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-gamma (IFN-gamma) in vitro. Differentiation of lung fibroblasts to myofibroblasts was characterized by the expression of alpha-smooth muscle actin (alpha-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 alpha-SMA expression and myofibroblastic differentiation. This effect was attenuated by IFN-gamma 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-gamma. 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.