BACKGROUND & AIMS We have shown that IL-1 and IL-6, possibly originating from the mucosa in response to injury, inhibit neurally mediated contraction of esophageal circular muscle, but do not affect ACh-induced contraction, reproducing the effect of experimental esophagitis on esophageal contraction. METHODS To examine the interaction of mucosa and circular muscle in inflammation, we examined the effect of HCl on in vitro esophageal mucosa and circular muscle. RESULTS Circular muscle strips, when directly exposed to HCl, contracted normally. However, when, exposed to supernatants of mucosa incubated in HCl (2-3 h, pH 5.8), contraction decreased, and the inhibition was partially reversed by an IL-6 antibody. Supernatants from the mucosa of animals with in vivo-induced acute esophagitis (AE) similarly reduced contraction. IL-6 levels were higher in mucosal tissue from AE animals than in control mucosa, and in AE mucosa supernatant than in normal mucosa supernatant. IL-6 levels increased significantly in normal mucosa and supernatants in response to HCl, suggesting increased production and release of IL-6 by the mucosa. IL-6 increased H₂O₂ levels in circular muscle layer but not in mucosa. Exposure of mucosa to HCl, caused IL-1 to increase only in mucosa and not in supernatant. CONCLUSION These data suggest that HCl-induced damage occurs first in the mucosa, leading to production of IL-1 and IL-6, but not H₂O₂. IL-1 appears to remain in the mucosa. In contrast IL-6 is produced and released by mucosa, eventually resulting in production of H₂O₂ by the circular muscle and this affecting circular muscle contraction.