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NEUROREGULATION AND MOTILITY

Proinflammatory cytokines alter/reduce esophageal circular muscle contraction in experimental cat esophagitis

¹Department of Medicine, Rhode Island Hospital and Brown University, Providence, Rhode Island 02903; and ²Division of Gastroenterology, University of Cleveland, Case Western Reserve University, Cleveland, Ohio 44106

Submitted 12 May 2004 ; accepted in final form 9 July 2004

Cholinergic mechanisms are largely responsible for esophageal contraction in response to swallowing or to in vitro electrical field stimulation (EFS). After induction of experimental esophagitis by repeated acid perfusion, the responses to swallowing and to EFS were significantly reduced but contraction in response to ACh was not affected, suggesting that cholinergic mechanisms are damaged by acid perfusion but that myogenic mechanisms are not. Measurements of ACh release in response to EFS confirmed that release of ACh was reduced in esophagitis compared with normal controls. To examine factors contributing to this neuropathy, normal esophageal strips were incubated for 1–2 h with the proinflammatory cytokines IL-1 (100 U/ml), IL-6 (1 ng/ml), or TNF- (1 ng/ml). IL-1 and IL-6 levels, measured by Western blot analysis, increased in esophagitis compared with normal circular muscle. IL-1 and IL-6 reduced contraction in response to EFS (2–10 Hz, 0.2 ms) but did not affect ACh-induced contraction, suggesting that these cytokines inhibit ACh release without affecting myogenic contractile mechanisms. EFS-induced ACh release was significantly reduced in normal esophageal strips by incubation in IL-1 or IL-6, suggesting that they may contribute to the contractility changes. TNF- at 1 ng/ml, however, did not affect the response to ACh or to electrical stimulation but inhibited both at higher concentrations. TNF- levels were low in normal muscle and did not increase with esophagitis. The data suggest that the proinflammatory cytokines IL-1 and IL-6 contribute to reduced esophageal contraction by inhibiting release of ACh from myenteric neurons.

smooth muscle; signal transduction; hydrogen peroxide

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