Rebamipide suppresses TLR-TBK1 signaling pathway resulting in regulating IRF3/7 and IFN-α/β reduction

• Published in: Journal of Clinical Biochemistry and Nutrition 2011, Vol.48(2), pp.154-160
• Main Authors: Ogasawara, Naotaka, Sasaki, Makoto, Itoh, Yukimi, Tokudome, Kentaro, Kondo, Yoshihiro, Ito, Yoshitsugi, Tanida, Satoshi, Kamiya, Takeshi, Kataoka, Hiromi, Joh, Takashi, Kasugai, Kunio
• Format: Article
• Language: English
• Subjects: inflammatory bowel disease; interferon regulatory factor 3/7; Original; rebamipide; TANK-binding kinase 1; toll-like receptor 3/4
• ISSN: 0912-0009; 1880-5086
• DOI: 10.3164/jcbn.10-69

TANK-binding kinase 1 (TBK1) regulates the interferon regulatory factor (IRF) 3 and IRF7 activation pathways by double strand RNA (dsRNA) via Toll-like receptor (TLR) 3 and by lipopolysaccharide (LPS) via TLR4. Rebamipide is useful for treating inflammatory bowel disease (IBD). Although IBD is associated with nuclear factor-κB (NF-κB), any association with the TBK1-IRF pathway remains unknown. How rebamipide affects the TBK1-IRF pathway is also unclear. We analyzed the relationship between IBD (particularly ulcerative colitis; UC) and the TLR-TBK1-IRF3/7 pathway using human colon tissue, a murine model of colitis and human colonic epithelial cells. Inflamed colonic mucosa over-expressed TKB1, NAP1, IRF3, and IRF7 mRNA compared with normal mucosa. TBK1 was mainly expressed in inflammatory epithelial cells of UC patients. The expression of TBK1, IRF3, IRF7, IFN-α and IFN-β mRNA was suppressed in mice given oral dextran sulfate-sodium (DSS) and daily rectal rebamipide compared with mice given only DSS. Rebamipide reduced the expression of TBK1, IRF3 and IRF7 mRNA induced by LPS/dsRNA, but not of NF-κB mRNA in colonic epithelial cells. Rebamipide might suppress the TLR-TBK1 pathway, resulting in IRF3/7-induction of IFN-α/β and inflammatory factors. TBK1 is important in the induction of inflammation in patients with UC. If rebamipide represses the TLR-TBK1 pathway, then rectal administration should suppress inflammation of the colonic mucosa in patients with UC.