IL-27 suppresses CD28-mediated [correction of medicated] IL-2 production through suppressor of cytokine signaling 3.
IL-27 is a novel IL-6/IL-12 family cytokine that not only plays a role in the early regulation of Th1 differentiation, but also exerts an inhibitory effect on immune responses, including the suppression of proinflammatory cytokine production. However, the molecular mechanism by which IL-27 exerts the inhibitory effect remains unclear. In this study we demonstrate that IL-27 inhibits CD28-mediated IL-2 production and that suppressor of cytokine signaling 3 (SOCS3) plays a critical role in the inhibitory effect. Although IL-27 enhanced IFN-gamma production from naive CD4+ T cells stimulated with plate-coated anti-CD3 and anti-CD28 in the presence of IL-12, IL-27 simultaneously inhibited CD28-mediated IL-2 production. Correlated with the inhibition, IL-27 was shown to augment SOCS3 expression. Analyses using various mice lacking a signaling molecule revealed that the inhibition of IL-2 production was dependent on STAT1, but not on STAT3, STAT4, and T-bet, and was highly correlated with the induction of SOCS3 expression. Similar inhibition of CD28-mediated IL-2 production and augmentation of SOCS3 expression by IL-27 were observed in a T cell hybridoma cell line, 2B4. Forced expression of antisense SOCS3 or dominant negative SOCS3 in the T cell line blocked the IL-27-inudced inhibition of CD28-mediated IL-2 production. Furthermore, pretreatment with IL-27 inhibited IL-2-mediated cell proliferation and STAT5 activation, although IL-27 hardly affected the induction level of CD25 expression. These results suggest that IL-27 inhibits CD28-mediated IL-2 production and also IL-2 responses, and that SOCS3, whose expression is induced by IL-27, plays a critical role in the inhibitory effect in a negative feedback mechanism.
Intractable Immune System Disease Research Center, Tokyo Medical University, Shinjuku, Tokyo, Japan.
Toshiyuki
T
Owaki
Masayuki
M
Asakawa
Sadahiro
S
Kamiya
Kiyoshi
K
Takeda
Fumio
F
Fukai
Junichiro
J
Mizuguchi
Takayuki
T
Yoshimoto
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation / Q000276:immunology; D025461:Feedback, Physiological / Q000276:immunology; D005786:Gene Expression Regulation / Q000502:physiology; D006825:Hybridomas; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D007378:Interleukins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*
D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; C486767:Il27 protein, mouse; D007376:Interleukin-2; D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins