Modulation of Human Airway Smooth Muscle Migration by Lipid Mediators and Th-2 Cytokines
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abstract
Cysteinyl leukotrienes and the T helper (Th)-2 cytokines IL-5 and IL-13 directly modulate human airway smooth muscle functions such as contraction and proliferation. We studied the effects of other lipid mediators involved in asthma pathophysiology such as prostaglandin D(2) (PGD(2)), lipoxin, and isoprostanes, and the cytokines, IL-5, IL-4, and IL-13 on human airway smooth muscle cell migration. Chemotaxis and chemokinesis of cultured airway smooth muscle cells from humans without asthma (second to fifth passages, n = 6) were studied using collagen-I-coated polycarbonate membranes in Transwell culture plates. Receptor expression and kinase activation were studied by flow cytometry, polymerase chain reaction, and Western blotting techniques. In contrast to LTE(4)- stimulated (10(-6) M) chemokinesis and LTE(4)-primed migration toward platelet-derived growth factor (PDGF), isoprostane 15-F(2t)-IsoP, and IL-5 were neither chemotactic nor chemokinetic. PGD(2) (10(-10)-10(-6) M) was a chemoattractant and primed migration toward PDGF through the DP(2)/CRTh(2) receptor. Although airway smooth muscle cells did not express the lipoxin A(4) cognate receptor, LTE(4)-primed migration toward PDGF was blocked by lipoxin A(4) (10(-6) M), suggesting that this is mediated through CysLT(1)R antagonism. IL-13 (10 ng/ml), but not IL-4 (0.1-100 ng/ml), augmented migration toward PDGF. This was associated with increased Src-kinase phosphorylation and up-regulation of PDGF-alpha and -beta receptors, and was attenuated by IL-13Ralpha- and IL-4Ralpha-neutralizing antibodies, an Src-kinase antagonist (PP1, 3 muM), a CysLT(1)R antagonist, montelukast (10(-6) M), and by lipoxin A(4) (10(-6) M). PGD(2) and IL-13 promote human airway smooth muscle migration. IL-13 can promote airway smooth muscle migration through Src-kinase and leukotriene-dependent pathways. This may contribute to the accumulation of smooth muscle cells in remodeled airway submucosa.
