Interleukin-4 and interleukin-13 enhance human bronchial smooth muscle cell proliferation

Background: T(H)2 inflammation and bronchial smooth muscle cell (BSMC) hyperplasia are characteristic features of asthma, but whether these phenomena are linked remains unknown. This study aims to define the effect of the T(H)2 cytokines IL-4 and IL-13 on human BSMC proliferation when administered alone or in combination with the fibroblast growth factor 2 (FGF2) growth factor. In addition, the effects of the proinflammatory mediators TNF alpha and IL-1 beta and the involvement of members of the well-known family of platelet-derived growth factor (PDGF) mitogens were tested. Methods: BSMC proliferation was measured by crystal violet staining and PDGF and PDGF receptor (PDGFR) expression were determined by RT-PCR, immunocytochemistry, ELISA, flow cytometry and dot plot analysis. Results: Neither IL-4 nor IL-13 alone induced BSMC proliferation, despite both being potent inducers of PDGF-CC. However, following a pretreatment with FGF2, which increased PDGFR alpha chain expression, both IL-4 and IL-13 increased FGF2-induced BSMC proliferation in a time- and concentration-dependent manner. TNF alpha and IL-1 beta did not affect basal or FGF2-induced BSMC proliferation, but both proinflammatory mediators enhanced the proliferative synergism between FGF2 and the T(H)2 cytokines. Conclusions: IL-4 and IL-13 potently induce FGF2-primed BSMC proliferation via an autocrine loop involving PDGFR alpha and PDGF-CC, and this proliferative synergism is amplified by proinflammatory cytokines. Copyright (C) 2008 S. Karger AG, Basel.