Leukotriene C₄ induces TGF-β₁ production in airway epithelium via p38 kinase pathway

Cysteinyl leukotrienes (CysLTs) play an important role in the pathogenesis of airway remodeling. We investigated the interaction between epithelium and CysLTC₄, and the contribution of this interaction to airway fibrosis. Human airway epithelial cells were grown on air-liquid interface culture inserts. CysLTC₄ was employed to stimulate the cells. Conditioned medium following CysLTC₄ stimulation was coincubated with human lung fibroblasts. Our results have demonstrated that CysLTC₄ stimulates airway epithelial cells, through a p38 mitogen-activated protein kinase (MAPK) activation mechanism, to produce transforming growth factor β₁ (TGF-β₁), which results in fibroblast proliferation. The selective p38 MAPK inhibitor S203580 successfully inhibits p38 MAPK phosphorylation and subsequent TGF-β₁ production. CysLT ₁ receptor antagonist montelukast and corticosteroid inhibit TGF-β₁ production at the mRNA and protein levels. When treated with LTC₄, the conditioned medium from epithelial cells enhances fibroblast proliferation, this mitogenic effect being attributed to TGF-β₁ and LTC₄ remaining in the culture medium. In addition, LTC₄ itself acts as a potential growth factor for lung fibroblasts. These data indicate that interactions between LTC₄ and airway epithelial cells may contribute to the pathogenesis of airway remodeling. Early intervention to stop these processes may be useful in preventing airway fibrosis in chronic allergic inflammation.