Interleukin-4 and Interleukin-13 Enhance Human Bronchial Smooth Muscle Cell Proliferation

Abstract

Background: T_H2 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_H2 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 TNFα and IL-1β 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 α chain expression, both IL-4 and IL-13 increased FGF2-induced BSMC proliferation in a time- and concentration-dependent manner. TNFα and IL-1β did not affect basal or FGF2-induced BSMC proliferation, but both proinflammatory mediators enhanced the proliferative synergism between FGF2 and the T_H2 cytokines. Conclusions: IL-4 and IL-13 potently induce FGF2-primed BSMC proliferation via an autocrine loop involving PDGFRα and PDGF-CC, and this proliferative synergism is amplified by proinflammatory cytokines.

IL-13 Promotes Collagen Accumulation in Crohn’s Disease Fibrosis by Down-Regulation of Fibroblast MMP Synthesis: A Role for Innate Lymphoid Cells?

“…In our study, nerve cells and smooth muscle cells (SMC) expressed IL-13Rα1, and SMC signalled in response to exogenous IL-13. IL-13, derived from KIR + cells, may drive muscle hyperplasia in CD by stimulating proliferation of SMC [6], so contributing to stricture formation [5]. We have also shown that nerve cells express IL-13 receptors and are increased in active UC and CD.…”

“…Fibroses in lung, liver and kidney have been linked to T cell synthesis of IL-13 [3]. This can promote collagen synthesis independently of TGF-β [4]; and cause smooth muscle cell proliferation [5], [6] and contraction [7], which may contribute to fibrotic stricture formation. IL-13 activates many other cells, including macrophages, mast cells, B cells and nerve cells (reviewed [8]), potentially contributing to pathology.…”

Airway Inflammation and Remodeling in Two Mouse Models of Asthma: Comparison of Males and Females

“…Several studies have shown that inflammatory cytokines such as IL-4 and IL-13 can contribute to goblet cell hyperplasia [15,16] and smooth muscle cell growth in vitro [17]. The lack of an association between goblet cell hyperplasia and airway smooth muscle layer on the one hand and IL-4 on the other hand in this study does not necessarily imply that this cytokine does not contribute to the remodeling process at all in our mouse models of asthma.…”

A Critical Evaluation of Anti-IL-13 and Anti-IL-4 Strategies in Severe Asthma

“…An IL-13 induced role in goblet cell differentiation, mucus production, bronchial hyperresponsiveness, immunoglobulin E (IgE) synthesis (a switch of B cell antibody production) and the recruitment of eosinophils and basophils [14,15,16,17,18,19,20] has been repeatedly demonstrated [21]. …”