Inhibition of cytokine secretion from human leukemic mast cells and basophils by H-1- and H-2-receptor antagonists

H-1-type antihistamines have recently been reported to inhibit cytokine sec retion from human and murine mast cells and basophils. In order to confirm and expand these studies, we have compared several H-1-blockers and the H-2 -blocker ranitidine for their effect on TNF-alpha, IL-3, 6, 8 and GM-CSF re lease from human leukemic mast (HMC-1) and basophilic (KU812) cells, compar ed to dexamethasone. Cells were stimulated for 24 h with phorbol myristate acetate (35 ng/ml) and calcium ionophore A 23187 (2.5x10(-7) M) alone or wi th the drugs added at 10(-4) to 10(-15) M, and production of cytokines was measured by ELISA. All antihistamines caused a dose-dependent inhibition of TNF-alpha release from HMC-1 cells, with maximal effects at 10(-12) M for azelastine, 10(-9) M for loratadine and cetirizine, and 10(-8) M for raniti dine. The inhibitory potency of H1-blockers on cytokines from HMC-1 cells w as TNF-alpha >IL-8 greater than or equal to IL-6 greater than or equal to I L-3, with no significant effects on GM-CSF. In KU812 cells which failed to secrete TNF-alpha and GM-CSF, the sequence was IL-6 >IL-8 after preincubati on. Dexamethasone inhibited all cytokines, but ranitidine only TNF-alpha an d IL-3. Antihistamines had no effect on calcium flux in resting or stimulat ed cells. At the mRNA level, inhibition was only seen with KU812 cells and IL-8 in the presence of azelastine at 10(-10) M. These data show thus disti nct inhibitory patterns for different antihistamines during cytokine produc tion from human roast cells and basophils which may contribute to the anti- inflammatory effects of these drugs during treatment of allergic diseases.