HUMAN SYNOVIAL MAST-CELLS .2. HETEROGENEITY OF THE PHARMACOLOGICAL EFFECTS OF ANTIINFLAMMATORY AND IMMUNOSUPPRESSIVE DRUGS

Objective. To evaluate the in vitro effects of 4 antiinflammatory and 5 immunosuppressive agents on the release of preformed and de novo-syn thesized mediators from human synovial mast cells (HSyMC) activated by immunologic and nonimmunologic stimuli. Methods. The effects of antii nflammatory and immunosuppressive agents were evaluated on the in vitr o release of histamine and tryptase and the de novo synthesis of prost aglandin D-2 (PGD(2)) and leukotriene C-4 (LTC(4)) by HSyMC challenged with anti-IgE and substance P. Results. Nimesulide, a sulfonanilide n onsteroidal antiinflammatory drug (NSAID) chemically unrelated to othe r acidic NSAIDs (such as acetylsalicylic acid [ASA], diclofenac, and p iroxicam) inhibited in a concentration-dependent manner the release of preformed (histamine and tryptase) mediators from HSyMC challenged wi th anti-IgE, In contrast, diclofenac and piroxicam had little or no ef fect on HSyMC activated by anti-IgE, ASA, diclofenac, piroxicam, and n imesulide caused a concentration-dependent inhibition of IgE-mediated PGD(2) release from HSyMC, Nimesulide, but not diclofenac or piroxicam , also inhibited the de novo synthesis of LTC(4) by HSyMC challenged w ith anti-IgE, Nimesulide, diclofenac, and piroxicam had no effect on H SyMC activated by substance P. Cyclosporin A (CSA) inhibited histamine release from HSyMC challenged with anti-IgE, whereas cyclosporin H (C SH) had no effect, FK-506 also inhibited histamine release from HSyMC activated by anti-IgE, whereas rapamycin had no effect, Neither CSA, C SH, FK-506, nor rapamycin inhibited the release of histamine from HSyM C induced by substance P. Methotrexate had no effect on the release of mediators from these cells, whereas adenosine (R-phenylisopropyl aden osine and 5'-N-ethylcarboxamide adenosine) enhanced histamine release from immunologically activated HSyMC in a concentration-dependent mann er. Conclusion. Mast cells isolated from human synovia display 4 level s of pharmacologic heterogeneity with regard to 1) the inhibitory effe cts of 4 antiinflammatory drugs; 2) the capacity of different immunosu ppressive drugs to exert antiinflammatory activity; 3) the inhibition of the release of different mediators; and 4) the capacity of antiinfl ammatory and immunosuppressive drugs to modulate HSyMC activated by di fferent stimuli, This complexity of pharmacologic modulation of HSyMC in vitro might help explain the different activity of the compounds us ed to treat various pathophysiologic aspects of the inflammatory arthr itides.