented diabetes in vivo in C57BL/6J mice fed a high-fat/high-sucrose diet (HFD) for 12 wk; it improved glucose tolerance and insulin secretion. High-fat diet treatment increased serum levels of free fatty acids and of the adipokines resistin and leptin, which were reduced by IL-1Ra treatment. In addition, IL-1Ra counteracted adiponectin levels, which were decreased by high-fat feeding. Studies on isolated islets revealed that IL-1Ra specifically acted on the β-cell. IL-1Ra protected islets from HFD treated animals from β-cell apoptosis, induced β-cell proliferation, and improved glucose-stimulated insulin secretion. Insulin mRNA was reduced in islets from mice fed a HFD but normalized in the IL-1Ra group. Our results show that IL-1Ra improves β-cell survival and function, and support the potential role for IL-1Ra in the treatment of diabetes.
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Meier, Raphael, Jeremy Meyer, Elisa Montanari, Stephanie Lacotte, Alexandre Balaphas, Yannick Muller, Sophie Clément, et al. "Interleukin-1 Receptor Antagonist Modulates Liver Inflammation and Fibrosis in Mice in a Model-Dependent Manner." International Journal of Molecular Sciences 20, no. 6 (March 14, 2019): 1295. http://dx.doi.org/10.3390/ijms20061295.
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Background: Interleukin-1 (IL-1)β and IL-1 receptor antagonist (IL-1Ra) have been proposed as important mediators during chronic liver diseases. We aimed to determine whether the modulation of IL-1β signaling with IL-1Ra impacts on liver fibrosis. Methods: We assessed the effects of IL-1β on human hepatic stellate cells (HSC) and in mouse models of liver fibrosis induced by bile duct ligation (BDL) or carbon tetrachloride treatment (CCl-4). Results: Human HSCs treated with IL-1β had increased IL-1β, IL-1Ra, and MMP-9 expressions in vitro. HSCs treated with IL-1β had reduced α-smooth muscle actin expression. These effects were all prevented by IL-1Ra treatment. In the BDL model, liver fibrosis and Kuppfer cell numbers were increased in IL-1Ra KO mice compared to wild type mice and wild type mice treated with IL-1Ra. In contrast, after CCl-4 treatment, fibrosis, HSC and Kupffer cell numbers were decreased in IL-1Ra KO mice compared to the other groups. IL-1Ra treatment provided a modest protective effect in the BDL model and was pro-fibrotic in the CCl-4 model. Conclusions: We demonstrated bivalent effects of IL-1Ra during liver fibrosis in mice. IL-1Ra was detrimental in the CCl-4 model, whereas it was protective in the BDL model. Altogether these data suggest that blocking IL-1-mediated inflammation may be beneficial only in selective liver fibrotic disease.
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Akita, Koji, Kikuo Isoda, Fumie Ohtomo, Sarasa Isobe, Tomiharu Niida, Yayoi Sato-Okabayashi, Motoaki Sano, Kazunori Shimada, Yoichiro Iwakura, and Tohru Minamino. "Blocking of interleukin-1 suppresses angiotensin II-induced renal injury." Clinical Science 135, no. 17 (August 31, 2021): 2035–48. http://dx.doi.org/10.1042/cs20201406.
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Abstract Clinical hypertension (HT) is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. Interleukin (IL)-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (Ang II)-induced HT response. The present study aimed to elucidate the effects of IL-1Ra and anti-IL-1β antibody (01BSUR) on Ang II-induced renal injury. To determine the contribution of IL-1Ra to Ang II-induced renal inflammation, male wildtype (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with Ang II (1000 ng/kg/min) using subcutaneous osmotic pump for 14 days. We checked renal function, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197 ± 5 vs 169 ± 9 mmHg, P<0.05) in IL-1Ra−/− mice significantly increased compared with WT mice. Furthermore, on day 14 of Ang II infusion, plasma IL-6 was 5.9-fold higher in IL-1Ra−/− versus WT mice (P<0.001); renal preproendothelin-1 mRNA expression was also significantly higher in IL-1Ra−/− mice (P<0.05). In addition, renal histology revealed greater damage in IL-1Ra−/− mice compared with WT mice 14 days after infusion. Finally, we administrated 01BSUR to both IL-1Ra−/− and WT mice, and 01BSUR treatment decreased Ang II-induced HT and renal damage (glomerular injury and fibrosis of the tubulointerstitial area) in both IL-1Ra−/− and WT mice compared with IgG2a treatment. Inhibition of IL-1 decreased Ang II-induced HT and renal damage in both IL-1Ra−/− and WT mice, suggesting suppression of IL-1 may provide an additional strategy to protect against renal damage in hypertensive patients.
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Huang, Hong-Yuan, Yan Wen, Jan S. Kruessel, Francisco Raga, Yung-Kuei Soong, and Mary Lake Polan. "Interleukin (IL)-1β Regulation of IL-1β and IL-1 Receptor Antagonist Expression in Cultured Human Endometrial Stromal Cells1." Journal of Clinical Endocrinology & Metabolism 86, no. 3 (March 1, 2001): 1387–93. http://dx.doi.org/10.1210/jcem.86.3.7284.
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The interleukin (IL)-1 system is a major regulator of local cellular interactions during embryonic implantation. Because IL-1β and IL receptor antagonist (IL-1ra) are both expressed in human endometrium, we hypothesized that an appropriate ratio of IL-1β to IL-1ra might favor the process of embryo implantation. Therefore, we investigated IL-1 regulation of the quantitative ratio of IL-1β/IL-1ra messenger RNA (mRNA) expression in human endometrial stromal cells using quantitative competitive PCR, as well as intracellular protein expression after stromal cell solubilization. Confluent stromal cell cultures were stimulated with human IL-1β (0–1000 IU/mL) for 24 h. After 24 h, total RNA was extracted, reverse transcribed, and coamplified by PCR with a defined amount of internal standard. The quantitative ratio was determined by the density of target to the internal standard. After culture with IL-1β for 24 and 48 h, stromal cells were solubilized, and the intracellular protein levels of IL-1β and IL-1ra were measured by enzyme-linked immunosorbent assay. The IL-1β and IL-1ra mRNA were both up-regulated, and IL-1R tI mRNA was down-regulated, by IL-1β in a dose-dependent manner. The quantitative ratio of IL-1β to IL-1ra mRNA was constant with the presence of increasing concentrations of IL-1β (1–1000 IU/mL). IL-1β and IL-1ra protein was not detected in conditioned media of cultures before addition of IL-1β. IL-1β and IL-1ra protein levels increased with increasing amounts of IL-1β after solubilization of stromal cells. The IL-1β was detectable after 12 h of culture, in comparison with IL-1ra, which was detectable after 24 h of IL-1β stimulation. These results suggest that IL-1 may play a crucial role in embryo-maternal interaction by regulating stromal cell expression of IL-1β and IL-1ra, resulting in an appropriate ratio during the process of embryonic implantation.
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Wong, H. L., G. L. Costa, M. T. Lotze, and S. M. Wahl. "Interleukin (IL) 4 differentially regulates monocyte IL-1 family gene expression and synthesis in vitro and in vivo." Journal of Experimental Medicine 177, no. 3 (March 1, 1993): 775–81. http://dx.doi.org/10.1084/jem.177.3.775.
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Interleukin (IL) 4 is a multifunctional T cell-derived cytokine that inhibits cytokine production and certain effector functions in human monocytes, while enhancing others. We show that IL-4 may contribute to the downregulation and resolution of an inflammatory response by selectively promoting expression of the IL-1 receptor antagonist (IL-1ra) that blocks the action of IL-1. IL-1ra specifically binds to the IL-1 receptor without initiating signal transduction. Peripheral blood monocytes obtained from cancer patients, before and immediately after a regimen of IL-4 immunotherapy, were examined for IL-1ra gene expression. After IL-4 therapy, monocytes from the patients showed a marked increase in IL-1ra mRNA. This selective induction of IL-1ra mRNA in circulating monocytes was reflected by significantly enhanced serum levels of IL-1ra (p < 0.01) during IL-4 therapy, which declined after IL-4 treatment. In vitro analysis of IL-4 regulation of monocytes from normal individuals revealed a dose-dependent induction of IL-1ra mRNA within 2-4 h after stimulation without a concomitant effect on the expression of IL-1 mRNA. Increased IL-1ra mRNA was not due to RNA stabilization, but occurred at the level of transcription. In the presence of LPS, IL-4 not only augmented IL-1ra levels, but markedly inhibited LPS-induced IL-1 mRNA expression. The selective upregulation of IL-1ra by resting or activated monocytes, coupled with inhibition of IL-1 production by activated monocytes, as we demonstrate both in vitro and in vivo, suggests that IL-4 may prove clinically useful as a systemic antiinflammatory agent.
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Tran, Paul M. H., Fran Dong, Khaled Bin Satter, Katherine P. Richardson, Roshni Patel, Lynn K. H. Tran, Diane Hopkins, et al. "Serum IL-1ra Is Associated with but Has No Genetic Link to Type 1 Diabetes." Endocrines 3, no. 3 (September 13, 2022): 570–77. http://dx.doi.org/10.3390/endocrines3030048.
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Interleukin-1 antagonism is a proposed biomarker and potential therapy for the delay and/or treatment of type 1 diabetes (T1D). We evaluated the role of circulating interleukin-1 receptor antagonist (IL-1ra) in a prospectively monitored cohort of T1D patients. In order to determine a mechanistic association between IL-1ra and T1D, we performed co-localization analyses between serum IL-1ra protein quantitative trait loci and T1D genome-wide analysis studies. Adjusting for human leukocyte antigen (HLA) genotypes, first degree relative status, gender, and age, serum levels of IL-1ra were lower in subjects who progressed to T1D compared to the controls (p = 0.023). Our results suggest that females have higher levels of IL-1ra compared to males (p = 0.005). The 2q14.1 region associated with serum IL-1ra levels is not associated with a risk of developing T1D. Our data suggest that IL-1 antagonism by IL-1ra is not an effective therapy in T1D, but IL-1ra may be a biomarker for progression to T1D.
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Redlitz, Karen H., Vladimir F. Yamshchikov, and Fabio Cominelli. "Differential Contribution of IL-1Ra Isoforms to Allele-Specific IL-1Ra mRNA Accumulation." Journal of Interferon & Cytokine Research 24, no. 4 (April 2004): 253–60. http://dx.doi.org/10.1089/107999004323034123.
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Sauer, J., U. Renner, U. Hopfner, M. Lange, A. Müller, C. J. Strasburger, U. Pagotto, E. Arzt, and G. K. Stalla. "Interleukin-1β Enhances Interleukin-1 Receptor Antagonist Content in Human Somatotroph Adenoma Cell Cultures1." Journal of Clinical Endocrinology & Metabolism 83, no. 7 (July 1, 1998): 2429–34. http://dx.doi.org/10.1210/jcem.83.7.4963.
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In addition to the well-known modulation of immune and inflammatory responses, the interleukin-1 (IL-1) system has been shown to be involved in the regulation of anterior pituitary hormone secretion and growth. We previously demonstrated that IL-1 receptor antagonist (IL-1ra) is expressed in human pituitary adenomas cultured in vitro. In the present study, we investigated the regulation of IL-1ra protein by IL-1β (1–100 U/mL) in human somatotroph adenomas (n = 9) cultured for 12–48 h. IL-1β significantly enhanced the concentration of IL-1ra dose dependently in the somatotroph adenoma cell lysates, whereas IL-1ra concentrations remained unchanged in the culture supernatants. Furthermore, basal IL-1ra concentrations were significantly higher in the cell lysates compared with the corresponding culture supernatants. The regulation of IL-1ra in somatotroph adenoma cells is different from human cultured monocytes, in which IL-1β significantly stimulated IL-1ra secretion into the culture supernatants, and no change of intracellular IL-1ra content was observed. Incubation of the somatotroph adenoma cells with 100 U/mL IL-1β did not result in a change of GH concentrations in the culture supernatants. Enhancement of intracellular IL-1ra protein by IL-1β may represent a mechanism intrinsic to somatotroph adenoma cells to counterregulate the response to IL-1β on hormone secretion or cellular growth.
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Li, Rong-Juan, Yan Sun, Qin Wang, Jiao Yang, Ya Yang, Li Song, Zheng Wang, Xiang-Hong Luo, and Rui-Juan Su. "Ultrasound Biomicroscopic Imaging for Interleukin-1 Receptor Antagonist–Inhibiting Atherosclerosis and Markers of Inflammation in Atherosclerotic Development in Apolipoprotein-E Knockout Mice." Texas Heart Institute Journal 42, no. 4 (August 1, 2015): 319–26. http://dx.doi.org/10.14503/thij-14-4318.
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We sought to validate the hypothesis that the development of atherosclerosis can be suppressed by the interleukin-1 receptor antagonist (IL-1Ra) in murine models of atherosclerosis in vivo, noninvasively seen by means of high-resolution ultrasound biomicroscopy, and we studied changes in inflammatory markers such as IL-1 and C-reactive protein (CRP) plasma levels in these models of atherosclerosis. We divided IL-1Ra+/−/apolipoprotein-E (apoE)−/− and IL-1Ra+/+/apoE−/− mice into 2 age groups, used as atherosclerotic models. The control groups were age-matched IL-1Ra+/+/apoE+/+ mice. Plaque thickness was measured in the ascending aorta in short-axis images by means of ultrasound and histology. Plasma levels of IL-1 and CRP were quantified in the 3 murine groups. At 16 weeks, plaque thickness in the ascending aortas of the IL-1Ra+/−/apoE−/− mice was significantly greater than that in the IL-1Ra+/+/apoE−/− mice, on ultrasound and histology (P <0.01). In contrast, at 32 weeks, the differences between these 2 genotypes were not statistically significant. Serum IL-1 levels were lower in the IL-1Ra+/−/apoE−/− mice than in the IL-1Ra+/+/apoE−/− mice at 16 and 32 weeks (P <0.05). At 16 weeks, serum CRP levels in the IL-1Ra+/−/apoE−/− mice were higher than in the IL-1Ra+/+/apoE−/− mice (P <0.01). Our results suggest that ultrasound biomicroscopy enables evaluation of atherosclerotic lesions in vivo, noninvasively and in real-time, in apoE−/− mice. Partial IL-1Ra deficiencies might promote early plaque development in 16-week-old apoE−/− mice. The balance of IL-1 and IL-1Ra might influence atherosclerotic development. Finally, CRP might affect the initiation of atherosclerosis, rather than its progression.
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Josephs, Michael D., Carmen C. Solorzano, Michael Taylor, Jason J. Rosenberg, Daniel Topping, Amer Abouhamze, Sally L. D. Mackay, et al. "Modulation of the acute phase response by altered expression of the IL-1 type 1 receptor or IL-1ra." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 278, no. 4 (April 1, 2000): R824—R830. http://dx.doi.org/10.1152/ajpregu.2000.278.4.r824.
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A complete understanding of the role for endogenously produced interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and IL-1 receptor antagonist (IL-1ra) in the acute phase response to inflammation remains unknown. In the present studies, knockout mice lacking either a functional IL-1 type I receptor (IL-1RI− / −), a TNF type I receptor (TNFR-I− / −), or both IL-1 type I and TNF type I receptors (IL-1RI− / −/TNFR-I− / −) received a turpentine abscess. Additional mice deficient in IL-1ra protein (IL-1ra− / −) or overexpressing IL-1ra protein (IL-1ratg) were similarly treated. After a turpentine abscess, IL-1 receptor knockout mice exhibited an attenuated inflammatory response compared with wild-type or animals lacking a functional TNFR-I. Mice overexpressing IL-1ra also had an attenuated hepatic acute phase protein response, whereas IL-1ra knockout mice had a significantly greater hepatic acute phase response. We conclude that the inflammatory response to a turpentine abscess is the result of a balance between IL-1ra expression and IL-1 binding to its type I receptor. Endogenously produced IL-1ra plays a central role in mitigating the magnitude of the IL-1-mediated inflammatory response and, ultimately, the outcome to a turpentine abscess.
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Arend, W. P., M. F. Smith, R. W. Janson, and F. G. Joslin. "IL-1 receptor antagonist and IL-1 beta production in human monocytes are regulated differently." Journal of Immunology 147, no. 5 (September 1, 1991): 1530–36. http://dx.doi.org/10.4049/jimmunol.147.5.1530.
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Abstract Human monocytes may synthesize simultaneously both the agonist IL-1 beta and a specific receptor antagonist of IL-1 (IL-1ra). These studies examined whether monocyte production of these two structurally related cytokines was regulated differently. IL-1ra and IL-1 beta protein levels in cell supernatants and lysates were measured with specific ELISA. Relative steady-state mRNA levels, relative transcriptional rates as determined by the nuclear run-on technique, and mRNA stability were all assessed using specific cDNA probes. Monocytes were stimulated with LPS alone, adherent IgG, or both LPS and adherent IgG. Monocytes stimulated with LPS produced near equivalent amounts of IL-1ra and IL-1 beta proteins over 22 h; relative steady-state mRNA levels paralleled the protein levels. In addition, LPS-induced monocytes exhibited enhanced rates of transcription for both IL-1ra and IL-1 beta, in comparison to adherent control cells without LPS. mRNA half-lives in LPS-induced monocytes also were similar for IL-1ra and IL-1 beta. Monocytes cultured on adherent IgG exhibited a low level of IL-1 beta transcription with an absence of protein production. In contrast, adherent IgG led to a high and prolonged rate of IL-1ra protein production. Furthermore, monocytes cultured on adherent IgG exhibited a specific induction of IL-1ra transcription and a marked prolongation in IL-1ra mRNA stability. However, LPS in a high concentration, 1 microgram/ml, reversed the IgG induction of IL-1ra production by decreasing both transcriptional rate and mRNA stability. These results indicate that production of IL-1ra by human monocytes is characterized by different patterns of regulation in comparison with IL-1 beta. LPS induces production of both proteins whereas adherent IgG stimulates only IL-1ra production. The effects of IgG and LPS on induction of IL-1ra production in human monocytes are mediated at both transcriptional and post-transcriptional levels.
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Beasley, D., M. E. McGuiggin, and C. A. Dinarello. "Human vascular smooth muscle cells produce an intracellular form of interleukin-1 receptor antagonist." American Journal of Physiology-Cell Physiology 269, no. 4 (October 1, 1995): C961—C968. http://dx.doi.org/10.1152/ajpcell.1995.269.4.c961.
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Interleukin-1 (IL-1) is a proinflammatory monocyte- and macrophage-derived cytokine that has potent vasorelaxant effects on vascular smooth muscle cells (VSMC). VSMC themselves also express both IL-1 alpha- and beta-genes, suggesting that IL-1 may be an autocrine regulator of VSMC function. The present study demonstrates that human saphenous vein VSMC (HSVSMC) produce IL-1 receptor antagonist (IL-1Ra), a specific inhibitor of IL-1 action. IL-1Ra was produced constitutively in most experiments, and its production was upregulated by phorbol 12-myristate 13-acetate and by IL-1 beta. IL-1Ra produced by HSVSMC remained predominately cell associated and was not detectable extracellularly. Furthermore, reverse transcription-polymerase chain reaction analysis and cDNA sequencing indicated that HSVSMC express the alternatively spliced form of IL-1Ra which lacks the signal peptide present in secreted IL-1Ra. HSVSMC also produced IL-1 alpha and the precursor form but not the mature form of IL-1 beta. These results suggest that HSVSMC lack active IL-1 beta-converting enzyme. Like IL-1Ra, IL-1 beta precursor and IL-1 alpha remained cell associated, predominately in the cytosolic fraction. IL-1 beta induced production of both IL-1Ra and IL-1 alpha at each time point and concentration tested. In contrast, platelet-derived growth factor and transforming growth factor-beta augmented production of IL-1Ra, but not that of IL-1 alpha. These results are suggestive of an autocrine role for cell-associated IL-1Ra, as well as for IL-1 alpha and IL-1 beta, in the regulation of VSMC function.
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Orino, E., S. Sone, A. Nii, and T. Ogura. "IL-4 up-regulates IL-1 receptor antagonist gene expression and its production in human blood monocytes." Journal of Immunology 149, no. 3 (August 1, 1992): 925–31. http://dx.doi.org/10.4049/jimmunol.149.3.925.
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Abstract IL-4 down-regulates the productions of IL-1 and TNF-alpha in human monocytes. We examined whether the productions of IL-1 and a specific receptor antagonist of IL-1 (IL-1Ra) in human blood monocytes were regulated differently. Highly purified blood monocytes, isolated by centrifugal elutriation from healthy donors, were stimulated with LPS in the presence or absence of IL-4, and their productions of IL-1 and IL-1Ra were measured by Northern blot and immunoblot analyses. IL-1 and IL-1Ra were produced by monocytes stimulated with LPS, but not with IL-4 alone. Marked up-regulation by IL-4 of IL-1Ra production in LPS-stimulated monocytes was observed at both the mRNA and protein levels. Maximal expressions of IL-1 beta and IL-1Ra mRNA in LPS-stimulated monocytes were observed 2 h and 8 h, respectively, after stimulation. The enhancement of IL-1Ra production by IL-4 was concluded to be due to enhanced gene transcription, because there was no difference in the half-lives of IL-1Ra mRNA in monocytes cultured with and without IL-4. Up-regulation of IL-1Ra production by IL-4 was also observed in monocytes stimulated with adherent IgG at both the mRNA and protein levels. This unique property of IL-4 may be important in down-regulation of the IL-1-initiated immune and/or inflammatory response, not only directly through inhibition of IL-1 production, but also indirectly through up-regulation of IL-1Ra production.
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Muzio, M., F. Re, M. Sironi, N. Polentarutti, A. Minty, D. Caput, P. Ferrara, A. Mantovani, and F. Colotta. "Interleukin-13 induces the production of interleukin-1 receptor antagonist (IL-1ra) and the expression of the mRNA for the intracellular (keratinocyte) form of IL-1ra in human myelomonocytic cells." Blood 83, no. 7 (April 1, 1994): 1738–43. http://dx.doi.org/10.1182/blood.v83.7.1738.1738.
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Abstract The aim of this study was to examine the expression of interleukin-1 receptor antagonist (IL-1ra) in human myelomonocytic cells treated with IL-13. IL-13 induced IL-1ra transcripts in human circulating monocytes and polymorphonuclear cells (PMN). Induction by IL-13 was not blocked, but rather superinduced, in the presence of the protein synthesis inhibitor cycloheximide. Actinomycin D blocked induction, suggesting involvement of gene transcription. The half-life of IL-1ra transcripts was prolonged by IL-13 from 1.3 hours to 4.5 hours in monocytes and to 12 hours in PMN. By reverse transcriptase-polymerase chain reaction, IL- 13 was found to augment the transcripts coding for the soluble form of IL-1ra, but also to induce the expression of the intracellular (keratinocyte) form of IL-1ra, the latter being extremely low or undetectable in myelomonocytic cells. IL-13 induced production of IL- 1ra in myelomonocytic cells, augmenting both cell-associated and released protein. Induction of IL-1ra by IL-13 may represent a further mechanism by which this molecule can counteract the potent proinflammatory properties of IL-1.
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Muzio, M., F. Re, M. Sironi, N. Polentarutti, A. Minty, D. Caput, P. Ferrara, A. Mantovani, and F. Colotta. "Interleukin-13 induces the production of interleukin-1 receptor antagonist (IL-1ra) and the expression of the mRNA for the intracellular (keratinocyte) form of IL-1ra in human myelomonocytic cells." Blood 83, no. 7 (April 1, 1994): 1738–43. http://dx.doi.org/10.1182/blood.v83.7.1738.bloodjournal8371738.
