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

Abstract

IL-27, a member of the IL-6/IL-12 family, activates both STAT1 and STAT3 through its receptor, which consists of WSX-1 and gp130 subunits, resulting in augmentation of Th1 differentiation and suppression of proinflammatory cytokine production. In the present study, we investigated the role of STAT3 in the IL-27-mediated immune functions. IL-27 induced phosphorylation of STAT1, -2, -3 and -5 in wild-type naive CD4+ T cells, but failed to induce that of STAT3 and STAT5 in STAT3-deficient cohorts. IL-27 induced not only proinflammatory responses including up-regulation of ICAM-1, T-box expressed in T cells, and IL-12Rβ2 and Th1 differentiation, but also anti-inflammatory responses including suppression of proinflammatory cytokine production such as IL-2, IL-4, and IL-13 even in STAT3-deficient naive CD4+ T cells. In contrast, IL-27 augmented c-Myc and Pim-1 expression and induced cell proliferation in wild-type naive CD4+ T cells but not in STAT3-deficient cohorts. Moreover, IL-27 failed to activate STAT3, augment c-Myc and Pim-1 expression, and induce cell proliferation in pro-B BaF/3 transfectants expressing mutant gp130, in which the putative STAT3-binding four Tyr residues in the YXXQ motif of the cytoplasmic region was replaced by Phe. These results suggest that STAT3 is activated through gp130 by IL-27 and is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Th1 differentiation and suppression of proinflammatory cytokine production. Thus, IL-27 may be a cytokine, which activates both STAT1 and STAT3 through distinct receptor subunits, WSX-1 and gp130, respectively, to mediate its individual immune functions.

Antiproliferative Activity of IL-27 on Melanoma

“…We, and others, previously demonstrated that IL-27 can augment the proliferation of naive CD4 ϩ T cells (1,6). Our preliminary data suggest that activation of gp130/STAT3 signaling is important for the IL-27-induced proliferation (48). In contrast, WSX-1-deficient T cells were reported to show enhanced proliferation, indicating that WSX-1 signaling has an inhibitory effect on T cell proliferation (5,49).…”

Signaling Events Involved in Interleukin 27 (IL-27)-induced Proliferation of Human Naive CD4+ T Cells and B Cells

“…In human B cells, differential response to IL-27 was observed in naive and memory B cells, despite similar levels of IL-27 receptor expression (8). In mice, the differential effect of IL-27 on cytokine production in naive versus effector CD4 ϩ T cells was associated with down-regulation of gp130 and up-regulation of IL-27R␣ in effector CD4 ϩ T cells (24). Surprisingly, although IL-27R␣ is assumed to contribute preferentially to STAT1 activation and gp130 to STAT3 activation, a stronger activation of STAT3 over STAT1 was observed in effector CD4…”

“…Whereas only STAT5 was activated at higher levels in naive than memory CD4 ϩ T cells, activation of STAT1, 3 and 5 as well was more prolonged in naive than memory CD4 ϩ T cells. This sustained activation of STAT molecules, in particular that of STAT3, known to be important for IL-27-mediated proliferation (24), and possibly that of STAT5 also known to regulate T cell proliferation, may be responsible for the stronger proliferative response of naive CD4…”

“…In the IL-27 receptor, IL-27R␣ has been shown to constitutively interact with Jak1 and contribute to STAT1 activation, while gp130 that constitutively interacts with Jak1, Jak2, and Tyk2, contributes to STAT3 activation (20,23,24). By using murine T cells specifically deficient for either STAT1 or STAT3, STAT3 was shown to be indispensable for IL-27 proliferative effect on murine naive CD4 ϩ T cells, whereas STAT1 was found to be dispensable (22,24). In addition to Jak/STAT pathway, p38 and erk1/2 MAPKs have been shown to be activated by IL-27 in murine naive CD4…”

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

“…Encounters that produce longstanding cellular immunity induce a balanced cytokine milieu, using both stimulatory (STAT1) and suppressive (STAT3) signaling pathways. IL-27 is a member of the IL-12 family of cytokines and, via its signaling through both STAT1 and STAT3 (8)(9)(10)(11)(12), contributes to a spectrum of T-cell functions and phenotypes.…”