IL-27 Limits IL-2 Production during Th1 Differentiation

Abstract

Although the ability of IL-27 to promote T cell responses is well documented, the anti-inflammatory properties of this cytokine remain poorly understood. The current work demonstrates that during infection with Toxoplasma gondii, IL-27R-deficient mice generate aberrant IL-2 responses that are associated with the development of a lethal inflammatory disease. Because in vivo depletion of IL-2 prolongs the survival of infected IL-27R−/− mice, these data suggest that IL-27 curbs the development of immunopathology by limiting parasite-induced IL-2 production. Consistent with this hypothesis, IL-27R−/− CD4+ T cells produce more IL-2 than wild-type counterparts during in vitro differentiation, and when rIL-27 is introduced, it can suppress the expression of IL-2 mRNA and protein by the latter group. Additionally, these studies reveal that, like IL-27, IL-12 can inhibit IL-2 production, and although each employs distinct mechanisms, they can synergize to enhance the effect. In contrast, this property is not shared by closely related cytokines IL-6 and IL-23. Thus, while traditionally viewed as proinflammatory agents, the present findings establish that IL-27 and IL-12 cooperate to limit the availability of IL-2, a potent T cell growth and survival factor. Moreover, because the current studies demonstrate that both can induce expression of suppressor of cytokine signaling 3, a protein that tempers cytokine receptor signaling, they also suggest that IL-27 and IL-12 share additionally inhibitory properties.

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

“…On the contrary, given that there is abundant evidence that the pathology of malaria infections is mediated by inflammatory cytokine such as IFN-g and TNF-a (reviewed in Refs. 1 and 2), it was very surprising that singular or combined neutralization of IFN-g or TNF-a had no effect on the liver pathology of infected WSX-1 2/2 mice, although this is in agreement with a previous study where administration of anti-IFN-g did not affect the outcome of T. gondii infection (15). Alternatively, WSX-1 2/2 CD4 + T cells may mediate their damaging effects on hepatocytes directly via FAS-FAS ligand or CD154-CD40 interactions and/or by the production of proteases (39)(40)(41).…”

“…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).…”

General Nature of the STAT3-Activated Anti-Inflammatory Response

“…Rather, excessive production of IL-12 and TNF-␣ is strongly linked to faster death of WSX-1 Ϫ/Ϫ mice compared with control mice. Similarly, large increases in systemic cytokines were observed in WSX-1 Ϫ/Ϫ mice infected with T. cruzi or Leishmania donovani (50, 52) and similar increases in cytokine production from T cells were also observed (53,54). These examples appear to be an IL-10-independent AIR and support the concept that the STAT3-regulated AIR could be used in diverse settings.…”

STAT3 Is Indispensable to IL-27-Mediated Cell Proliferation but Not to IL-27-Induced Th1 Differentiation and Suppression of Proinflammatory Cytokine Production

“…These results may presumably imply a role of STAT3 in IL-27-induced cell proliferation. In addition, because one of the IL-27R subunits is the common gp130, and IL-27 can activate STAT3 and induce the suppressor of cytokine signaling (SOCS)-3 expression (19,20), the possibility that IL-27 induces anti-inflammatory response in a mechanism similar to the IL-10-induced STAT3-mediated one was discussed previously (21,22). However, the precise role of STAT3 and its molecular mechanism in not only IL-27-induced cell proliferation but also IL-27-induced anti-inflammatory response remain to be elucidated.…”