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The aim of this study was to examine the expression of interleukin-1 receptor antagonist (IL-1ra) in human myelomonocytic cells treated with IL-13. IL-13 induced IL-1ra transcripts in human circulating monocytes and polymorphonuclear cells (PMN). Induction by IL-13 was not blocked, but rather superinduced, in the presence of the protein synthesis inhibitor cycloheximide. Actinomycin D blocked induction, suggesting involvement of gene transcription. The half-life of IL-1ra transcripts was prolonged by IL-13 from 1.3 hours to 4.5 hours in monocytes and to 12 hours in PMN. By reverse transcriptase-polymerase chain reaction, IL- 13 was found to augment the transcripts coding for the soluble form of IL-1ra, but also to induce the expression of the intracellular (keratinocyte) form of IL-1ra, the latter being extremely low or undetectable in myelomonocytic cells. IL-13 induced production of IL- 1ra in myelomonocytic cells, augmenting both cell-associated and released protein. Induction of IL-1ra by IL-13 may represent a further mechanism by which this molecule can counteract the potent proinflammatory properties of IL-1.
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Donovan, Kathleen A., Laurie L. Moon-Tasson, and John A. Lust. "Interplay Between IL-1, IL-6 and IL-17 in IL-1 Receptor Antagonist (IL-1Ra) Treated Multiple Myeloma Patients." Blood 120, no. 21 (November 16, 2012): 1874. http://dx.doi.org/10.1182/blood.v120.21.1874.1874.
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Abstract Abstract 1874 In early stage myeloma, IL-6 is a central myeloma growth factor and we have shown that abnormal production of IL-1 in the myeloma microenvironment stimulates the generation of IL-6 in a paracrine fashion. IL-1 has also been shown to be a crucial factor in the induction of IL-17 producing T-cells in vivo. IL-1Ra is a specific blocker of IL-1 activity. We have previously reported on a Phase II trial using IL-1Ra and dexamethasone, in patients with smoldering/indolent MM (SMM/IMM), showing that IL-1Ra targets the myeloma proliferative component which parallels a decrease in the C-reactive protein (CRP), a surrogate for IL-6 production. These patients are the individuals most likely to benefit from anti-cytokine therapy in an attempt to delay/prevent the development of active myeloma. Patients that had > 10% bone marrow plasma cells and/or an IgG or IgA M-spike > 3 g/dL and did not require immediate chemotherapy were eligible. All patients received 100 mg of Anakinra (IL-1Ra) SQ qd for 6 months. Patients with evidence of reduction in M-protein levels continued receiving IL-1Ra alone. Patients with stable disease at 6 months or those with a rising M-protein before 6 months received low dose dexamethasone (20 mg qweek) in addition; the dose was adjusted based on response/toxicity. Data were available on 47 patients based on intent to treat, and patients were classified as smoldering (72%) vs. indolent (28%). All 47 patients received IL-1Ra initially and 25/47 subsequently received IL-1Ra/Dex. Myeloma cell growth rate (PCLI), C-reactive protein (an in vivo marker of IL-6 levels) and IL-17 were measured in patients on trial. Seven patients had a decrease in the plasma cell labeling index (PCLI) on IL-1Ra alone which paralleled a decrease in the C-reactive protein in all cases. Three patients achieved a minor response to IL-1Ra alone and 9 patients achieved a PR/MR after addition of dexamethasone. When patients were grouped into whether they exhibited a reduction in the C-reactive protein from baseline after 6 months of therapy, the median PFS for patients without (21 patients) or with (26 patients) a greater than one-third reduction in baseline CRP was 1 year vs more than 8 years (p<.01). Analyses of biomarkers suggest that patients with elevated IL-17 levels may be less likely to respond to IL-1Ra treatment. Only 25% of the responders with a decrease in CRP had IL-17 levels > 10 pg/ml versus 60% of those without a CRP decrease. Although not statistically significant do to the small sample size, the median PFS in the IL-17 < 10 pg/ml group was 2047days vs 1367 days in the IL-17 > 10 pg/ml group. In conclusion, the above results suggest that agents such as IL-1Ra that specifically inhibit IL-1 induced paracrine IL-6 production are effective at targeting the proliferative myeloma component and warrant further investigation in combination with standard myeloma therapies. Elevated IL-17 levels may suggest that the inflammatory process is too far advanced in some individuals to respond to IL-1 blockade. Biomarkers such as CRP and IL-17 may be useful to predict those patients that are most likely to benefit from IL-1 treatment. Disclosures: Off Label Use: IL-1Ra in myeloma.
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Planck, Stephen R., April Woods, Jenna S. Clowers, Martin J. Nicklin, James T. Rosenbaum, and Holly L. Rosenzweig. "Impact of IL-1 signalling on experimental uveitis and arthritis." Annals of the Rheumatic Diseases 71, no. 5 (January 20, 2012): 753–60. http://dx.doi.org/10.1136/annrheumdis-2011-200556.
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BackgroundUveitis, or inflammatory eye disease, is a common extra-articular manifestation of many systemic autoinflammatory diseases involving the joints. Anakinra (recombinant interleukin (IL)-1 receptor antagonist (Ra)) is an effective therapy in several arthritic diseases; yet, few studies have investigated the extent to which IL-1 signalling or IL-1Ra influences the onset and/or severity of uveitis.ObjectiveTo seek possible links between arthritis and uveitis pathogenesis related to IL-1 signalling.MethodsThe eyes of IL-1Ra-deficient BALB/c mice were monitored histologically and by intravital videomicroscopy to determine if uveitis developed along with the expected spontaneous arthritis in ankles and knees. Expression levels of IL-1R and its negative regulators (IL-1Ra, IL-1RII, IL-1RAcP and single Ig IL-1R-related molecule) in eye and joint tissues were compared. Differences in uveitis induced by intraocular injection of lipopolysaccharide (LPS) in mice lacking IL-1R or IL-1Ra were assessed.ResultsDeficiency in IL-1Ra predisposes to spontaneous arthritis, which is exacerbated by previous systemic LPS exposure. The eye, however, does not develop inflammatory disease despite the progressive arthritis or LPS exposure. Organ-specific expression patterns for IL-1Ra and negative regulators of IL-1 activity were observed that appear to predict predisposition to inflammation in each location in IL-1Ra knockout mice. The eye is extremely sensitive to locally administered LPS, and IL-1Ra deficiency markedly exacerbates the resulting uveitis.ConclusionThis study demonstrates that IL-1Ra plays an important role in suppressing local responses in eyes injected with LPS and that there is discordance between murine eyes and joints in the extent to which IL-1Ra protects against spontaneous inflammation.
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Poutsiaka, DD, M. Mengozzi, E. Vannier, B. Sinha, and CA Dinarello. "Cross-linking of the beta-glucan receptor on human monocytes results in interleukin-1 receptor antagonist but not interleukin-1 production." Blood 82, no. 12 (December 15, 1993): 3695–700. http://dx.doi.org/10.1182/blood.v82.12.3695.3695.
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Abstract The beta-glucan receptor, found on monocytes and neutrophils, binds glucose polymers derived from fungi. Ligands for the receptor have various immunomodulatory effects, including increased microbicidal killing activity. We have investigated the effect of beta-glucans on the production of interleukin-1 (IL-1) and its naturally occurring inhibitor, the IL-1 receptor antagonist (IL-1Ra). Particulate beta- glucan induced IL-1Ra production from human peripheral blood mononuclear cells (PBMC) but did not stimulate IL-1 beta synthesis or gene expression in these same cells. Monomeric (soluble) beta-glucan did not induce IL-1Ra production. However, when preincubated with PBMC, monomeric beta-glucan significantly (P <.01) reduced particulate beta- glucan induction of IL-1Ra by 40%, suggesting that crosslinking of beta- glucan receptors is required for induction of IL-1Ra. In support of this, monomeric beta-glucan immobilized on plastic surfaces stimulated IL-1Ra production. Vitamin D3, which increases the functional capacity of beta-glucan receptors, increased IL-1Ra production induced by particulate beta-glucan, whereas dexamethasone suppressed IL-1Ra synthesis. Because of their differential effects on cytokine production, beta-glucans may be used to therapeutic advantage in the diseases in which IL-1 is implicated.
