ETS-1 facilitates Th1 cell-mediated mucosal inflammation in inflammatory bowel diseases through upregulating CIRBP: Role of ETS-1 and CIRBP in IBD

Qiong He, Han Gao, Yun Li Chang, Xiaohan Wu, Ritian Lin, Gengfeng Li, Jian Lin, Huiying Lu, Huimin Chen, Zhitao Li, Yingzi Cong, Jun Yao, Zhanju Liu

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Background & aims: As a susceptibility gene for human inflammatory bowel diseases (IBD), how avian erythroblastosis virus E26 oncogene homolog-1 (ETS-1) modulates intestinal mucosal immune response remains unclear. Here we studied the potential roles of ETS-1 in the pathogenesis of IBD. Methods: ETS-1 expression was examined in IBD patients. CD45RBhighCD4+ T cell-transfer colitis, dextran sulfate sodium (DSS)-induced colitis, and azomethane (AOM)/DSS-induced colitis-associated cancer (CAC) models were constructed to probe the function of ETS-1 in vivo. RNA-sequencing of CD4+ T cells from Ets-1 transgenic (Tg) mice was performed to decipher the key differentially expressed genes. Adenovirus transduction was conducted to verify the therapeutic potentials of ETS-1 in vivo. Results: ETS-1 expression was significantly increased in CD4+ T cells from active IBD patients compared with healthy controls, which was upregulated by TNF-α but markedly suppressed by anti-TNF-α mAb therapy. More severe colitis was observed in Rag1−/− mice reconstituted with Ets-1TgCD45RBhighCD4+ T cells or in Ets-1 Tg mice after DSS exposure compared with controls, characterized by higher TNF-α and IFN-γ expression in inflamed colon. Ets-1 Tg mice were more prone to develop AOM/DSS-induced CAC, and bone marrow chimeras further proved that lamina propria immune cells but not intestinal epithelial cells contributed to the development of colitis. RNA-sequencing and luciferase analysis revealed cold-inducible RNA-binding protein (CIRBP) as a functional target of ETS-1 to promote Th1 cell-driven immune response. Consistently, intraperitoneal administration of adenovirus-m-cirbp-shRNA ameliorated trinitrobenzene sulfonic acid (TNBS)-induced colitis of Ets-1 Tg mice. Conclusions: Our data identify that ETS-1 is highly expressed in IBD patients and promotes Th1-driven mucosal inflammation through CIRBP. CIRBP may serve as a novel therapeutic target for treatment of human IBD.

Original languageEnglish (US)
Article number102872
JournalJournal of Autoimmunity
Volume132
DOIs
StatePublished - Oct 2022

Keywords

  • CIRBP
  • Colitis
  • ETS-1
  • Inflammatory bowel diseases
  • Th1 immune response

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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