Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting T H 1/T H 17 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 CD45RBhigh 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 TH 1 and TH 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-γ, TNF-α, and IL-17A in the colon. TRIM21-/- CD45RBhigh 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 TH 1 and TH 17 cells.

CONCLUSIONS: TRIM21 plays a protective role in mucosal inflammation through inhibiting TH 1 and TH 17 cell differentiation. Thus TRIM21 might serve as a potential therapeutic target for the treatment of IBDs.