Inhibition of cytokine secretion from human leukemic mast cells and basophils by H1- and H2-receptor antagonists

Abstract: H1-type antihistamines have recently been reported to inhibit cytokine secretion from human and murine mast cells and basophils. In order to confirm and expand these studies, we have compared several H1-blockers and the H2-blocker ranitidine for their effect on TNF-α, IL-3, 6, 8 and GM-CSF release from human leukemic mast (HMC-1) and basophilic (KU812) cells, compared to dexamethasone. Cells were stimulated for 24 h with phorbol myristate acetate (25 ng/ml) and calcium ionophore A 23187 (2.5×10−7 M) alone or with 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-α 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 ranitidine. The inhibitory potency of H1-blockers on cytokines from HMC-1 cells was TNF-α >IL-8≥IL-6≥IL-3, with no significant effects on GM-CSF. In KU812 cells which failed to secrete TNF-α and GM-CSF, the sequence was IL-6 >IL-8 after preincubation. Dexamethasone inhibited all cytokines, but ranitidine only TNF-α and IL-3. Antihistamines had no effect on calcium flux in resting or stimulated 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 distinct inhibitory patterns for different antihistamines during cytokine production from human mast cells and basophils which may contribute to the anti-inflammatory effects of these drugs during treatment of allergic diseases.