A Role for IL-27 in Early Regulation of Th1 Differentiation

• Published in: The Journal of immunology (1950) 2005-08, Vol.175 (4), p.2191-2200
• Main Authors: Owaki, Toshiyuki, Asakawa, Masayuki, Morishima, Noriko, Hata, Kikumi, Fukai, Fumio, Matsui, Masanori, Mizuguchi, Junichiro, Yoshimoto, Takayuki
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells - immunology; CD28 Antigens - immunology; CD3 Complex - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Line, Tumor; Immune Sera - pharmacology; Immunity, Cellular - genetics; Intercellular Adhesion Molecule-1 - biosynthesis; Intercellular Adhesion Molecule-1 - genetics; Interferon-gamma - deficiency; Interferon-gamma - genetics; Interferon-gamma - physiology; Interleukin-12 - deficiency; Interleukin-12 - genetics; Interleukin-12 - physiology; Interleukin-12 Subunit p40; Interleukins - administration & dosage; Interleukins - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Protein Subunits - deficiency; Protein Subunits - genetics; Protein Subunits - physiology; Resting Phase, Cell Cycle - immunology; Th1 Cells - cytology; Th1 Cells - immunology; Th1 Cells - metabolism; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.175.4.2191

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.