Expression of TNFAIP3 in intestinal epithelial cells protects from DSS- but not TNBS-induced colitis

Abstract

Intestinal epithelial cells (IEC) maintain gastrointestinal homeostasis by providing a physical and functional barrier between the intestinal lumen and underlying mucosal immune system. The activation of NF-κB and prevention of apoptosis in IEC are required to maintain the intestinal barrier and prevent colitis. How NF-κB activation in IEC prevents colitis is not fully understood. TNFα-induced protein 3 (TNFAIP3) is a NF-κB-induced gene that acts in a negative-feedback loop to inhibit NF-κB activation and also to inhibit apoptosis; therefore, we investigated whether TNFAIP3 expression in the intestinal epithelium impacts susceptibility of mice to colitis. Transgenic mice expressing TNFAIP3 in IEC (villin-TNFAIP3 Tg mice) were exposed to dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS), and the severity and characteristics of mucosal inflammation and barrier function were compared with wild-type mice. Villin-TNFAIP3 Tg mice were protected from DSS-induced colitis and displayed reduced production of NF-κB-dependent inflammatory cytokines. Villin-TNFAIP3 Tg mice were also protected from DSS-induced increases in intestinal permeability and induction of IEC death. Villin-TNFAIP3 Tg mice were not protected from colitis induced by TNBS. These results indicate that TNFAIP3 expression in IEC prevents colitis involving DSS-induced IEC death, but not colitis driven by T cell-mediated inflammation. As TNFAIP3 inhibits NF-κB activation and IEC death, expression of TNFAIP3 in IEC may provide an avenue to inhibit IEC NF-κB activation without inducing IEC death and inflammation.

Intestinal epithelial expression of TNFAIP3 results in microbial invasion of the inner mucus layer and induces colitis in IL-10-deficient mice

“…In addition, we found that v-TNFAIP3 mice are protected from DSS-induced IEC death and colitis but not from TNBS-induced colitis (33). This suggested that IEC might play distinct roles in T cell-mediated colitis that are regulated by epithelial expression of TNFAIP3.…”

“…Histological examination was performed on tissue fixed in 10% formalin, paraffin embedded, and sectioned longitudinally. Sections (5 m) were stained with hematoxylin and eosin and scored by a pathologist blinded to the genotype using previously described criteria (33).…”

“…Colons were removed and rinsed, and mucosal scrapings were performed, as previously described (33). Briefly, colons were opened longitudinally and rinsed, and the lumen was scraped using a glass slide.…”

“…Lineage-specific deletion of TNFAIP3 in IEC does not result in spontaneous colitis but makes mice more susceptible to dextran sulfate sodium (DSS)-induced intestinal inflammation, potentially driven by TNF receptor-induced IEC death (38). Consistent with this, transgenic expression of TNFAIP3 in IEC ameliorates DSS-induced colitis and reduces DSS-induced IEC death (33). These phenotypes are not likely to result directly from inhibition of NF-B signaling by TNFAIP3 in IEC because NF-B signaling in IEC prevents inflammation and protects against DSS-induced colitis (31,41).…”

“…Additionally, TNFAIP3 may have distinct functions in IEC, as it promotes intestinal barrier function, regulates the ubiquitination of the tight junction protein occludin, and inhibits Wnt signaling and colon carcinogenesis (21,35). The role of TNFAIP3 expression in IEC during inflammation may be context dependent, as mice expressing TNFAIP3 in IEC were not protected from 4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and instead displayed a worse course of disease in that model (33). Therefore, we examined the effect of IEC expression of TNFAIP3 on intestinal homeostasis and inflammation in other mouse models of colitis.…”