Inbred Lewis (LEW/N) female rats develop an arthritis in response to group A streptococcal cell wall peptidoglycan polysaccharide (SCW), which mimics human rheumatoid arthritis. Histocompatible Fischer (F344/N) rats do not develop arthritis in response to the same SCW stimulus. To evaluate this difference in inflammatory reactivity, we examined the function of the hypothalamic-pituitary-adrenal (HPA) axis and its ability to modulate the development of the inflammatory response in LEW/N and F344/N rats. We have found that, in contrast to F344/N rats, LEW/N rats had markedly impaired plasma corticotropin and corticosterone responses to SCW, recombinant human interleukin la, the serotonin agonist quipazine, and synthetic rat/human corticotropin-releasing hormone. LEW/N rats also had smaller adrenal glands and larger thymuses. Replacement doses of dexamethasone decreased the severity of LEW/N rats' SCWinduced arthritis. Conversely, treatment of F344/N rats with the glucocorticoid receptor antagonist RU 486 or the serotonin antagonist LY53857 was associated with development of severe inflammatory disease, including arthritis, in response to SCW. These findings support the concept that susceptibility of LEW/N rats to SCW arthritis is related to defective HPA axis responsiveness to inflammatory and other stress mediators and that resistance of F344/N rats to SCW arthritis is regulated by an intact HPA axis-immune system feedback loop.A single intraperitoneal injection of group A streptococcal cell wall fragments (peptidoglycan group-specific polysaccharide; SCW) into euthymic LEW/N female rats induces severe, rapid onset, acute arthritis, followed by a chronic proliferative and erosive arthritis. Athymic LEW.rnu/rnu rats develop the rapid-onset acute-phase arthritis, but the chronic disease is significantly blunted, indicating that the late-, but not the early-, onset disease is thymus dependent. In contrast, histocompatible euthymic and athymic F344 rats develop only minimal, early-onset, swelling of the hind paws that rapidly subsides. These differences in disease pattern and severity are paralleled by the intensity of class II major histocompatibility antigen (Ia) expression in synovial tissues.The presence of a strain difference in the early-onset, thymic-independent phase of SCW arthritis in athymic LEW.rnu/rnu versus F344.rnu/rnu rats indicates that the thymic-independent phase of arthritis is genetically regulated and that the regulating factor or factors are operative very early in the disease (1). The mechanisms involved in this regulation are unknown.Corticosteroids are both potent endogenous anti-inflammatory and immunosuppressive agents and potent endogenous down-regulators of Ia expression (2-4). Corticosterone is released early in the course of inflammation, possibly through stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by inflammatory mediators such as endotoxin and interleukin 1 (IL-1) and may be important in maintaining the normal feedback loop between the immune system and the c...