STAT3 Regulates Cytokine-mediated Generation of Inflammatory Helper T Cells

• Published in: The Journal of biological chemistry Vol. 282; no. 13; pp. 9358 - 9363
• Main Authors: Yang, Xuexian O., Panopoulos, Athanasia D., Nurieva, Roza, Chang, Seon Hee, Wang, Demin, Watowich, Stephanie S., Dong, Chen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.03.2007; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Differentiation - genetics; Cell Differentiation - immunology; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Interferon-gamma - deficiency; Interferon-gamma - genetics; Interferon-gamma - physiology; Interleukin-6 - deficiency; Interleukin-6 - genetics; Interleukin-6 - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; STAT3 Transcription Factor - metabolism; STAT3 Transcription Factor - physiology; T-Lymphocytes, Helper-Inducer - metabolism; T-Lymphocytes, Helper-Inducer - pathology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C600321200

Interleukin-17 (IL-17)-producing helper T (TH) cells, named as THIL-17, TH17, or inflammatory TH (THi), have been recently identified as a novel effector lineage. However, how cytokine signals mediate THi differentiation is unclear. We found that IL-6 functioned to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi generation. STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development. A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly impaired in STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor γ-T (RORγt), a THi-specific transcriptional regulator; STAT3 deficiency impaired RORγt expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3). Our data thus demonstrate a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression.