Obesity is associated with asthma and airway hyper-responsiveness.Leptin modulates some of the pro-inflammatory effects observed in obesity.The objective of this study was to determine the effects of leptin on airway smooth muscle responses. The effect of leptin (0.1-100 ng/ml) on migration (towards PDGF, 10 ng/ml, across collagen-coated membrane in Transwell culture plates), proliferation (by BrDU incorporation), and cytokine production (by Bioplex bead assay) of cultured human airway smooth muscle cells from 9 non-asthmatic donors was assessed.Effects of leptin on the contractile responses were studied in bovine tracheal smooth muscle rings. Leptin receptor expression and activation of STAT-3, Src kinase, Suppressor of Cytokine Signalling-3 (SOCS-3), and COX were evaluated by Western blotting and polymerase chain reaction.PGE₂ levels in supernatant were assessed by enzyme immunoassay. Human airway smooth muscle cells express leptin receptor, which when engaged, phosphorylated STAT-3. Leptin inhibited PDGF-induced human airway smooth muscle migration and proliferation and IL-13-induced eotaxin production.Leptin did not stimulate cytokine synthesis, and did not evoke contractile responses or inhibit isoproterenol-induced relaxation of carbachol-induced contraction of bovine tracheal rings. The inhibitory effects on migration and eotaxin production are not due to activation of SOCS-3, but are partly due to increased production of PGE₂ because they were attenuated by indomethacin.In conclusion, leptin inhibited human airway smooth muscle proliferation, migration towards PDGF and IL-13-induced eotaxin production.This is partly mediated by PGE₂ secretion from smooth muscle cells induced by leptin.The association between obesity and asthma are unlikely to be due to a direct effect of leptin on airway smooth muscle.