IL-27 Blocks RORc Expression to Inhibit Lineage Commitment of Th17 Cells

Diveu, Caroline; McGeachy, Mandy J.; Boniface, Katia; Stumhofer, Jason S.; Sathe, Manjiri; Joyce-Shaikh, Barbara; Chen, Yi; Tato, Cristina M.; McClanahan, Terrill K.; Malefyt, René de Waal; Hunter, Christopher A.; Daniel, J.; Kastelein, Robert A.

doi:10.4049/jimmunol.0801162

Cited by 295 publications

(295 citation statements)

References 40 publications

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“…During inflammatory diseases and other protozoan infections, such as T. gondii and virulent strains of L. major, one function of IL-27 appears to be suppressing Th17 responses (16)(17)(18)(19)31). It is perhaps surprising, therefore, that we observed no differences in IL-17 responses, or in expression of ROR g t, between WT and WSX-1 2/2 mice during P. berghei NK65 infection.…”

Section: Discussioncontrasting

confidence: 50%

“…IL-27 exerts both proinflammatory and suppressive effects on T cells, augmenting Th1 polarization by the induction of T-bet and increasing expression of ICAM-1 and responsiveness to IL-12 (4,(8)(9)(10)(11)(12)(13), and suppressing CD4 + T cell proliferation and effector function, for example, via suppressor of cytokine signaling 3-dependent downregulation of CD28-mediated IL-2 production (14,15) or downregulation of the RORc/IL-17 pathway (16)(17)(18)(19). IL-27 also promotes the production of IL-10 by various effector CD4 + T cell populations, including Th1 and Th2 cells and CD4 + T cells polarized under Th17-inducing conditions (20)(21)(22)(23)(24)(25).…”

mentioning

confidence: 99%

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Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Findlay

Greig

Stumhofer

et al. 2010

The Journal of Immunology

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107

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Successful resolution of malaria infection requires induction of proinflammatory immune responses that facilitate parasite clearance; however, failure to regulate this inflammation leads to immune-mediated pathology. The pathways that maintain this immunological balance during malaria infection remain poorly defined. In this study, we demonstrate that IL-27R–deficient (WSX-1−/−) mice are highly susceptible to Plasmodium berghei NK65 infection, developing exacerbated Th1-mediated immune responses, which, despite highly efficient parasite clearance, lead directly to severe liver pathology. Depletion of CD4+ T cells—but not CD8+ T cells—prevented liver pathology in infected WSX-1−/− mice. Although WSX-1 signaling was required for optimal IL-10 production by CD4+ T cells, administration of rIL-10 failed to ameliorate liver damage in WSX-1−/− mice, indicating that additional, IL-10–independent, protective pathways are modulated by IL-27R signaling during malaria infection. These data are the first to demonstrate the essential role of IL-27R signaling in regulating effector T cell function during malaria infection and reveal a novel pathway that might be amenable to manipulation by drugs or vaccines.

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Section: Discussioncontrasting

confidence: 50%

mentioning

confidence: 99%

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Findlay

Greig

Stumhofer

et al. 2010

The Journal of Immunology

Self Cite

107

123

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“…These results are in line with a recent study showing that IL-27 inhibits the expansion of Th17 cells and required for up-regulation of IL-10 in CNS during EAE. 24 The data presented here suggest that endogenous production of IL-27 and IL-10 in the retina suppresses intraocular inflammation. However, endogenous production of IL-27 and IL-10 by retinal cells may not be the sole mechanism that limits expansion of auto-aggressive T cells in this immune privileged tissue.…”

Section: Stat1 Is Required For the Production Of Il-27 And Anti-inflamentioning

confidence: 84%

Retinal cells suppress intraocular inflammation (uveitis) through production of interleukin-27 and interleukin-10

Lee

Amadi-Obi

et al. 2011

Immunology

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Summary Neuronal or photoreceptor deficit observed in uveitis and multiple sclerosis derives in part from inability to control inflammatory responses in neuroretina or brain. Recently, IL‐27 was found to play a role in suppressing experimental autoimmune uveitis and experimental autoimmune encephalomyelitis, two animal models that share essential pathological features of human uveitis and multiple sclerosis, respectively. However, the mechanism by which interleukin‐27 (IL‐27) inhibits central nervous system (CNS) inflammation is not clear. In this study we have investigated mechanisms that mitigate or curtail intraocular inflammation (uveitis) and examined whether inhibitory effects of IL‐27 are mediated locally by neuroretinal cells or by regulatory T cells. We show here that microglia cells in the neuroretina constitutively secrete IL‐27 and its expression is up‐regulated during uveitis. We further show that photoreceptors constitutively express IL‐27 receptor and respond to IL‐27 signalling by producing anti‐inflammatory molecules, IL‐10 and suppressor of cytokine signalling 1 (SOCS1) through signal transducer and activator of transcription 1 (STAT1) ‐dependent mechanisms. Moreover, STAT1‐deficient mice produced reduced amounts of IL‐27, IL‐10 and SOCS1 and developed more severe uveitis. Surprisingly, IL‐10‐producing regulatory T cells had marginal roles in suppressing uveitis. These results suggest that suppression of intraocular inflammation might be mediated through endogenous production of IL‐27 and IL‐10 by retinal cells, whereas SOCS proteins induced by IL‐27 during uveitis may function to protect the neuroretinal cells from the toxic effects of pro‐inflammatory cytokines. Targeted delivery of IL‐27 into immune privileged tissues of the CNS may therefore be beneficial in the treatment of CNS inflammatory diseases, such as uveitis and multiple sclerosis.

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“…IL-27 was originally reported as cytokine promoting Th1 development and secretion of IFN-g (39,40). However, more recently IL-27 has been defined as an important anti-inflammatory mediator that can induce both Treg1 and Foxp3 + Tregs and additionally inhibit the induction of Th17 cells (34,41,42). Our results also show that the increase in IL-27 is followed by an upregulation of IL-10 and regulatory cell differentiation, which was inhibited after in vivo neutralization of IL-27.…”

Section: Discussionmentioning

confidence: 99%

IL-12p35 Subunit Contributes to Autoimmunity by Limiting IL-27–Driven Regulatory Responses

Vasconcellos

Carter²,

Rosser³

et al. 2011

The Journal of Immunology

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Contrasting results have emerged from studies performed using IL-12p35−/− mice. Animals lacking the IL-12p35 subunit can either be protected from or develop exacerbated autoimmune diseases, intracellular infections, and delayed-type hypersensitivity responses. In this study, we report that mice lacking the IL-12p35 subunit develop a significantly milder Ag-induced arthritis compared with wild-type (WT) mice. Lack of severe inflammation is accompanied by an increase in the mRNA levels of the Ebi-3 and p28 subunits and increased secretion of IL-27 and IL-10. This anti-inflammatory environment contributed to increased differentiation of regulatory T and B cells with intact suppressive function. Furthermore, IL-12p35−/− mice display reduced numbers of Th17 cells compared with WT arthritic mice. Neutralization of IL-27, but not the systemic administration of IL-12, restored inflammation and Th17 to levels seen in WT mice. The restoration of disease phenotype after anti–IL-27 administration indicates that the IL-12p35 subunit acts as negative regulator of the developing IL-27 response in this model of arthritis.

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IL-27 Blocks RORc Expression to Inhibit Lineage Commitment of Th17 Cells

Cited by 295 publications

References 40 publications

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Retinal cells suppress intraocular inflammation (uveitis) through production of interleukin-27 and interleukin-10

IL-12p35 Subunit Contributes to Autoimmunity by Limiting IL-27–Driven Regulatory Responses

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