STAT3 is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Th1 differentiation and suppression of proinflammatory cytokine production.
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-12Rbeta2 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.
Owaki
Toshiyuki
T
Intractable Immune System Disease Research Center, Department of Immunology, Tokyo Medical University, Tokyo, Japan.
Asakawa
Masayuki
M
Morishima
Noriko
N
Mizoguchi
Izuru
I
Fukai
Fumio
F
Takeda
Kiyoshi
K
Mizuguchi
Junichiro
J
Yoshimoto
Takayuki
T
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D007378:Interleukins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D021122:Protein Subunits / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D016207:Cytokines; C486767:Il27 protein, mouse; D018836:Inflammation Mediators; D007378:Interleukins; D021122:Protein Subunits; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse