Platelet activating factor (PAF) and interleukin 6 (IL-6) are produced in the esophagus in response to HCl, and affect ACh release, causing changes in esophageal motor function similar to esophagitis (16). We therefore examined HCl-activated mechanisms for production of PAF and IL-6 in cat esophageal mucosa and circular muscle. A segment of normal mucosa was tied at both ends, forming a mucosal sac (15) that was filled with acidic Krebs' buffer (pH 5.8) or normal Krebs' (pH 7.0) as conrol and kept in oxygenated Krebs' for 3 h. The supernatant of the acidic sac (MS-HCl) abolished contraction of normal muscle strips in response to electric field stimulation. The inhibition was reversed by the PAF antagonist CV-3988 and by IL-6 antibodies. PAF and IL-6 levels in MS-HCl and mucosa were significantly elevated over control. IL-6 levels in mucosa and supernatant were reduced by CV-3988, suggesting that formation of IL-6 depends on PAF. PAF receptor mRNA levels were not detected by RT-PCR in normal mucosa, but were significantly elevated after exposure to HCl, indicating that HCl causes production of PAF, expression of PAF receptors in esophageal mucosa, and that PAF causes production of IL-6. PAF and IL-6, produced in the mucosa are released to affect the circular muscle layer. In the circular muscle PAF causes production of additional IL-6 that activates NADPH oxidase, to induce production of H₂O₂. H₂O₂ causes formation of IL-1 that may induce production of PAF in the muscle, possibly closing a self-sustaining cycle of production of inflammatory mediators.