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Poutsiaka, DD, M. Mengozzi, E. Vannier, B. Sinha, and CA Dinarello. "Cross-linking of the beta-glucan receptor on human monocytes results in interleukin-1 receptor antagonist but not interleukin-1 production." Blood 82, no. 12 (December 15, 1993): 3695–700. http://dx.doi.org/10.1182/blood.v82.12.3695.bloodjournal82123695.
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The beta-glucan receptor, found on monocytes and neutrophils, binds glucose polymers derived from fungi. Ligands for the receptor have various immunomodulatory effects, including increased microbicidal killing activity. We have investigated the effect of beta-glucans on the production of interleukin-1 (IL-1) and its naturally occurring inhibitor, the IL-1 receptor antagonist (IL-1Ra). Particulate beta- glucan induced IL-1Ra production from human peripheral blood mononuclear cells (PBMC) but did not stimulate IL-1 beta synthesis or gene expression in these same cells. Monomeric (soluble) beta-glucan did not induce IL-1Ra production. However, when preincubated with PBMC, monomeric beta-glucan significantly (P <.01) reduced particulate beta- glucan induction of IL-1Ra by 40%, suggesting that crosslinking of beta- glucan receptors is required for induction of IL-1Ra. In support of this, monomeric beta-glucan immobilized on plastic surfaces stimulated IL-1Ra production. Vitamin D3, which increases the functional capacity of beta-glucan receptors, increased IL-1Ra production induced by particulate beta-glucan, whereas dexamethasone suppressed IL-1Ra synthesis. Because of their differential effects on cytokine production, beta-glucans may be used to therapeutic advantage in the diseases in which IL-1 is implicated.
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Ruggiero, P., P. Bossù, G. Macchia, E. Del Grosso, V. Sabbatini, R. Bertini, A. Colagrande, et al. "Inhibitory activity of IL-1 receptor antagonist depends on the balance between binding capacity for IL-1 receptor type 1 and IL-1 receptor type II." Journal of Immunology 158, no. 8 (April 15, 1997): 3881–87. http://dx.doi.org/10.4049/jimmunol.158.8.3881.
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Abstract A series of mutants of human IL-1 receptor antagonist (IL-1ra) has been designed by comparison of IL-1ra and IL-1beta structures in order to increase receptor antagonist capacity. Upon in vitro and in vivo assay of IL-1 antagonism, the IL-1ra mutants DoB 0039 (N91-->R), DoB 0040 (T109-->A) and DoB 0041 (N91/T109-->R/A) could inhibit IL-1beta effects more efficiently than wild-type IL-1ra, with DoB 0041 being the most active. Analysis of the receptor-binding capacity of the IL-1ra mutants showed that all three mutants could inhibit binding of IL-1alpha or IL-1beta to IL-1RI-bearing cells more efficiently than wild-type IL-1ra. Conversely, binding of IL-1beta to IL-1RII-bearing cells could be inhibited by DoB 0041 much less efficiently than by wild-type IL-1ra. It is known that the two types of IL-1 receptors (IL-1RI and IL-1RII) play different roles in the regulation of IL-1 activity, with IL-1RI being solely responsible for cell triggering upon IL-1 binding, whereas IL-1RII acts as a scavenger of IL-1 and can thus be considered as a natural IL-1 inhibitor. Thus, the enhanced inhibitory capacity of DoB 0041 as compared with wild-type IL-1ra is explained in terms of better binding to the activating receptor IL-1RI and poorer interaction with the inhibitory receptor IL-1RII.
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Janson, R. W., K. R. Hance, and W. P. Arend. "Production of IL-1 receptor antagonist by human in vitro-derived macrophages. Effects of lipopolysaccharide and granulocyte-macrophage colony-stimulating factor." Journal of Immunology 147, no. 12 (December 15, 1991): 4218–23. http://dx.doi.org/10.4049/jimmunol.147.12.4218.
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Abstract The objective of these experiments was to evaluate the production of IL-1ra, a specific receptor antagonist of IL-1, by human in vitro-derived macrophages, a model for differentiated macrophages. IL-1ra protein levels in supernatants and lysates of cultured cells were determined by a specific ELISA. Relative steady-state IL-1ra mRNA levels were measured using a specific cDNA probe. Human monocytes were differentiated by 6 days culture in either medium or granulocyte-macrophage colony-stimulating factor (GM-CSF), after which the effects of subsequent LPS and/or GM-CSF on the production of IL-1ra were evaluated. In vitro-derived macrophages cultured in medium for 6 days constitutively produced IL-1ra protein during the 24-h period of the 7th day in culture. The constitutive production of IL-1ra by medium-aged cells correlated with low steady-state IL-1ra mRNA levels determined over this same time period. In contrast, cells cultured for 6 days in GM-CSF synthesized significantly increased levels of IL-1ra protein during the 7th day in culture but the secreted levels remained unchanged. Cells differentiated in GM-CSF displayed enhanced steady-state levels of IL-1ra mRNA in comparison with cells aged in medium. Stimulation of in vitro-derived macrophages aged for 6 days in medium or in GM-CSF, with LPS or adherent IgG, did not result in increased levels of IL-1ra protein production in comparison with non-LPS stimulated cells. The IL-1ra protein detected in the supernatants of cells differentiated in GM-CSF was biologically active in the IL-1-augmented murine thymocyte proliferation assay. By Western blot analysis, the IL-1ra protein in the in vitro-derived macrophage supernatants was predominantly the 22- to 24-kDa glycosylated species, whereas the lysates contained additional lower molecular weight forms. These results suggest that as monocytes differentiate in vitro into macrophages, they constitutively produce IL-1ra protein and that this production is enhanced by the continuous presence of GM-CSF.
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Bevan, S., and J. G. Raynes. "IL-1 receptor antagonist regulation of acute phase protein synthesis in human hepatoma cells." Journal of Immunology 147, no. 8 (October 15, 1991): 2574–78. http://dx.doi.org/10.4049/jimmunol.147.8.2574.
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Abstract The hepatoma cell line HuH-7 has recently been shown to synthesize serum amyloid A (SAA) in response to IL-1. IL-1 receptor antagonist (IL-1Ra) was able to completely inhibit the response of SAA to IL-1 but not the increase seen in response to IL-6. IL-1Ra was equally effective at inhibiting IL-1 alpha or IL-1 beta. At a 10-fold molar excess of IL-1Ra over IL-1 there was complete inhibition of the SAA response. Removal of IL-1 at 24 h rapidly reduced the SAA secreted over the next 24 h. Addition of IL-1Ra to the cells at this time was as effective as removal of IL-1 at inhibiting the subsequent secretion of SAA. IL-1Ra was less effective at inhibition of IL-1-induced haptoglobin secretion. We would conclude that IL-1Ra may play an important role in the regulation of acute phase protein synthesis.
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Liu, Judy S. H., Terry D. Amaral, Celia F. Brosnan, and Sunhee C. Lee. "IFNs Are Critical Regulators of IL-1 Receptor Antagonist and IL-1 Expression in Human Microglia." Journal of Immunology 161, no. 4 (August 15, 1998): 1989–96. http://dx.doi.org/10.4049/jimmunol.161.4.1989.
