Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting TH1/TH17 cell differentiation in patients with inflammatory bowel diseases

Background: Tripartite motif-containing (TRIM) 21 has been implicated in the pathogenesis of several types of autoimmune diseases. Objective: We sought to elucidate TRIM21 expression in patients with inflammatory bowel diseases (IBDs) and its role in regulating intestinal mucosal inflammation. Methods: TRIM21 expression was analyzed in the inflamed mucosa of patients with IBDs by means of quantitative RT-PCR and immunohistochemistry. Peripheral blood CD4(+) T cells were transfected with lentivirus-expressing TRIM21 (LV-TRIM21) or LV-sh-TRIM21, and cytokine expression was determined by using quantitative RT-PCR and ELISA. TRIM21(-/-) mice were generated, and trinitrobenzene sulfonic acid- and CD45RB(high) CD4(+) T cell-induced colitis models were established to determine its role in induction of intestinal inflammation. Results: TRIM21 was expressed predominantly in CD4(+) T cells and decreased markedly in the inflamed mucosa of patients with IBDs compared with healthy control subjects. Ectopic expression of TRIM21 inhibited IBD CD4(+) T cells to differentiate into T(H)1 and T(H)17 cells, whereas downregulation of TRIM21 had the opposite effects. TRIM21(-/-) mice had more severe colitis after administration of trinitrobenzene sulfonic acid compared with wild-type mice, which was characterized by increased expression of IFN-gamma, TNF-alpha, and IL-17A in the colon. TRIM21(-/-) CD45RB(high) CD4(+) T cells reconstituted into recombination-activating gene (Rag1)(-/-) mice induced more severe colitis than in wild-type control mice. Mechanistically, interferon regulatory factor 3 was identified as a functional downstream target of TRIM21 in that silencing of interferon regulatory factor 3 suppressed TRIM21(-/-) CD4(+) T-cell differentiation into T(H)1 and T(H)17 cells. Conclusions: TRIM21 plays a protective role in mucosal inflammation through inhibiting T(H)1 and T(H)17 cell differentiation. Thus TRIM21 might serve as a potential therapeutic target for the treatment of IBDs.