Human synovial mast cells. II. Heterogeneity of the pharmacologic effects of antiinflammatory and immunosuppressive drugs

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Abstract
Objective. To evaluate the in vitro effects of 4 antiinflammatory and 5 immunosuppressive agents on the release of preformed and de novo-synthesized mediators from human synovial mast cells (HSyMC) activated by immunologic and nonimmunologic stimuli. Methods. The effects of antiinflammatory and immunosuppressive agents were evaluated on the in vitro release of histamine and tryptase and the de novo synthesis of prostaglandin D2 (PGD2) and leukotriene C4 (LTC4) by HSyMC challenged with anti-IgE and substance P. Results. Nimesulide, a sulfonanilide nonsteroidal antiinflammatory drug (NSAID) chemically unrelated to other acidic NSAIDs (such as acetylsalicylic acid [ASA], diclofenac, and piroxicam) inhibited in a concentration-dependent manner the release of preformed (histamine and tryptase) mediators from HSyMC challenged with anti-IgE. In contrast, diclofenac and piroxicam had little or no effect on HSyMC activated by anti-IgE. ASA, diclofenac, piroxicam, and nimesulide caused a concentration-dependent inhibition of IgE-mediated PGD2 release from HSyMC. Nimesulide, but not diclofenac or piroxicam, also inhibited the de novo synthesis of LTC4 by HSyMC challenged with anti-IgE. Nimesulide, diclofenac, and piroxicam had no effect on HSyMC activated by substance P. Cyclosporin A (CSA) inhibited histamine release from HSyMC challenged with anti-IgE, whereas cyclosporin H (CSH) had no effect. FK-506 also inhibited histamine release from HSyMC activated by anti-IgE, whereas rapamycin had no effect. Neither CSA, CSH, FK-506, nor rapamycin inhibited the release of histamine from HSyMC induced by substance P. Methotrexate had no effect on the release of mediators from these cells, whereas adenosine (R-phenylisopropyl adenosine and 5-N-ethylcarboxamide adenosine) enhanced histamine release from immunologically activated HSyMC in a concentration-dependent manner. Conclusion. Mast cells isolated from human synovia display 4 levels of pharmacologic heterogeneity with regard to 1) the inhibitory effects of 4 antiinflammatory drugs; 2) the capacity of different immunosuppressive drugs to exert antiinflammatory activity; 3) the inhibition of the release of different mediators; and 4) the capacity of antiinflammatory and immunosuppressive drugs to modulate HSyMC activated by different stimuli. This complexity of pharmacologic modulation of HSyMC in vitro might help explain the different activity of the compounds used to treat various pathophysiologic aspects of the inflammatory arthritides.