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^highCD4⁺ 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_H1 and T_H17 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^−/−CD45RB^highCD4⁺ 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_H1 and T_H17 cells.

Conclusions

TRIM21 plays a protective role in mucosal inflammation through inhibiting T_H1 and T_H17 cell differentiation. Thus TRIM21 might serve as a potential therapeutic target for the treatment of IBDs.

中文翻译：

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含三部分基序（TRIM）21通过抑制炎症性肠病患者的T _H 1 / T _H 17细胞分化来负调节肠道粘膜炎症

背景

含三方基序（TRIM）21与多种类型的自身免疫性疾病的发病机制有关。

客观的

我们试图阐明TRIM21在炎症性肠病（IBDs）患者中的表达及其在调节肠粘膜炎症中的作用。

方法

通过定量RT-PCR和免疫组化的方法分析了IBD患者发炎的黏膜中TRIM21的表达。用表达慢病毒的TRIM21（LV-TRIM21）或LV-sh-TRIM21转染外周血CD4 ⁺ T细胞，并通过定量RT-PCR和ELISA测定细胞因子的表达。产生了TRIM21 ^-/-小鼠，并建立了三硝基苯磺酸和CD45RB^高CD4 ⁺ T细胞诱导的结肠炎模型，以确定其在诱导肠道炎症中的作用。

结果

与健康对照组相比，IBD患者的TRIM21主要在CD4 ⁺ T细胞中表达，并在发炎的黏膜中显着减少。TRIM21的异位表达抑制了IBD CD4 ⁺ T细胞分化为T _H 1和T _H 17细胞，而TRIM21的下调具有相反的作用。与野生型小鼠相比，施用三硝基苯磺酸后，TRIM21 ^-/-小鼠患有更严重的结肠炎，其特征在于结肠中IFN-γ，TNF-α和IL-17A的表达增加。TRIM21 ^-/- CD45RB^高CD4 ⁺ T细胞重组为重组激活基因（Rag1）^-/-小鼠比野生型对照小鼠诱发更严重的结肠炎。从机制上讲，干扰素调节因子3被确定为TRIM21的功能性下游目标，因为干扰素调节因子3的沉默抑制了TRIM21 ^-/- CD4 ⁺ T细胞分化为T _H 1和T _H 17细胞。

结论

TRIM21通过抑制T _H 1和T _H 17细胞分化而在粘膜炎症中起保护作用。因此，TRIM21可能作为IBD治疗的潜在治疗靶标。