title: Toll-like receptor 2 mediates ischemia-reperfusion injury of the small intestine in adult mice.
abstract: Toll-like receptor 2 (TLR2) recognizes conserved molecular patterns associated with both gram-negative and gram-positive bacteria, and detects some endogenous ligands. Previous studies demonstrated that in ischemia-reperfusion (I/R) injury of the small intestine, the TLR2-dependent signaling exerted preventive effects on the damage in young mice, but did not have a significant effect in neonatal mice. We investigated the role of TLR2 in adult ischemia-reperfusion injury in the small intestine. Wild-type and TLR2 knockout mice at 16 weeks of age were subjected to intestinal I/R injury. Some wild-type mice received anti-Ly-6G antibodies to deplete circulating neutrophils. In wild-type mice, I/R induced severe small intestinal injury characterized by infiltration by inflammatory cells, disruption of the mucosal epithelium, and mucosal bleeding. Compared to wild-type mice, TLR2 knockout mice exhibited less severe mucosal injury induced by I/R, with a 35%, 33%, and 43% reduction in histological grading score and luminal concentration of hemoglobin, and the numbers of apoptotic epithelial cells, respectively. The I/R increased the activity of myeloperoxidase (MPO), a marker of neutrophil infiltration, and the levels of mRNA expression of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2) in the small intestine of the wild-type mice by 3.3-, 3.2-, and 13.0-fold, respectively. TLR2 deficiency significantly inhibited the I/R-induced increase in MPO activity and the expression of mRNAs for TNF-α and ICAM-1, but did not affect the expression of COX-2 mRNA. I/R also enhanced TLR2 mRNA expression by 2.9-fold. TLR2 proteins were found to be expressed in the epithelial cells, inflammatory cells, and endothelial cells. Neutrophil depletion prevented intestinal I/R injury in wild-type mice. These findings suggest that TLR2 may mediate I/R injury of the small intestine in adult mice via induction of inflammatory mediators such as TNF-α and ICAM-1.
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tanigawa
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kobata
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nadatani
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Otani
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Yamagami
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Shiba
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Tominaga
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Arakawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007421:Intestine, Small / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics; D009195:Peroxidase / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2