Mucosal immunologySep 20, 2019

STAT6 outside blood cells disrupts gut lining, leading to inflammation and tumor growth

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 5, 2026

Abstract

STAT6 activation was detected in inflamed colonic epithelium of active IBD patients.

Non-hematopoietic STAT6 triggered DSS-induced colitis and tumor development.
STAT6 may enhance gut permeability and microbiota translocation by disrupting epithelial tight junctions.
Long-myosin light-chain kinase (MLCK1) is a target of STAT6 that contributes to tight junction dysfunction.
Neutralization of IL-13 improved gut permeability and reduced DSS-induced colitis by inhibiting epithelial STAT6 activation.
Pharmacological inhibition of STAT6 reduced intestinal tumor formation in mice.
Tumoral p-STAT6 levels are positively correlated with clinical stage and poor prognosis in human colorectal cancer.

Simplified

Enhanced gut permeability due to dysregulated epithelial tight junction is often associated with inflammatory bowel diseases (IBD), which have a greater risk for developing colorectal cancer. STAT6 activation was detected in inflamed colonic epithelium of active IBD patients, suggesting a role of epithelial STAT6 in colitis development. Here, we demonstrated that non-hematopoietic STAT6, but not hematopoietic STAT6, triggered DSS-induced colitis and subsequent tumorigenesis. This could be due to the enhancing-effect of STAT6 on gut permeability and microbiota translocation via interruption of epithelial tight junction integrity. Mechanistically, long-myosin light-chain kinase (MLCK1) was identified as a target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Furthermore, neutralization of IL-13, which was primarily derived from type 2 innate lymphoid cells (ILC2) in a microbiota-dependent way, inhibited epithelial STAT6 activation and improved gut permeability and DSS-induced colitis. Importantly, pharmacological inhibition of STAT6 reduces murine intestinal tumor formation, and tumoral p-STAT6 levels positively correlated to the clinical stage and poor prognosis of human colorectal cancer. Thus, our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity and colitis development, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer.

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STAT6 outside blood cells disrupts gut lining, leading to inflammation and tumor growth

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