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Abstract Because IL-1 is implicated in the pathogenesis of multiple sclerosis, and IFNs are known to alter disease course, we sought to determine whether IFNs can regulate the expression of IL-1 and IL-1R antagonist (IL-1Ra) in primary cultures of human microglia and astrocytes. We found that IL-1 and IL-1Ra are products of microglia but not astrocytes, and IFN-β and IFN-γ differentially modulate LPS- and cytokine-induced IL-1 and IL-1Ra. IFN-β induces IL-1Ra and augments LPS- and IL-4-induced IL-1Ra, but suppresses LPS- and IL-1-induced IL-1, shifting the balance toward the expression of the IL-1Ra. Like IFN-β, IFN-γ suppresses the expression of both LPS and IL-1-induced IL-1β. However, IFN-γ also suppresses the expression of IFN-β- and IL-4-induced IL-1Ra so that IFN-γ may enhance or suppress IL-1 activity depending on the other cytokines present. IL-4 has similar effects to IFN-β; however, other anti-inflammatory cytokines, did not regulate IL-1 or IL-1Ra in human microglia. Our data demonstrate a novel suppressive effect of IFN-β and IL-4 on IL-1 activity in human microglia, suggesting that IFN-β, a therapeutic agent used for multiple sclerosis, could have wider applications in the treatment of other central nervous system disorders in which IL-1 activity has been implicated in the pathogenesis.
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Sherry, Christina L., Stephanie S. Kim, and Gregory G. Freund. "Accelerated Recovery from Acute Hypoxia in Obese Mice Is Due to Obesity-Associated Up-Regulation of Interleukin-1 Receptor Antagonist." Endocrinology 150, no. 6 (February 12, 2009): 2660–67. http://dx.doi.org/10.1210/en.2008-1622.
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The proinflammatory consequences of obesity are thought to be due, in part, to macrophage infiltration into adipose tissue. There are, however, potential antiinflammatory consequences of obesity that include obesity-associated up-regulation of IL-1 receptor antagonist (IL-1RA). Here we show that obesity-associated up-regulation of IL-1RA speeds recovery from hypoxia. We found that high-fat diet-fed (HFD) mice recovered from acute hypoxia 5 times faster than normal-diet-fed (ND) mice. HFD mice had a 10-fold increase in serum IL-1RA when compared with ND mice. White adipose tissue (WAT) was a significant source of IL-RA, generating 330 ± 77 pg/mg protein in HFD mice as compared with 15 ± 5 pg/mg protein in ND mice. Peritoneal macrophages isolated from HFD mice showed little difference in IL-1RA production when compared with ND mice, but WAT macrophages from HFD mice generated 11-fold more IL-1RA than those from ND mice. When ND mice were given an ip transfer of the stromal vascular fraction portion of WAT from HFD mice, serum IL-1RA increased 836% and recovery from acute hypoxia was faster than in mice that did not receive a stromal vascular fraction transfer. To determine whether IL-1RA was important to this accelerated recovery, ND mice were administered exogenous IL-1RA prior to hypoxia, and their recovery matched that of HFD mice. Inversely, when IL-1RA was immunoabsorbed in HFD mice with IL-1RA antiserum, recovery from acute hypoxia was attenuated. Taken together these data demonstrate that HFD-induced obesity speeds recovery from hypoxia due to obesity-associated up-regulation of IL-1RA.
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Qiu, Bo, Ming Gong, Qi-Ting He, and Pang-Hu Zhou. "Controlled Release of Interleukin-1 Receptor Antagonist from Hyaluronic Acid-Chitosan Microspheres Attenuates Interleukin-1β-Induced Inflammation and Apoptosis in Chondrocytes." BioMed Research International 2016 (October 30, 2016): 1–12. http://dx.doi.org/10.1155/2016/6290957.
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This paper investigates the protective effect of interleukin-1 receptor antagonist (IL-1Ra) released from hyaluronic acid chitosan (HA-CS) microspheres in a controlled manner on IL-1β-induced inflammation and apoptosis in chondrocytes. The IL-1Ra release kinetics was characterized by an initial burst release, which was reduced to a linear release over eight days. Chondrocytes were stimulated with 10 ng/ml IL-1β and subsequently incubated with HA-CS-IL-1Ra microspheres. The cell viability was decreased by IL-1β, which was attenuated by HA-CS-IL-1Ra microspheres as indicated by an MTT assay. ELISA showed that HA-CS-IL-1Ra microspheres inhibited IL-1β-induced inflammation by attenuating increases in NO2- and prostaglandin E2 levels as well as increase in glycosaminoglycan release. A terminal deoxyribonucleotide transferase deoxyuridine triphosphate nick-end labeling assay revealed that the IL-1β-induced chondrocyte apoptosis was decreased by HA-CS-IL-1Ra microspheres. Moreover, HA-CS-IL-1Ra microspheres blocked IL-1β-induced chondrocyte apoptosis by increasing B-cell lymphoma 2 (Bcl-2) and decreasing Bcl-2-associated X protein and caspase-3 expressions at mRNA and protein levels, as indicated by reverse-transcription quantitative polymerase chain reaction and western blot analysis, respectively. The results of the present study indicated that HA-CS-IL-1Ra microspheres as a controlled release system of IL-1Ra possess potential anti-inflammatory and antiapoptotic properties in rat chondrocytes due to their ability to regulate inflammatory factors and apoptosis associated genes.
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Chakrabarti, Sudipta, Tim Prorok, Avik Roy, Dhruv Patel, Sridevi Dasarathi, and Kalipada Pahan. "Upregulation of IL-1 Receptor Antagonist by Aspirin in Glial Cells via Peroxisome Proliferator-Activated Receptor-Alpha." Journal of Alzheimer's Disease Reports 5, no. 1 (August 10, 2021): 647–61. http://dx.doi.org/10.3233/adr-210026.
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Background: Neuroinflammation is a recognized aspect of Alzheimer’s disease (AD) and other neurological illnesses. Interleukin 1 receptor antagonist (IL-1Ra) is an anti-inflammatory molecule, which inhibits inflammatory molecules in different cells including brain cells. However, mechanisms for upregulating IL-1Ra in brain cells are poorly understood. Objective: Since aspirin is a widely available pain reliever that shows promise beyond its known pain-relieving capacity, we examined whether aspirin could upregulate the IL-1Ra in the brain. Methods: We employed PCR, real-time PCR, western blot, immunostaining, chromatin immunoprecipitation (ChIP), and lentiviral transduction in glial cells. 5xFAD mice, an animal model of AD, were treated with aspirin orally via gavage. Results: Aspirin increased the expression of IL-1Ra mRNA and protein in primary mouse astrocytes and mouse BV-2 microglial cells. While investigating the mechanism, we found that the IL-1Ra gene promoter harbors peroxisome proliferator response element (PPRE) and that aspirin upregulated IL-1Ra in astrocytes isolated from peroxisome proliferator-activated receptor-beta knockout (PPARβ–/–), but not PPARα–/–, mice. Moreover, we observed that aspirin bound to tyrosine 314 residue of PPARα to stimulate IL-1Ra and that aspirin treatment also increased the recruitment of PPARα to the IL-1Ra promoter. Accordingly, aspirin increased IL-1Ra in vivo in the brain of wild type and PPARβ–/–, but not in PPARα–/– mice. Similarly, aspirin treatment also increased astroglial and microglial IL-1Ra in the cortex of 5xFAD, but not 5xFAD/PPARα–/– mice. Conclusion: Aspirin may reduce the severity of different neurological conditions by upregulating IL-1Ra and reducing the inflammation.
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Marsh, C. B., H. A. Pope, and M. D. Wewers. "Fc gamma receptor cross-linking down-regulates IL-1 receptor antagonist and induces IL-1 beta in mononuclear phagocytes stimulated with endotoxin or Staphylococcus aureus." Journal of Immunology 152, no. 9 (May 1, 1994): 4604–11. http://dx.doi.org/10.4049/jimmunol.152.9.4604.
