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STAT 4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation
Author(s) -
Zhang Yanan S,
Xin Dazhuan E,
Wang Zhizhang,
Song Xinyang,
Sun Yanyun,
Zou Quanli C,
Yue Jichen,
Zhang Chenxi,
Zhang Junxun M,
Liu Zhi,
Zhang Xiaoren,
Zhao Ting C,
Su Bing,
Chin Y Eugene
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899595
Subject(s) - leukemia inhibitory factor , biology , stat , inflammation , leukemia inhibitory factor receptor , leukemia , cancer research , immunology , interleukin 6 , signal transduction , pharmacology , stat3 , biochemistry
T helper 17 (Th17)‐cell differentiation triggered by interleukin‐6 ( IL ‐6) via STAT 3 activation promotes inflammation in inflammatory bowel disease ( IBD ) patients. However, leukemia inhibitory factor ( LIF ), an IL ‐6 family cytokine, restricts inflammation by blocking Th17‐cell differentiation via an unknown mechanism. Here, we report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells ( IEC s) in a mouse colitis model. LIF greatly activates STAT 4 phosphorylation on multiple SPXX elements within the C‐terminal transcription regulation domain. STAT 4 and STAT 3 act reciprocally on both canonical cis‐inducible elements ( SIE s) and noncanonical “ AGG ” elements at different loci. In lamina propria lymphocytes ( LPL s), STAT 4 activation by LIF blocks STAT 3‐dependent Il17a/Il17f promoter activation, whereas in IEC s, LIF bypasses the extraordinarily low level of STAT 4 to induce YAP gene expression via STAT 3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, serves as a potential therapy for IBD .