Effects of the phosphodiesterase inhibitor rolipram on streptococcal cell wall-induced arthritis in rats

The phosphodiesterase-IV (PDE-IV) inhibitor, rolipram, is antiinflammatory in a number of animal models and inhibits the release of a variety of cytok ines, including TNF alpha, Arthritis induced in rats by systemic reactivati on with streptococcal cell walls (SCW) following intraarticular sensitizati on is a TNF alpha-dependent, delayed-type hypersensitivity (DTH) reaction. Rolipram administered during the reactivation phase dose-dependently inhibi ted hind paw edema through day 24, the day of peak swelling. PMN and T-cell recruitment to the arthritic joint were also attenuated in rolipram-treate d rats. Histologic examination of ankle sections from rolipram-treated anim als showed a marked attenuation of synovial inflammation. Mechanistic studi es to determine the role of glucocorticoids in mediating rolipram action sh owed that the inhibitory effect of rolipram on swelling was not reversed by RU 486, a glucocorticoid antagonist. In contrast, RU 486 reversed the inhi bitory effects of rolipram on TNF alpha secretion. To further evaluate the role of cAMP in the model, the beta-adrenergic receptor (beta AR) agonist i soproterenol was tested, and found to inhibit swelling but not the release of TNF alpha, These results are consistent with the view that the inhibitor y effects of rolipram may be partially mediated by cAMP-dependent, but TNF alpha-independent, mechanisms. The beta AR antagonists propranolol and nado lol had no appreciable affect on the antiinflammatory effect of rolipram. H owever, rolipram reversed the lethal effects of the antagonists observed wh en either was administered alone. Apparently, beta-adrenergic mechanisms mo derate the response to challenge, and rolipram treatment, presumably as a r esult of its effects on cAMP levels, reverses the toxic effect of the antag onists. (C) 1999 International Society for Immunopharmacology. Published by Elsevier Science Ltd. All rights reserved.