Abstract
Ulcerative colitis (UC), an inflammatory disorder of the colon arises from dysregulated immune response towards gut microbes. Transcription factor NFκB is a major regulatory component influencing mucosal inflammation. We evaluated expression of Tumor Necrosis Factor Alpha Induced Protein3 (TNFAIP3), the inhibitor of NFκB activation and its associated partners ITCH, RNF11 and Tax1BP1 in inflamed mucosa of UC patients. We found highly significant up-regulated mRNA expression of TNFAIP3 that negatively correlated with disease activity in UC. mRNA levels of ITCH, RNF11 and Tax1BP1 were significantly down-regulated. Significant positive correlation with disease activity was noted for Tax1BP1. All four genes showed significant down-regulation at protein level. mRNA levels of inducers of TNFAIP3 expression, NFκB p65 subunit and MAST3 was determined. There was significant increase in p65 mRNA expression and down-regulated MAST3 expression. This suggested that increase in NFκB expression regulates TNFAIP3 levels. Deficiency of TNFAIP3 expression resulted in significant up-regulation of NFκB p65 sub-unit as well as its downstream genes such as iNOS, an inflammatory marker, inhibitors of apoptosis like cIAP2 and XIAP and mediators of anti-apoptotic signals TRAF1 and TRAF2. Taken together, decreased expression of TNFAIP3 and its partners contribute to inflammation and up-regulation of apoptosis inhibitors that may create microenvironment for colorectal cancer.
Highlights
Activated NFκB is a key player in pathogenesis of various diseases like atherosclerosis, asthma and diabetes[11,12,13]
We showed that expression of ubiquitin editing complex members was altered in inflamed colon tissues and genes involved in inflammation and inhibiting apoptosis were up-regulated
This is consistent with a previous finding that Tumor Necrosis Factor Alpha Induced Protein3 (TNFAIP3) mRNA expression increases in inflamed tissues compared to non-inflamed tissues during UC36
Summary
Activated NFκB is a key player in pathogenesis of various diseases like atherosclerosis, asthma and diabetes[11,12,13]. The cytoplasmic ubiquitin editing molecule Tumor Necrosis Factor Alpha Induced Protein[3] (TNFAIP3, known as A20) negatively regulates NFκB activation. Deficiency of ITCH and RNF11 in mice causes spontaneous inflammation and persistent NFκB activation[18, 20]. Both these ubiquitin ligases are required by TNFAIP3 to inactivate NFκB signaling[21]. This study reveals that expression of all four members of the ubiquitin editing complex members is altered at both mRNA and protein level which leads to dysregulated expression of some key NFκB regulated genes that are involved in outcome of the disease
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