INTERFERON-GAMMA PRIMES NEUTROPHIL-MEDIATED GASTRIC SURFACE CELL CYTOTOXICITY

The T lymphocyte product interferon-gamma (IFN-gamma) upregulates or p rimes polymerphonuclear leukocyte (PMN) oxidative responses to the rec eptor-initiated stimulant N-formyl-methionyl-leucyl-phenylalanine (FML P) but not to the transduction-mediated stimulant phorbol myristate ac etate (PMA). We sought a functional correlation between IFN-gamma-indu ced oxidative priming of PMNs and PMN-mediated cytotoxicity, using an in vitro assay of Cr-51 release from rabbit gastric surface cells. Com pared with control PMNs, IFN-gamma-primed PMNs exhibited a significant increase in cytotoxicity when stimulated with FMLP, but not when stim ulated with PMA. IFN-gamma-induced, FMLP-stimulated, PMN-mediated cyto toxicity was reduced by adding superoxide dismutase to scavenge supero xide anion or by adding catalase or glutathione peroxidase to scavenge hydrogen peroxide. Cytotoxicity was also reduced by inhibiting myelop eroxidase activity with azide or scavenging HOCl with alanine or methi onine. Cytotoxicity was blocked by a monoclonal antibody against the C D11/CD18 integrin of PMNs. The results indicate that the immunoregulat ory lymphokine IFN-gamma primes the FMLP-stimulated cytotoxic activity of PMNs via the increased generation of reactive oxygen metabolites a nd indicate that cytotoxicity may require effector-target cell adheren ce. Therefore, T lymphocyte-derived IFN-gamma may have a role in the p athogenesis of PMN-mediated injury to gastric and gastrointestinal tra ct mucosa.