Group A streptococcal cell walls (SCW) induce a biphasic pattern of chronic, erosive polyarthritis in the LEW, but not the genetically similar F344, rat. In studies to identify the cellular and molecular mechanisms of differential genetic susceptibility, peritoneal macrophages from the two strains were compared for their responsiveness to SCW in vitro and in vivo. LEW macrophages produced higher levels of differentiation and proliferative factors and reactive oxygen intermediates as compared to the F344, all of which promote chronic inflammation and may provide a basis for the differential development of disease. To determine the contribution of these factors relative to the two phases of arthritis, studies were performed using specific inhibitors. Administration of the cyclooxygenase inhibitors flurbiprofen and ketoprofen markedly suppressed both the acute and chronic phases of arthritis, as well as established arthritis, suggesting that cyclooxygenase metabolites of arachidonic acid contribute to the initiation and maintenance of this response. In contrast, nordihydroguaiaretic acid, a lipoxygenase inhibitor, had no effect on the acute with minor effects on the chronic phase. In additional studies, administration of gamma interferon (gamma IFN) suppressed both the acute and chronic phases of disease possibly due to its antiproliferative effects and its inhibitory effects on prostaglandin and collagenase synthesis. These studies reflect the effects of gammaIFN in human rheumatoid arthritis observed in ongoing clinical trials. By choosing pharmacologic agents with different target specificities, it may be possible to elucidate the mechanisms of pathogenesis of arthritis, in both experimental models and in humans.