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Abstract The cross-linking of monocyte Fc gamma R is a potent stimulus for IL-1ra production but does not induce IL-1 beta. However, during systemic infection, IgG-coated bacteria can activate mononuclear phagocytes via both cell wall components and opsonized IgG. Therefore, we analyzed the effect of combinations of Fc gamma R cross-linking and bacterial cell wall components on mononuclear phagocyte IL-1 beta and IL-1ra production. Human mononuclear cells and monocytes were cultured either alone or with combinations of immobilized IgG, LPS, or heat-killed Staphylococcus aureus (HKSA). Cells cultured on immobilized IgG released large amounts of IL-1ra but no detectable IL-1 beta. In response to LPS, mononuclear cells released IL-1ra at 1000-fold lower doses of LPS than was required to induce IL-1 beta. However, when measured in the presence of immobilized IgG, the LPS sensitivity for IL-1 beta release increased 100-fold, whereas IL-1ra release correlated inversely with the LPS dose. Furthermore, HKSA, a nonendotoxin stimulus, affected mononuclear cell IL-1 beta and IL-1ra release similarly. In addition, polymyxin B, a specific endotoxin inhibitor, blocked the LPS, but not the HKSA-induced changes in IL-1 beta and IL-1ra secretion, irrespective of immobilized IgG co-stimulation. In summary, these results suggest that mononuclear phagocyte stimulation with immobilized IgG favors IL-1ra over IL-1 beta production. Conversely, the addition of LPS or HKSA to the Fc gamma R-stimulated cells augments IL-1 beta but suppresses IL-1ra production.
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Casini-Raggi, V., L. Kam, Y. J. Chong, C. Fiocchi, T. T. Pizarro, and F. Cominelli. "Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation." Journal of Immunology 154, no. 5 (March 1, 1995): 2434–40. http://dx.doi.org/10.4049/jimmunol.154.5.2434.
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Abstract The etiology and pathogenesis of inflammatory bowel disease (IBD) are unknown. Increasing evidence supports the theory that chronic IBD is the result of dysfunctional immunoregulation manifested by an inappropriate production of mucosal cytokines. The aim of the present study was to test the hypothesis that a specific mucosal imbalance of IL-1 and IL-1 receptor antagonist (IL-1ra) production plays an important role in the perpetuation and chronicity of intestinal inflammation. Total IL-1, IL-1ra, and the IL-1ra/IL-1 ratio were measured in freshly isolated intestinal mucosal cells, as well as in mucosal biopsies obtained from control, Crohn's disease, and ulcerative colitis patients. IL-1 alpha, IL-1 beta, and IL-1 ra were measured by specific non-cross-reacting radioimmunoassays and ELISA. A markedly significant decrease in the intestinal mucosal IL-1ra/IL-1 ratio was found in both Crohn's disease and ulcerative colitis patients when compared with control subjects (p < 0.01). The IL-1ra/IL-1 ratio correlated closely with the clinical severity of disease (r = -0.7846, p < 0.001). Furthermore, the observed decrease in the IL-1ra/IL-1 ratio was specific for IBD because a decreased IL-1ra/IL-1 ratio was not found in patients with self-limiting colitis. These results support the hypothesis that an imbalance between IL-1 and IL-1ra production is of pathogenic importance in chronic inflammatory diseases, including IBD.
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McColl, S. R., R. Paquin, C. Ménard, and A. D. Beaulieu. "Human neutrophils produce high levels of the interleukin 1 receptor antagonist in response to granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha." Journal of Experimental Medicine 176, no. 2 (August 1, 1992): 593–98. http://dx.doi.org/10.1084/jem.176.2.593.
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Neutrophils, an abundant cell type at sites of inflammation, have the ability to produce a number of cytokines, including interleukin 1 (IL-1), IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNF-alpha). In this study, we have examined the ability of human neutrophils to produce the IL-1 receptor antagonist (IL-1Ra), a 17-23-kD protein recently isolated and cloned from macrophages. Since IL-1Ra has been shown to inhibit both the in vitro and in vivo effects of IL-1, its production by large numbers of tissue-invading neutrophils might provide a mechanism by which the effects of IL-1 are regulated in inflammation. Using antibodies that are specific for IL-1Ra and a cDNA probe encoding for this protein, we were able to show that neutrophils constitutively produce IL-1Ra. However, after activation by GM-CSF and TNF-alpha, IL-1Ra was secreted into the extracellular milieu where it constituted the major de novo synthesized product of activated neutrophils. None of a large array of other potent neutrophil agonists were found to affect the production of IL-1Ra by neutrophils. Quantitative measurements by enzyme-linked immunosorbent assay revealed that intracellular IL-1Ra is in eightfold excess of the amount secreted in supernatants when studying nonactivated neutrophils. However, in GM-CSF- and TNF-alpha-activated cells, this difference was reduced to values between four- and fivefold, as virtually all of the de novo synthesized IL-1Ra was secreted. In activated cells, the intracellular content of IL-1Ra was found to be in the 2-2.5-ng/ml range per 10(6) neutrophils, whereas levels reached the 0.5-ng/ml range in supernatants. This would imply that IL-1Ra is produced in excess of IL-1 by a factor of at least 100, an observation that is in agreement with the reported amounts of IL-1Ra needed to inhibit the proinflammatory effects of IL-1. Neutrophils isolated from an inflammatory milieu, the synovial fluid of patients with rheumatoid arthritis, were found to respond to GM-CSF and TNF-alpha in terms of IL-1Ra synthesis, indicating that the in vitro observations made in this study are likely to occur in an inflammatory setting in vivo.
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Chen, Hairong, Yang Zhao, and Hong Tang. "Role of interleukin-1 receptor antagonist in regulating specific Hepatitis B antibody production (IRM12P.646)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 133.5. http://dx.doi.org/10.4049/jimmunol.194.supp.133.5.
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Abstract While exogenous interleukin-1 beta was reported to facilitate antibody production, the function and mechanism of its conventional suppressor interleukin-1 receptor antagonist (IL-1Ra) in regulating specific antibody remain largely unknow. We showed that, upon aluminium-conjugated commercial hepatitis B surface antigen vaccination, hepatitis B antibody response was considerably amplified in IL-1Ra-/- mice, demonstrated by higher HBsAb level, increased germinal center and HBsAb secreting B cell numbers in dLN but not spleen. Mechanismly, IL-1 signalling pathway was, unexpectedly, found not to be involved in the process, evident by equivalent HBsAb titre in nalp3-/-, caspase-1-/- and IL-1R-/- mice as in wt. Surprisingly, the IL-17 production was amplified in IL-1Ra-/- mice, demonstrated by higher serum IL-17 level and higher number and frequency of IL-17 secreting cells in dLN of IL-1Ra-/- mice. Moreover, HBsAb level in IL1rn-/- x IL17-/- mice was comparable to that in wt mice, suggesting the essential role of IL-17 in regulating the elevated HBsAb level in IL-1Ra-/- mice. Furthermore, CD4 T cells was identified as the main source of IL-17 production in dLN of IL-1Ra-/- mice, indicating the essential role of IL-17 secreting CD4 T cells in upregulating HbsAb production. Therefore, the increased HBsAb production in IL-1Ra-/- was irrelevant to IL-1 pathway but dependend on evelated IL-17. We have thus proposed a novel mechanism of IL-1Ra in regulating specific antibody production.
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Wahl, S. M., G. L. Costa, M. Corcoran, L. M. Wahl, and A. E. Berger. "Transforming growth factor-beta mediates IL-1-dependent induction of IL-1 receptor antagonist." Journal of Immunology 150, no. 8 (April 15, 1993): 3553–60. http://dx.doi.org/10.4049/jimmunol.150.8.3553.
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Abstract Transforming growth factor-beta (TGF-beta) is a potent immunomodulatory molecule that promotes inflammation through recruitment of monocytes and induction of IL-1 and other cytokines. These proinflammatory processes may be modulated by the ability of TGF-beta to induce de novo synthesis and secretion of an IL-1 receptor antagonist (IL-1ra) that binds to and blocks IL-1 receptors. In this study, we show that the addition of TGF-beta to human peripheral blood monocytes induced the sequential transcription of the 1.8-kb mRNA for IL-1 beta and for IL-1ra. The expression of detectable mRNA and synthesis of IL-1 beta peptide routinely preceded that for IL-1ra, suggesting possible dependency of IL-1ra generation on IL-1 beta. Antibody to IL-1 blocked TGF-beta induction of IL-1ra mRNA expression demonstrating an unique IL-1-dependent induction of its own antagonist. Confirmatory evidence that IL-1 participates in the generation of IL-1ra was obtained when exogenously added IL-1 induced and, IL-1 receptor antagonist blocked, IL-1ra transcription. Thus, these data suggest that TGF-beta, after release at a site of inflammation, induces synthesis of IL-1 that participates in the initial cytokine cascade central to an inflammatory response, and then triggers the generation of its own natural inhibitor by autocrine or paracrine pathways. This TGF-beta-induced IL-1-dependent induction of IL-1ra may provide a negative feedback loop, thereby promoting the resolution of an inflammatory response.
