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NEUROREGULATION AND MOTILITY

IL-1 signaling in cat lower esophageal sphincter circular muscle

Department of Medicine, Rhode Island Hospital and Brown Medical School, Providence, Rhode Island

Submitted 8 March 2006 ; accepted in final form 26 April 2006

In a cat model of acute experimental esophagitis, resting in vivo lower esophageal sphincter (LES) pressure and in vitro tone are lower than in normal LES, and the LES circular smooth muscle layer contains elevated levels of IL-1 that decrease the LES tone of normal cats. We now examined the mechanisms of IL-1-induced reduction in LES tone. IL-1 significantly reduced acetylcholine-induced Ca²⁺ release in Ca²⁺-free medium, and this effect was partially reversed by catalase, demonstrating a role of H₂O₂ in these changes. IL-1 significantly increased the production of H₂O₂, and the increase was blocked by the p38 MAPK inhibitor SB-203580, by the cytosolic phospholipase A₂ (cPLA₂) inhibitor AACOCF3, and by the NADPH oxidase inhibitor apocynin, but not by the MEK1 inhibitor PD-98059. IL-1 significantly increased the phosphorylation of p38 MAPK and cPLA₂. IL-1-induced cPLA₂ phosphorylation was blocked by SB-203580 but not by AACOCF3, suggesting sequential activation of p38 MAPK-phosphorylating cPLA₂. The IL-1-induced reduction in LES tone was partially reversed by AACOCF3 and by the Ca²⁺-insensitive PLA₂ inhibitor bromoenol lactone (BEL). IL-1 significantly increased cyclooxygenase (COX)-2 and PGE₂ levels. The increase in PGE₂ was blocked by SB-203580, AACOCF3, BEL, and the COX-2 inhibitor NS-398 but not by PD-98059 or the COX-1 inhibitor valeryl salicylate. The data suggested that IL-1 reduces LES tone by producing H₂O₂, which may affect Ca²⁺-release mechanisms and increase the synthesis of COX-2 and PGE₂. Both H₂O₂ and PGE₂ production depend on sequential activation of p38 MAPK and cPLA₂. cPLA₂ activates NADPH oxidases, producing H₂O₂, and may produce arachidonic acid, converted to PGE₂ via COX-2.

acetylcholine; smooth muscle

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