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Am. J. Respir. Cell Mol. Biol., Volume 25, Number 3, September, 2001 385-391

The Contribution of Interleukin (IL)-4 and IL-13 to the Epithelial-Mesenchymal Trophic Unit in Asthma

Audrey Richter, Sarah M. Puddicombe, James L. Lordan, Fabio Bucchieri, Susan J. Wilson, Ratko Djukanovic', Gordon Dent, Stephen T. Holgate, and Donna E. Davies

Respiratory, Cell and Molecular Biology Division, School of Medicine, Southampton General Hospital, Southampton, United Kingdom

Interleukin (IL)-4 and IL-13 are key proinflammatory cytokines in asthma. Studies in transgenic mice show that both cytokines cause inflammation, but only IL-13 causes subepithelial fibrosis, a characteristic feature of asthma. We compared the in vitro profibrogenic effects of IL-4 and IL-13 using bronchial fibroblasts from asthmatic subjects. In the presence of transforming growth factor (TGF)-beta the cells transformed into contractile myofibroblasts and expressed alpha -smooth muscle actin and procollagen I. IL-4 and IL-13 also stimulated proliferation, but were relatively ineffective in promoting myofibroblast transformation. TGF-beta was more potent than the cytokines 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 cytokines caused a corticosteroid-insensitive stimulation of TGF-beta 2 release from 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-beta 2. TGF-beta 2 then activates the underlying myofibroblasts to secrete matrix proteins and smooth muscle and vascular mitogens to propagate remodeling changes into the submucosa. In contrast, direct activation of submucosal fibroblasts by IL-4 and IL-13 has a proinflammatory effect via eotaxin release and recruitment of eosinophils into the airways.

Abbreviations: absorbance at 630 nm, A630; alpha -smooth muscle actin, alpha -SMA; bronchial hyperresponsiveness, BHR; Dulbecco's modified Eagle's medium, DMEM; enzyme-linked immunosorbent assay, ELISA; epithelial- mesenchymal trophic unit, EMTU; endothelin, ET; fetal bovine serum, FBS; interleukin, IL; phosphate-buffered saline, PBS; polymerase chain reaction, PCR; standard deviation, SD; serum-free medium, SFM; smooth-muscle cell, SMC; transforming growth factor, TGF; T helper, Th; vascular endothelial growth factor, VEGF.




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