Abstract
Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat. Toll-like receptor 4 (TLR4) stimulates innate and acquired immunity in response to specific microbial components, but the role of TLR4 in intestinal fibrosis is largely unknown. We investigated its role in intestinal fibrosis using not only a murine fibrosis model but also human myofibroblasts and intestinal epithelial cells. Colon fibrosis was induced in TLR4-deficient (TLR4−/−) mice and its wild-type counterparts with 3% dextran sulfate sodium. Absence of TLR4 gene attenuated chronic inflammation and colonic macrophages infiltration; intestinal fibrosis and collagen deposition were suppressed. Also, the production of tumor necrosis factor-α, interleukin-12p40, and transforming growth factor-β was reduced in TLR4-deficient peritoneal macrophages. TLR4 was silenced in CCD-18Co cells by small interfering RNA (siRNA), and matrix metalloproteinase-1, tissue inhibitor of metalloproteinase, and collagen α1 expression was evaluated. Role of TLR4 in epithelial-mesenchymal transition (EMT) was evaluated in HCT116 cells. Suppression of TLR4 transcription by siRNAs affected myofibroblasts activity, collagen synthesis, and EMT in the human cancer cell line. Thus, we suggest that TLR4 can be an essential mediator in intestinal chronic inflammation and fibrosis, indicating that TLR4 signaling is a potential therapeutic target for intestinal fibrosis.
Highlights
Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat
To evaluate the role of Toll-like receptor 4 (TLR4) in chronic colon inflammation and fibrosis, we studied a dextran sulfate sodium (DSS)-induced murine chronic colitis model
The colon length of wild-type mice was significantly reduced as compared to that of TLR4−/− mice (Fig. 1D). These results indicated that TLR4 deletion alleviated colitis and fibrotic changes, suggesting that it may aggravate chronic colon inflammation and fibrosis
Summary
Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat. Absence of TLR4 gene attenuated chronic inflammation and colonic macrophages infiltration; intestinal fibrosis and collagen deposition were suppressed. Suppression of TLR4 transcription by siRNAs affected myofibroblasts activity, collagen synthesis, and EMT in the human cancer cell line. Intestinal fibrosis is a chronic progressive process involving excessive deposition of extracellular matrix (ECM) components in the intestinal wall. Intestinal fibrosis can occur as a long-term complication of numerous diseases such as inflammatory bowel disease (IBD), radiation enterocolitis, chronic ischemic enterocolitis, collagenous colitis, eosinophilic enteropathy, drug-induced enteropathy, and cystic fibrosis[6]. Clinically-used anti-inflammatory agents to treat IBD cannot prevent the intestinal fibrosis once excessive ECM deposition process b egins[11]. Development of new anti-fibrotic agents for IBD is urgently required
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