Colonic epithelial mTORC1 promotes ulcerative colitis through COX-2-mediated Th17 responses

Abstract

The functional role of colonic epithelium in the pathogenesis of ulcerative colitis (UC) remains unclear. Here, we reveal a novel mechanism by which colonic epithelia recruit T helper-17 (Th17) cells during the onset of UC. mTOR complex 1 (mTORC1) was hyper-activated in colonic epithelia of UC mice. While colonic epithelial TSC1 (mTORC1 negative regulator) disruption induced constitutive mTORC1 activation in the colon epithelia and aggravated UC, RPTOR (essential mTORC1 component) depletion inactivated mTORC1 and ameliorated UC. TSC1 deficiency enhanced, whereas RPTOR ablation reduced the expression of cyclooxygenase 2 (COX-2), interleukin-1 (IL-1), IL-6, and IL-23, as well as Th17 infiltration in the colon. Importantly, inhibition of COX-2 reversed the elevation in the expression of these proinflammatory mediators induced by TSC1 deficiency, and subsequently reduced the symptoms and pathological characteristics of UC in mouse models. Mechanistically, mTORC1 activates COX-2 transcription via phosphorylating STAT3 and enhancing it's binding to the COX-2 promoter. Consistently, enhanced mTORC1 activity and COX2 expression, as well as strong positive correlation between each other, were observed in colonic epithelial tissues of UC patients. Collectively, our study demonstrates an essential role of epithelial mTORC1 in UC pathogenesis and establishes a novel link between colonic epithelium, Th17 responses, and UC development.

Huangkui Lianchang Decoction Ameliorates DSS-Induced Ulcerative Colitis in Mice by Inhibiting the NF-kappaB Signaling Pathway

“…Multiple stimulating factors increase the inducible expression of iNOS and lead to the synthesis of a large amount of NO, which mediates the inflammatory response. Many studies have confirmed that COX-2 and iNOS are associated with the pathogenesis of UC [42, 43]. In our experiment, treatment with HLD remarkably suppressed the enhanced tissue levels of IL-6, IL-1 β , TNF- α , iNOS, and COX-2, which may account for the suppression of inflammatory infiltrates.…”

Porphyromonas gingivalis and Lactobacillus rhamnosus GG regulate the Th17/Treg balance in colitis via TLR4 and TLR2

“…On the one hand, excessive activation of IL‐17 + Th17 cells aggravates colitis 3 . Colitis can be induced by transferring well‐differentiated Th17 cells to mice lacking immune cells 4 .…”

Onion bulb extract can both reverse and prevent colitis in mice via inhibition of pro-inflammatory signaling molecules and neutrophil activity

“…In addition, using chemical inhibitors of these pro-inflammatory molecules ameliorated colitis severity. A recent study demonstrated an important role for COX-2 in colitis through enhancing the expression profile of Th17 cytokines [ 53 ]. Another study showed enhanced COX-2 colonic expression in TNBS-treated mice and quercitin reduced colitis severity through decreasing COX-2 expression [ 54 ].…”