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Gabay, C., B. Porter, G. Fantuzzi, and W. P. Arend. "Mouse IL-1 receptor antagonist isoforms: complementary DNA cloning and protein expression of intracellular isoform and tissue distribution of secreted and intracellular IL-1 receptor antagonist in vivo." Journal of Immunology 159, no. 12 (December 15, 1997): 5905–13. http://dx.doi.org/10.4049/jimmunol.159.12.5905.
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Abstract IL-1R antagonist (IL-1Ra) is a competitive inhibitor of the binding of IL-1 to IL-1R. IL-1Ra refers to two different proteins derived from the same gene by alternate splicing of two different first exons. One protein contains a leader sequence and is secreted (sIL-1Ra), whereas the other remains intracellular (icIL-1Ra). We describe the cloning of mouse icIL-1Ra cDNA, the expression of the recombinant mouse icIL-1Ra protein, and the tissue distribution of sIL-1Ra and icIL-1Ra mRNA and of icIL-1Ra protein in control and LPS-injected mice. As described in the human and the rabbit, mouse icIL-1Ra protein differs from mature mouse sIL-1Ra protein by seven amino acids at the amino terminus. In addition, human and mouse icIL-1Ra are 77% identical. Regulation of IL-1Ra isoforms was examined in normal mice and after LPS injection. Circulating levels were undetectable in control mice, but were strongly increased 4 h after LPS injection. Using a ribonuclease protection assay (RPA), we found that icIL-1Ra mRNA was expressed constitutively in skin and in LPS-stimulated RAW 264.7 murine macrophages. Consistent with the RNA studies, Western blot analysis showed that murine icIL-1Ra protein was constitutively expressed in skin and in LPS-stimulated RAW 264.7 cells. In contrast, sIL-1Ra mRNA was not detected by RPA in tissues of control mice, but was strongly up-regulated in the lung, spleen, and liver after LPS injection. Using RPA, primer extension assay and 5' rapid amplification of cDNA ends, we were able to demonstrate the presence of different transcription start sites for murine sIL-1Ra mRNA.
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Barton, Parrin T., Stefan Gerber, Daniel W. Skupski, and Steven S. Witkin. "Interleukin-1 Receptor Antagonist Gene Polymorphism, Vaginal Interleukin-1 Receptor Antagonist Concentrations, and Vaginal Ureaplasma urealyticum Colonization in Pregnant Women." Infection and Immunity 71, no. 1 (January 2003): 271–74. http://dx.doi.org/10.1128/iai.71.1.271-274.2003.
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ABSTRACT Ureaplasma urealyticum is the microorganism most frequently isolated from amniotic fluids of women in preterm labor. The relationship between vaginal colonization with U. urealyticum, vaginal interleukin-1 receptor antagonist (IL-1ra) levels, and the IL-1ra genotype in pregnant women was examined. Vaginal specimens, obtained with a cotton swab from 207 women in their first trimester of pregnancy, were tested for IL-1ra concentrations by enzyme-linked immunosorbent assay and for U. urealyticum and IL-1ra genotypes by PCR. U. urealyticum was detected in 85 (41.1%) women. The median IL-1ra level was 450 ng/ml in women positive for U. urealyticum, as opposed to 225 ng/ml in women negative for this microorganism (P < 0.0001). Sixty-two percent of the 16 women who were homozygous for allele 2 of the IL-1ra gene (IL-1RN*2) were colonized with U. urealyticum, as opposed to 47% of the 49 women who were IL-1RN*1/IL-1RN*2 heterozygotes and 34% of the 133 women who were IL-1RN*1 homozygotes (P < 0.05). Median IL-1ra levels were 750 ng/ml in IL-1RN*2 homozygotes, 300 ng/ml in IL-1RN*1/IL-1RN*2 heterozygotes, and 250 ng/ml in IL-1RN*1 homozygotes (P = 0.02). The vast majority of subjects had an uneventful pregnancy and delivered a healthy infant at term. The IL-1ra genotype or U. urealyticum colonization was unrelated to birth weight. Pregnant women who are colonized with U. urealyticum during the first trimester have elevated vaginal IL-1ra concentrations and a higher prevalence of the IL-1RN*2 homozygote genotype than do noncolonized women.
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Schrijver, Hans M., Jaco van As, J. Bart A. Crusius, Christien D. Dijkstra, and Bernard M. J. Uitdehaag. "Interleukin (IL)-1 gene polymorphisms: relevance of disease severity associated alleles with IL-1β and IL-1ra production in multiple sclerosis." Mediators of Inflammation 12, no. 2 (2003): 89–94. http://dx.doi.org/10.1080/0962933031000097691.
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Background:Multiple sclerosis (MS) is an autoimmune disorder, with a considerable genetic influence on susceptibility and disease course. Cytokines play an important role in MS pathophysiology, and genes encoding various cytokines are logical candidates to assess possible associations with MS susceptibility and disease course. We previously reported an association of a combination of polymorphisms in the interleukin (IL)-1Band IL-1 receptor antagonist(IL−1RN)genes (i.e.IL−1RNallele2+/IL−1B+3959allele 2−) with disease severity in MS. Extending this observation, we investigated whether IL-1β and IL-1ra production differed depending on carriership of this gene combination.Methods:Twenty MS patients and 20 controls were selected based upon carriership of the specific combination. In whole blood,in vitroIL-1β and IL-1ra production was determined by enzyme-linked immunosorbent-assay after 6 and 24 h of stimulation with lipopolysaccharide.Results:Carriers of the specific combination produced more IL-1ra, especially in MS patients, although not significantly. IL-1ra production was significantly higher in individuals homozygous forIL−1RNallele 2. In patients, Il-1ra production was higher and IL-1β production lower compared with controls. In primary progressive patients, the IL-1β /IL-1ra ratio was significantly lower than in relapsing-remitting patients.Conclusion:Our results suggest higher in vitro IL-1ra production in carriers ofIL−1RNallele 2, with an indication of an allelic dose-effect relationship.
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Almeida-Santiago, Cristina, Juan Carlos Quevedo-Abeledo, María Vanesa Hernández-Hernández, Antonia de Vera-González, Alejandra González-Delgado, Miguel Ángel González-Gay, and Iván Ferraz-Amaro. "Disease Activity Is More Associated with IL-1 Than with IL-6 in Patients with Rheumatoid Arthritis." Life 13, no. 1 (December 28, 2022): 82. http://dx.doi.org/10.3390/life13010082.
Full textAbstract:
Interleukin-1 receptor antagonist (IL-1ra) concentration reflects and is proportional to IL-1 production. Both IL-1 and IL-6 are involved in the pathogenesis of rheumatoid arthritis (RA). However, the relationship of serum levels of these two cytokines to each other in RA patients is not well-understood. In this study, our objective was to analyze the possible linear correlation between IL-1ra and IL-6 in patients with RA, and how both are related to the inflammatory activity of the disease. IL-6 and IL-1ra levels were measured in 407 patients with RA. Linear regression and partial correlations were conducted to analyze the relationship between both cytokines, and their association with RA characteristics. No correlation was found between serum levels of IL-6 and IL-1ra (Pearson’s r 0.031, p = 0.61). However, disease activity and acute phase reactants were positively and significantly associated with both cytokines. Nevertheless, after controlling for covariates, disease activity scores were more strongly associated with IL-1ra compared to IL-6. Circulating IL-6 and IL-1ra do not correlate with each other in RA patients. Although both are associated with disease activity and acute phase reactants, the relationship of disease activity to IL-1ra is greater than that to IL-6.