NIMESULIDE, A SULFONANILIDE NONSTEROIDAL ANTIINFLAMMATORY DRUG, INHIBITS MEDIATOR RELEASE FROM HUMAN BASOPHILS AND MAST-CELLS

Nimesulide (NIM) is a sulfonanilide nonsteroidal anti-inflammatory dru g (NSAID) used in the treatment of various inflammatory diseases and c hemically unrelated to other acidic NSAIDs, such as acetylsalicylic ac id (ASA) and indomethacin (INDO). We investigated the effects of NIM a nd of its in vivo metabolite, 4-hydroxy-NIM (OH-NIM), on the release o f preformed (histamine) and de novo synthesized mediators (sulfidopept ide leukotriene C4 [LTC4] and prostaglandin D2 [PGD2]) from human baso phils and mast cells isolated from lung parenchyma (HLMC) and skin (HS MC). Histamine release from basophils challenged with rabbit anti-huma n IgE antibody (anti-IgE) was enhanced by preincubation with ASA or IN DO (92.2 +/- 7.1% at 10(-3) M and 61.1 +/- 6.7% at 3 x 10(-6) M, respe ctively; P < .001). In contrast, NIM and its metabolite, OH-NIM (10(-6 ) to 10(-3) M), caused concentration-dependent inhibition (2.9 to appr oximately 60% and 3.7 to approximately 90%, respectively) of IgE-media ted histamine release from basophils. NIM and OH-NIM also inhibited hi stamine release from basophils induced by the Ca++ ionophore A23187 an d different protein kinase C activators, such as 12-O-tetradecanoyl-ph orbol-13-acetate, bryostatin 1 and bryostatin 5. NIM and OH-NIM also i nhibited the IgE-mediated histamine release from HLMC (52.3 +/- 9.6% a nd 66.1 +/- 12.1% at 10(-3) M, respectively; P < .0001) and HSMC (67.3 +/- 3.7% and 77.7 +/- 12.0% at 10(-3) M, respectively; P < .0001) but had little or no effect on HLMC and HSMC activated by A23187. NIM ( 1 0(-6) to 10(-3) M) markedly inhibited the de novo synthesis of LTC4 fr om basophils, LTC4 and PGD2 from HLMC and PGD2 from HSMC. NIM and OH-N IM potentiated, whereas ASA and INDO reversed, the inhibitory effect o f adenylate cyclase agonists, such as prostaglandin El and forskolin. In addition, NIM and OH-NIM reversed the enhancing effects of ASA and INDO on IgE-mediated histamine release from basophils.