Cutting Edge: A Key Pathogenic Role of IL-27 in T Cell- Mediated Hepatitis

Siebler, Juergen; Wirtz, Stefan; Frenzel, Christian; Schuchmann, Marcus; Lohse, Ansgar W.; Galle, Peter R.; Neurath, Markus F.

doi:10.4049/jimmunol.180.1.30

Cited by 38 publications

(51 citation statements)

References 19 publications

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“…In IL-27R-deficient mice, the hyper-production of various proinflammatory cytokines was reported, concomitant with severe inflammation in affected organs (16-18, 25, 49-52). Furthermore, the study of Siebler et al demonstrated that IL-27 acted very early in a ConA model of Th1-cell-mediated liver injury, in agreement with the pro-Th1 activity of IL-27 (1,19). We have shown that our IL-27 antagonist can moderate liver inflammation by down-regulating the synthesis of CXCR3 ligands, as well as a subset of acute-phase proteins.…”

Section: Resultssupporting

confidence: 82%

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IL-27 structural analysis demonstrates similarities with ciliary neurotrophic factor (CNTF) and leads to the identification of antagonistic variants

Rousseau

Basset

Froger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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IL-27, consisting of the subunits IL-27p28 and Epstein–Barr virus-induced gene 3 (EBI3), is a heterodimeric cytokine belonging to the IL-6/IL-12 family of cytokines. IL-27p28 is a four-helical cytokine requiring association with the soluble receptor EBI3 to be efficiently secreted and functionally active. Computational and biological analyses of the IL-27 binding site 1 to its receptor revealed important structural proximities with the ciliary neurotrophic factor group of cytokines and highlighted the contribution of p28 Trp 97 , as well as of EBI3 Phe 97 , Asp 210 , and Glu 159 , as key residues in the interactions between both cytokine subunits. WSX-1 (IL-27R) and gp130 compose the IL-27 receptor-signaling complex, recruiting the STAT-1 and STAT-3 pathways. A study of IL-27 binding site 3 showed that Trp 197 was crucial for the cytokine's interaction with gp130, but that the mutated cytokine still recognized IL-27R on the cell surface. IL-27 exerts both pro- and anti-inflammatory functions, promoting proliferation and differentiation of Th1 and inhibiting Th17 differentiation. Our results led us to develop mutated forms of human and mouse IL-27 with antagonistic activities. Using an in vivo mouse model of concanavalin A-induced Th1-cell–mediated hepatitis, we showed that the murine IL-27 antagonist W195A decreased liver inflammation by downregulating the synthesis of CXCR3 ligands and several acute phase proteins. Together, these data suggest that IL-27 antagonism could be of interest in down-modulating acute IL-27–driven Th1-cell–mediated immune response.

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Section: Resultssupporting

confidence: 82%

“…Similarly, IL-27 can control parasitemia by suppressing Th2 responses through the STAT-1-mediated down-regulation of GATA-3 expression (14). Recently, IL-27 has been associated with T cell-mediated hepatitis in an acute liver injury model (19).…”

mentioning

confidence: 99%

IL-27 structural analysis demonstrates similarities with ciliary neurotrophic factor (CNTF) and leads to the identification of antagonistic variants

Rousseau

Basset

Froger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Marked differences have been observed between mice deficient in EBI3 and WSX-1. EBI3 Ϫ/Ϫ mice are protected from Con A-induced liver injury, whereas WSX-1 Ϫ/Ϫ mice showed exacerbated hepatitis (19,20). Similarly, naive T cells from WSX-1 Ϫ/Ϫ and EBI3 Ϫ/Ϫ mice showed opposites phenotypes with respect to IFN-␥ production (5,21).…”

mentioning

confidence: 91%

The IL-27 p28 Subunit Binds Cytokine-Like Factor 1 to Form a Cytokine Regulating NK and T Cell Activities Requiring IL-6R for Signaling

Crabé

Guay-Giroux

Tormo

et al. 2009

The Journal of Immunology

125

142

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IL-27 is formed by the association of a cytokine subunit, p28, with the soluble cytokine receptor EBV-induced gene 3 (EBI3). The IL-27R comprises gp130 and WSX-1. The marked difference between EBI3−/− and WSX-1−/− mice suggests that p28 has functions independent of EBI3. We have identified an alternative secreted complex formed by p28 and the soluble cytokine receptor cytokine-like factor 1 (CLF). Like IL-27, p28/CLF is produced by dendritic cells and is biologically active on human NK cells, increasing IL-12- and IL-2-induced IFN-γ production and activation marker expression. Experiments with Ba/F3 transfectants indicate that p28/CLF activates cells expressing IL-6Rα in addition to the IL-27R subunits. When tested on CD4 and CD8 T cells, p28/CLF induces IL-6Rα-dependent STAT1 and STAT3 phosphorylation. Furthermore, p28/CLF inhibits CD4 T cell proliferation and induces IL-17 and IL-10 secretion. These results indicate that p28/CLF may participate in the regulation of NK and T cell functions by dendritic cells. The p28/CLF complex engages IL-6R and may therefore be useful for therapeutic applications targeting cells expressing this receptor. Blocking IL-6R using humanized mAbs such as tocilizumab has been shown to be beneficial in pathologies like rheumatoid arthritis and juvenile idiopathic arthritis. The identification of a new IL-6R ligand is therefore important for a complete understanding of the mechanism of action of this emerging class of immunosuppressors.

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“…In fact, the available evidence show that IL-27 suppresses inflammation in Leishmania donovani infection 83 , intraocular inflammation 84 , chronic inflammation of the central nervous system 85 , autoimmune arthritis 86 , experimental autoimmune encephalitis 87 , and allergic asthma 88 . In contrast, it promotes inflammation in systemic sclerosis 89 , experimental crescentic glomerulonephritis 90 , experimental colitis 91 , and hepatitis 92 .…”

Section: Il-27mentioning

confidence: 99%

Innate Immunity in Coronary Disease. The Role of Interleukin-12 Cytokine Family in Atherosclerosis

Posadas-Sánchez

Vargas‐Alarcón

2018

RIC

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Atherosclerosis is a chronic, progressive, and multifactorial disease modulated by genetic and environmental factors. In recent years, the paradigm that explained atherosclerosis as resulting from a complex interaction between factors not accessible to medical intervention, and modifiable risk factors has changed. In this paradigm, alterations in lipid metabolism were the pivotal concept of atherosclerosis as a chronic degenerative disease. In the last years, an increasing number of observations have shown that the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall significantly influence atherosclerosis. Currently, it is well recognized that the pathogenesis of atherosclerosis and its complications involves the inflammatory process, which includes the participation of several cytokines. Besides the classic cytokines involved in this process, the role of the interleukin-12 (IL-12) family has been recently demonstrated. This review describes our current understanding about the role of the family of IL-12 in atherosclerosis considering the participation of the genes that encode these cytokines in the genetic susceptibility to developing this disease.

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Cutting Edge: A Key Pathogenic Role of IL-27 in T Cell- Mediated Hepatitis

Cited by 38 publications

References 19 publications

IL-27 structural analysis demonstrates similarities with ciliary neurotrophic factor (CNTF) and leads to the identification of antagonistic variants

IL-27 structural analysis demonstrates similarities with ciliary neurotrophic factor (CNTF) and leads to the identification of antagonistic variants

The IL-27 p28 Subunit Binds Cytokine-Like Factor 1 to Form a Cytokine Regulating NK and T Cell Activities Requiring IL-6R for Signaling

Innate Immunity in Coronary Disease. The Role of Interleukin-12 Cytokine Family in Atherosclerosis

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