A Role for IL-27 in Early Regulation of Th1 Differentiation

Abstract

IL-27 is a novel IL-6/IL-12 family cytokine that is considered to play a role in Th1 differentiation, whereas the exact role of IL-27 in Th1 differentiation and its molecular mechanism remain unclear. In this study we demonstrate a role for IL-27 in the early regulation of Th1 differentiation and its possible molecular mechanism. The ability of IL-27 to induce Th1 differentiation was most prominent under Th1-polarizing conditions, but without IL-12 in a STAT4- and IFN-γ-independent manner, and was overruled by IL-12 dose dependently. IL-27 rapidly up-regulated the expression of ICAM-1 on naive CD4+ T cells, but not on APCs, and blocking Abs against ICAM-1 and LFA-1 inhibited the IL-27-induced Th1 differentiation. Although IL-27 augmented T-bet expression in naive CD4+ T cells as previously reported, T-bet was not necessary for the IL-27-induced rapid up-regulation of ICAM-1 expression and Th1 differentiation. In contrast, STAT1 was revealed to be required for the rapid up-regulation of ICAM-1 expression and Th1 differentiation by directly mediating the transcriptional enhancement of ICAM-1 gene expression. These results indicate that IL-27 efficiently induces Th1 differentiation under Th1-polarizing conditions, but without IL-12, and that the rapid up-regulation of ICAM-1 expression on naive CD4+ T cells is important for the IL-27-induced Th1 differentiation. Considering that IL-27 is produced from macrophages and DCs earlier than IL-12, the present results suggest that IL-27 may play a pivotal role in early efficient induction of Th1 differentiation until sufficient IL-12 is produced.

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

“…In addition, IL-27-induced STAT3 activation was mediated through four Tyr residues in the YXXQ motif of the cytoplasmic region of gp130 as in the case of IL-6 (38). These results are consistent with our previous results using STAT1-deficient mice, showing that STAT1 activation is important for IL-27-induced augmentation of Th1 differentiation but not for IL-27-induced cell proliferation (6,8).…”

“…We recently demonstrated that IL-27 differentiates naive CD4 ϩ T cells into Th1 cells under Th1 polarizing conditions but without IL-12 via two distinct pathways. One is to rapidly up-regulate ICAM-1 expression followed by ERK1/2 activation through ICAM-1/LFA-1 interaction (8), and the other is to augment T-bet expression through p38 MAPK activation (9). Several previous studies using mice lacking one of the IL-27R subunits, T cell cytokine receptor (10)/ WSX-1 (11), revealed that IL-27 plays multiple roles including positive and negative regulation of immune responses (12,13).…”

“…We previously investigated the role of STAT1 in IL-27-mediated immune responses using STAT1-deficient naive CD4 ϩ T cells, and demonstrated that STAT1 is critically important for IL-27-induced augmentation of ICAM-1, T-bet, and IL-12R␤2 expression, synergistic primary IFN-␥ production with IL-12, and consequent Th1 differentiation (6,8). In contrast, STAT1 was revealed to not be required for IL-27-induced activation of STAT3 and cell proliferation (6).…”

“…No significant difference was observed between STAT3 ϩ/ϩ and STAT3 Ϫ/Ϫ . IL-12, and Th1 differentiation, which were previously demonstrated to be mediated by STAT1 using STAT1-deficient mice (6,8). Wild-type and STAT3-deficient naive CD4 ϩ T cells were stimulated with plate-coated anti-CD3 and anti-CD28 in the presence or absence of IL-27 and/or IL-12 for 16 and/or 48 h and analyzed for expression of ICAM-1 ( Fig.…”

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

“…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).…”