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

Ogasawara N, Sasaki M, Itoh Y, Tokudome K, Kondo Y, Ito Y, Tanida S, Kamiya T, Kataoka H, Joh T, Kasugai K - J Clin Biochem Nutr (2011)

Bottom Line: Inflamed colonic mucosa over-expressed TKB1, NAP1, IRF3, and IRF7 mRNA compared with normal mucosa.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 might suppress the TLR-TBK1 pathway, resulting in IRF3/7-induction of IFN-α/β and inflammatory factors.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Effect of rebamipide on protein expression level of TBK1. Western blots show that rebamipide suppressed TBK1 protein expression in human colonic epithelial cells induced by either poly(I:C) or LPS. These results indicate that rebamipide suppresses TLR3/4-TBK1 signaling in these cells.
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Figure 7: Effect of rebamipide on protein expression level of TBK1. Western blots show that rebamipide suppressed TBK1 protein expression in human colonic epithelial cells induced by either poly(I:C) or LPS. These results indicate that rebamipide suppresses TLR3/4-TBK1 signaling in these cells.

Mentions: To clarify the mechanism of rebamipide on the TLR-TBK1 signaling pathway in colitis, we performed both real-time RT-PCR of TBK1, NAP1, IRF3 and IRF7, and Western blotting of TBK1 using human colonic epithelial cells. Poly(I:C) (a TLR3 ligand) was added to CaCo2 colonic epithelial cells with or without rebamipide. Poly(I:C) alone increased the mRNA expression of all of these genes in the cells. However, the mRNA expression of these genes was suppressed to control levels when both poly(I:C) and rebamipide were added to the cells (Fig. 5). LPS, which is a ligand for TLR4, increased the mRNA expression of all these genes in CaCo2 cells, whereas rebamipide suppressed these LPS-induced increases to control levels (Fig. 6). Western blotting showed that rebamipide with either poly(I:C) or LPS suppressed TBK1 protein expression (Fig. 7). Immunofluorescence image of TBK1 indicated that rebamipide with LPS suppressed TBK1 protein expression (Fig. 8). Rebamipide also suppressed the expression of TBK-1 with poly(I:C) (data not shown). These results indicated that rebamipide suppresses the TLR3/4-TBK1 signaling pathway in human colonic epithelial and serves as an important factor in anti-inflammation via this pathway.


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

Ogasawara N, Sasaki M, Itoh Y, Tokudome K, Kondo Y, Ito Y, Tanida S, Kamiya T, Kataoka H, Joh T, Kasugai K - J Clin Biochem Nutr (2011)

Effect of rebamipide on protein expression level of TBK1. Western blots show that rebamipide suppressed TBK1 protein expression in human colonic epithelial cells induced by either poly(I:C) or LPS. These results indicate that rebamipide suppresses TLR3/4-TBK1 signaling in these cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045689&req=5

Figure 7: Effect of rebamipide on protein expression level of TBK1. Western blots show that rebamipide suppressed TBK1 protein expression in human colonic epithelial cells induced by either poly(I:C) or LPS. These results indicate that rebamipide suppresses TLR3/4-TBK1 signaling in these cells.
Mentions: To clarify the mechanism of rebamipide on the TLR-TBK1 signaling pathway in colitis, we performed both real-time RT-PCR of TBK1, NAP1, IRF3 and IRF7, and Western blotting of TBK1 using human colonic epithelial cells. Poly(I:C) (a TLR3 ligand) was added to CaCo2 colonic epithelial cells with or without rebamipide. Poly(I:C) alone increased the mRNA expression of all of these genes in the cells. However, the mRNA expression of these genes was suppressed to control levels when both poly(I:C) and rebamipide were added to the cells (Fig. 5). LPS, which is a ligand for TLR4, increased the mRNA expression of all these genes in CaCo2 cells, whereas rebamipide suppressed these LPS-induced increases to control levels (Fig. 6). Western blotting showed that rebamipide with either poly(I:C) or LPS suppressed TBK1 protein expression (Fig. 7). Immunofluorescence image of TBK1 indicated that rebamipide with LPS suppressed TBK1 protein expression (Fig. 8). Rebamipide also suppressed the expression of TBK-1 with poly(I:C) (data not shown). These results indicated that rebamipide suppresses the TLR3/4-TBK1 signaling pathway in human colonic epithelial and serves as an important factor in anti-inflammation via this pathway.

Bottom Line: Inflamed colonic mucosa over-expressed TKB1, NAP1, IRF3, and IRF7 mRNA compared with normal mucosa.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 might suppress the TLR-TBK1 pathway, resulting in IRF3/7-induction of IFN-α/β and inflammatory factors.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus