Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals. Recently, accumulating evidence demonstrated that TRAIL regulates autoimmune inflammation and immune cell homeostasis in several autoimmune animal models, suggesting a novel immunoregulatory role of TRAIL in autoimmune diseases. However, the impact of TRAIL in inflammatory bowel disease is yet undefined. This study is to address the therapeutic effects and immunoregulatory role of TRAIL in autoimmune gut inflammation. We demonstrated herein that TRAIL significantly suppressed gut inflammation and reduced the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis model. Suppression of gut inflammation was not due to induction of apoptosis in colonic T cells, dendritic cells, or epithelium cells by TRAIL. In contrast, TRAIL directly inhibited activation of colitogenic T cells and development of gut inflammation in an adoptive transfer-induced colitis model. The antiinflammatory effects of TRAIL on colitis were abolished when T cells from TRAIL receptor (TRAIL-R) knockout mice were adoptively transferred, suggesting that TRAIL regulates autoreactive colitogenic T-cell activation in the development of gut inflammation. Our results demonstrate that TRAIL effectively inhibited colonic T-cell activation and suppressed autoimmune colitis, suggesting a potential therapeutic application of TRAIL in human inflammatory bowel disease.

The thioredoxin domain-containing 5 (TXNDC5) gene is associated with susceptibility to rheumatoid arthritis (RA) and exhibits increased expression in the synovial tissues. TXNDC5 is also associated strongly with diabetes, a metabolic disease characterized by interrupted insulin signalling. This study investigated whether TXNDC5 contributes to RA via the insulin signalling pathway. In this study, RA synovial fibroblast-like cells (RASFs) transfected with an anti-TXNDC5 small interfering RNA (siRNA) were analysed with an insulin signaling pathway RT profiler polymerase chain reaction (PCR) array and an insulin resistance RT profiler PCR array. The PCR arrays detected significantly increased expression of insulin-like growth factor binding protein 1 (IGFBP1) in RASFs with suppressed TXNDC5 expression. The result was verified using real-time PCR and Western blot analyses. Significantly elevated IGFBP1 expression and decreased interleukin (IL)-6 secretion were also detected in culture medium of transfected RASFs. Furthermore, decreased IGFBP1 mRNA and protein expression levels were detected in RA synovial tissues. Additionally, significantly increased apoptosis and decreased cell proliferation and cell migration were observed in RASFs transfected with the anti-TXNDC5 siRNA, whereas transfection with the anti-IGFBP1 siRNA or a mixture of the anti-IGFBP1 and anti-TXNDC5 siRNAs restored normal cell proliferation, migration and IL-6 level in RASFs. Insulin-like growth factor (IGF) has potent prosurvival and anti-apoptotic functions, and IGFBP1 can suppress IGF activity. Based on the results of the present study, we suggest that TXNDC5 contributes to abnormal RASF proliferation, migration and IL-6 production by inhibiting IGFBP1 expression.

Downregulation of TXNDC5 could contribute to RASF antiangiogenic and proapoptotic features through the suppression of CXCL10 and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand).