Potential Action of IL-4 and IL-13 as Fibrogenic Factors on Lung Fibroblasts in vitro

Background: Asthma is characterized by chronic inflammation of the airway with the presence of Th2 cytokines. Airway remodeling in asthma is closely related to clinical manifestations. Lung myofibroblasts play a critical role in the airway remodeling and Th2 cytokines may modulate their behavior. We examined the effect of two major Th2 cytokines, IL-4 and IL-13, on differentiation of lung fibroblasts to myofibroblasts. We hypothesized that these cytokines would stimulate fibroblast proliferation in association with decreased prostaglandin E 2 (PGE 2 ). Methods: Lung fibroblasts were incubated with IL-4 and IL-13 with or without Th1 cytokine interferon-γ (IFN-γ) in vitro. Differentiation of lung fibroblasts to myofibroblasts was characterized by the expression of α-smooth muscle actin (α-SMA) as well as a morphological and immunohistochemical analysis. Fibroblast proliferation stimulated by IL-4 and IL-13 was assessed with the MTT assay. We also investigated the effect of these cytokines on cyclooxygenase (COX) gene expression and PGE 2 production. Results: IL-4 and IL-13 increased α-SMA expression and myofibroblastic differentiation. This effect was attenuated by IFN-γ and dexamethasone failed to have an influence on differentiation. IL-4 and IL-13 stimulated fibroblast proliferation. These cytokines downregulated the expression of both COX-1 and COX-2 genes and decreased the production of PGE 2 . Conclusions: IL-4 and IL-13 induce differentiation of fibroblasts to myofibroblasts and this response is attenuated by IFN-γ. IL-4 and IL-13 stimulate fibroblast proliferation and this effect is at least partly due to suppressed COX gene expressions and subsequently decreased PGE 2 production. These findings suggest that IL-4 and IL-13 directly act on lung fibroblast to induce a fibrogenic response.