The contribution of interleukin (IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma

Interleukin (IL)-4 and IL-13 are key proinflammatory cytokines in asthma. S tudies in transgenic mice show that both cytokines cause inflammation, but only IL-13 causes subepithelial fibrosis, a characteristic feature of asthm a. We compared the in vitro profibrogenic effects of IL-4 and IL-13 using b ronchial fibroblasts from asthmatic subjects. In the presence of transformi ng growth factor (TGF)-beta the cells transformed into contractile myofibro blasts and expressed alpha -smooth muscle actin and procollagen I. IL-4 and IL-13 also stimulated proliferation, but were relatively ineffective in pr omoting myofibroblast transformation. TGF-P was more potent than the cytoki nes in stimulating release of endothelin-1 and vascular endothelial growth factor, whereas IL-4 and IL-13 were more potent stimuli for eotaxin release . Although neither IL-4 nor IL-13 induced profibrotic responses, both cytok ines caused a corticosteroid-insensitive stimulation of TGF-beta2 release f rom primary bronchial epithelial cells. These data indicate that epithelial activation by IL-13 or IL-4 plays a critical role in initiating remodeling through release of TGF-beta2. TGF-beta2 then activates the underlying myof ibroblasts to secrete matrix proteins and smooth muscle and vascular mitoge ns to propagate remodeling changes into the submucosa. In contrast, direct activation of submucosal fibroblasts by IL-4 and IL-13 has a proinflammator y effect via eotaxin release and recruitment of eosinophils into the airway s.