Inactive Rhomboid Protein 2 Mediates Intestinal Inflammation by Releasing Tumor Necrosis Factor-alpha

Abstract

Background: Tumor necrosis factor (TNF)-alpha is a major proinflammatory cytokine that plays a key role in inflammatory bowel disease (IBD). Inactive rhomboid protein 2 (iRhom2) is essential for activating TNF-alpha-converting enzyme (TACE) in immune cells, which regulates TNF-alpha release. The aim of the study was to investigate the role of iRhom2 in intestinal inflammation in IBD. Methods: The expression of iRhom2 and TACE in lipopolysaccharide (LPS)-stimulated COLO 205 and RAW 264.7 cells was assessed by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. The expression of iRhom2 and TACE in the colonic tissue of IBD patients and 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-treated mice was determined by RT-PCR and immunohistochemistry. To assess the role of iRhom2 in intestinal inflammation, colitis was induced in wild-type and iRhom2(-/-) mice by the administration of TNBS enema. Results: In LPS-stimulated COLO 205 and RAW 264.7 cells, the mRNA and protein levels of TACE and iRhom2 were upregulated. The expression of TACE and iRhom2 in the colon of the IBD patients and TNBS-treated mice was significantly enhanced. The inflammatory cells that expressed high levels of iRhom2 in the colon were identified as macrophages. Finally, iRhom2 deficiency ameliorated TNBS-induced colitis by inhibiting TNF-alpha release. Conclusions: iRhom2 has an important role in intestinal inflammation through TNF-alpha secretion in immune cells, which suggests that iRhom2 could be a novel therapeutic target for IBD.