A role for IL-27 in early regulation of Th1 differentiation.
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-gamma-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.
Owaki
Toshiyuki
T
Intractable Immune System Disease Research Center, Tokyo Medical University, Japan.
Asakawa
Masayuki
M
Morishima
Noriko
N
Hata
Kikumi
K
Fukai
Fumio
F
Matsui
Masanori
M
Mizuguchi
Junichiro
J
Yoshimoto
Takayuki
T
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D007106:Immune Sera / Q000494:pharmacology; D007111:Immunity, Cellular / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D053762:Interleukin-12 Subunit p40; D007378:Interleukins / Q000008:administration & dosage / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D018106:CD28 Antigens; D017252:CD3 Complex; C486767:Il27 protein, mouse; D007106:Immune Sera; D053762:Interleukin-12 Subunit p40; D007378:Interleukins; D021122:Protein Subunits; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D007371:Interferon-gamma