title: Activation of the MyD88 signaling pathway inhibits ischemia-reperfusion injury in the small intestine.
abstract: Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates innate and adaptive immunity. Recent studies have shown that the activation of TLR-dependent signaling pathways plays important roles in the pathogenesis of ischemia-reperfusion (I/R) injuries in many organs. All TLRs, except TLR3, use a common adaptor protein, MyD88, to transduce activation signals. We investigated the role of MyD88 in I/R injury of the small intestine. MyD88 and cyclooxygenase-2 (COX-2) knockout and wild-type mice were subjected to intestinal I/R injury. I/R-induced small intestinal injury was characterized by infiltration of inflammatory cells, disruption of the mucosal epithelium, destruction of villi, and increases in myeloperoxidase activity and mRNA levels of TNF-α and the IL-8 homolog KC. MyD88 deficiency worsened the severity of I/R injury, as assessed using the histological grading system, measuring luminal contents of hemoglobin (a marker of intestinal bleeding), and counting apoptotic epithelial cells, while it inhibited the increase in mRNA expression of TNF-α and KC. I/R significantly enhanced COX-2 expression and increased PGE(2) concentration in the small intestine of wild-type mice, which were markedly inhibited by MyD88 deficiency. COX-2 knockout mice were also highly susceptible to intestinal I/R injury. Exogenous PGE(2) reduced the severity of injury in both MyD88 and COX-2 knockout mice to the level of wild-type mice. These findings suggest that the MyD88 signaling pathway may inhibit I/R injury in the small intestine by inducing COX-2 expression.
authors.affiliation: Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka Japan. watanabet@med.osaka-cu.ac.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Watanabe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kobata
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tanigawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nadatani
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Yamagami
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
authors.forename: Kazunari
authors.initials: K
authors.lastname: Tominaga
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Arakawa
mesh_terms: D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D007421:Intestine, Small / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000502:physiology*; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D000667:Ampicillin; D051546:Cyclooxygenase 2; D015232:Dinoprostone