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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 NF-κB signaling pathway. Real-time RT-PCR of NF-κB in human colonic epithelial cells shows that LPS and poly(I:C) each increased NF-κB gene mRNA expression in colonic epithelial cells, and that adding rebamipide did not suppress either of these increases.
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Figure 9: Effect of rebamipide on NF-κB signaling pathway. Real-time RT-PCR of NF-κB in human colonic epithelial cells shows that LPS and poly(I:C) each increased NF-κB gene mRNA expression in colonic epithelial cells, and that adding rebamipide did not suppress either of these increases.

Mentions: To determine the effect of rebamipide on the NF-κB signaling pathway, we performed real-time RT-PCR of NF-κB in CaCo2 cells using the same procedure as described above. We found that LPS increased the expression of NF-κB mRNA in CaCo2 cells (Fig. 9), whereas LPS/poly(I:C) plus rebamipide did not suppress the expression and the level was similar to that in the presence of LPS/poly(I:C) (Fig. 9). These results indicated that rebamipide does not exert anti-inflammatory effects via the NF-κB signaling 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 NF-κB signaling pathway. Real-time RT-PCR of NF-κB in human colonic epithelial cells shows that LPS and poly(I:C) each increased NF-κB gene mRNA expression in colonic epithelial cells, and that adding rebamipide did not suppress either of these increases.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: Effect of rebamipide on NF-κB signaling pathway. Real-time RT-PCR of NF-κB in human colonic epithelial cells shows that LPS and poly(I:C) each increased NF-κB gene mRNA expression in colonic epithelial cells, and that adding rebamipide did not suppress either of these increases.
Mentions: To determine the effect of rebamipide on the NF-κB signaling pathway, we performed real-time RT-PCR of NF-κB in CaCo2 cells using the same procedure as described above. We found that LPS increased the expression of NF-κB mRNA in CaCo2 cells (Fig. 9), whereas LPS/poly(I:C) plus rebamipide did not suppress the expression and the level was similar to that in the presence of LPS/poly(I:C) (Fig. 9). These results indicated that rebamipide does not exert anti-inflammatory effects via the NF-κB signaling 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