STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

被引：39

作者：

Zhang, Yanan S. ^{[1
,2
,3
]}

Xin, Dazhuan E. ^{[3
]}

Wang, Zhizhang ^{[3
]}

Song, Xinyang ^{[4
]}

Sun, Yanyun ^{[3
]}

Zou, Quanli C. ^{[3
]}

Yue, Jichen ^{[1
,2
]}

Zhang, Chenxi ^{[3
]}

Zhang, Junxun M. ^{[3
]}

Liu, Zhi ^{[5
]}

Zhang, Xiaoren ^{[3
]}

Zhao, Ting C. ^{[6
]}

Su, Bing ^{[7
,8
]}

Chin, Y. Eugene ^{[1
,2
,3
]}

机构：

[1] Soochow Univ, Med Coll, Inst Biol, Suzhou, Jiangsu, Peoples R China

[2] Soochow Univ, Med Coll, Inst Med Sci, Suzhou, Jiangsu, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Shanghai, Peoples R China

[4] Harvard Med Sch, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA

[5] Salk Inst Biol Studies, Immunobiol & Microbial Pathogenesis Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA

[6] Boston Univ, Med Sch, Roger Williams Med Ctr, Dept Surg, Providence, RI USA

[7] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA

[8] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Immunol, Dept Immunol & Microbiol, Shanghai, Peoples R China

来源：

EMBO JOURNAL | 2019年 / 38卷 / 06期

基金：

中国国家自然科学基金;

关键词：

intestinal inflammation; intestinal repair; LIF; STAT4; Th17-cell differentiation; INNATE LYMPHOID-CELLS; ULCERATIVE-COLITIS; SIGNAL TRANSDUCER; DENDRITIC CELLS; LIF RECEPTOR; TH17; CELLS; T-CELLS; TRANSCRIPTION; EXPRESSION; CYTOKINE;

D O I：

10.15252/embj.201899595

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

T helper 17 (Th17)-cell differentiation triggered by interleukin-6 (IL-6) via STAT3 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 (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C-terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis-inducible elements (SIEs) and noncanonical "AGG" elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3-dependent Il17a/Il17f promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 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.

引用

页码：1 / 20

页数：20

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