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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

Rebamipide suppressed TLR3-TBK1 signaling pathway in human colonic epithelial cells. Effect of rebamipide on TLR3-TBK1 signaling pathway in human colonic epithelial cells examined by both real-time RT-PCR of TBK1, IRF3 and IRF7 and by Western blotting of TBK1. Poly(I:C) (TLR3 ligand) was added to colonic epithelial cell line, CaCo2 with or without rebamipide. Poly(I:C) alone increased, whereas poly(I:C) plus rebamipide suppressed the mRNA expression of all of these genes to control levels.
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Figure 5: Rebamipide suppressed TLR3-TBK1 signaling pathway in human colonic epithelial cells. Effect of rebamipide on TLR3-TBK1 signaling pathway in human colonic epithelial cells examined by both real-time RT-PCR of TBK1, IRF3 and IRF7 and by Western blotting of TBK1. Poly(I:C) (TLR3 ligand) was added to colonic epithelial cell line, CaCo2 with or without rebamipide. Poly(I:C) alone increased, whereas poly(I:C) plus rebamipide suppressed the mRNA expression of all of these genes to control levels.

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)

Rebamipide suppressed TLR3-TBK1 signaling pathway in human colonic epithelial cells. Effect of rebamipide on TLR3-TBK1 signaling pathway in human colonic epithelial cells examined by both real-time RT-PCR of TBK1, IRF3 and IRF7 and by Western blotting of TBK1. Poly(I:C) (TLR3 ligand) was added to colonic epithelial cell line, CaCo2 with or without rebamipide. Poly(I:C) alone increased, whereas poly(I:C) plus rebamipide suppressed the mRNA expression of all of these genes to control levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 5: Rebamipide suppressed TLR3-TBK1 signaling pathway in human colonic epithelial cells. Effect of rebamipide on TLR3-TBK1 signaling pathway in human colonic epithelial cells examined by both real-time RT-PCR of TBK1, IRF3 and IRF7 and by Western blotting of TBK1. Poly(I:C) (TLR3 ligand) was added to colonic epithelial cell line, CaCo2 with or without rebamipide. Poly(I:C) alone increased, whereas poly(I:C) plus rebamipide suppressed the mRNA expression of all of these genes to control levels.
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