olopatadine-hydrochloride and Leukemia--Basophilic--Acute

Olopatadine hydrochloride (olopatadine) is an anti-allergic drug that functions as a histamine H(1) antagonist and inhibits both mast cell degranulation and the release of arachidonic acid metabolites in various types of cells. In this study, we examined the ability of olopatadine to inhibit the expression of cytokine genes in vitro via high-affinity receptors for immunoglobulin E in mast cells, using a rat basophilic leukemia (RBL-2H3) cell line and an in vivo mouse model. Levels of gene expression in RBL-2H3 cells were determined by semi-quantitative RT-PCR, and serum interleukin-4 (IL-4) level in mice was quantified by ELISA. Olopatadine inhibited significantly the induction of IL-4 expression by mast cells both in vivo and in vitro. Olopatadine inhibited Ca(2+) influx through receptor-operated channels (ROC) without affecting Ca(2+) release from intracellular stores. Comparative analysis of olopatadine with other anti-allergic drugs and the ROC blocker SKF-96365 demonstrated that the potency of inhibition of Ca(2+) influx correlated with the degree of suppression of degranulation and arachidonic acid release. Inhibition of Ca(2+) influx decreased phosphorylation of p38 mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase, which participate in regulation of cytokine (e.g. IL-4) gene expression. However, the rank order of inhibition of Ca(2+) influx did not correspond to reduction of IL-4 expression, suggesting that an unknown mechanism(s) of action, in addition to inhibition of Ca(2+) influx, is involved in the expression of cytokines in mast cells.

Topics: Animals; Anti-Allergic Agents; Arachidonic Acid; Calcium; Cell Degranulation; Cyclic AMP; Dibenzoxepins; Gene Expression; Granulocyte-Macrophage Colony-Stimulating Factor; Imidazoles; Interleukin-13; Interleukin-2; Interleukin-3; Interleukin-4; Interleukin-6; Leukemia, Basophilic, Acute; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases; Olopatadine Hydrochloride; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; RNA, Messenger; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha