Two-sided roles of IL-27: induction of Th1 differentiation on naive CD4+ T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4+ T cells partially through STAT3-dependent mechanism.
Recent lines of evidence have demonstrated that IL-27, a newly identified IL-12-related cytokine, has two apparently conflicting roles in immune responses: one as an initiator of Th1 responses and the other as an attenuator of inflammatory cytokine production. Although the IL-27-mediated Th1 initiation mechanism has been elucidated, little is known about the molecular basis for the suppression of cytokine production. In the present study, we demonstrated that IL-27 suppressed the production of various proinflammatory cytokines by fully activated CD4+ T cells while it had no effect on the cytokine production by CD4+ T cells at early phases of activation. IL-27 also suppressed IL-17 production by activated CD4+ T cells, thereby counteracting IL-23, another IL-12-related cytokine with proinflammatory effects. In fully activated CD4+ T cells, STAT3 was preferentially activated by IL-27 stimulation, whereas both STAT1 and 3 were activated by IL-27 in early activated CD4+ T cells. Lack of STAT3 in fully activated cells impaired the suppressive effects of IL-27. These data indicated that the preferential activation of STAT3 in fully activated CD4+ T cells plays an important role in the cytokine suppression by IL-27/WSX-1.
Yoshimura
Takeru
T
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation and Department of Opthalmology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan.
Takeda
Atsunobu
A
Hamano
Shinjiro
S
Miyazaki
Yoshiyuki
Y
Kinjyo
Ichiko
I
Ishibashi
Tatsuro
T
Yoshimura
Akihiko
A
Yoshida
Hiroki
H
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000502:physiology*; D007378:Interleukins / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D018121:Receptors, Cytokine / Q000502:physiology; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology*
D016207:Cytokines; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor