Expression and effects of cardiotrophin‐1 (CT‐1) in human airway smooth muscle cells

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Abstract
Cellular hypertrophy and/or a reduced rate of apoptosis could increase airway smooth muscle mass. As cardiotrophin‐1 (CT‐1) induces hypertrophy and inhibits apoptosis in cardiomyocytes, we tested for the expression and effects of CT‐1 in human bronchial smooth muscle cells (HBSMC). CT‐1 was detected in abundance in normal adult human lung and was expressed in both fetal and adult HBSMC. Following serum deprivation, CT‐1 was released by reintroduction of serum and by TGF‐β2/IL‐4 in fetal but not adult cells. TGF‐β2/IL‐4 triggered the release of CT‐1 in serum‐fed adult cells. Hypoxia and strain had no effect on the release of CT‐1. CT‐1 reduced the apoptosis induced both by serum deprivation and by Fas antibody/TNF‐α treatment in adult cells, with greater efficacy than other members of the IL‐6 superfamily. The MAPK/ERK kinase inhibitor PD98059 (1–10 μM) reduced the effect of CT‐1. Fetal cells were more resistant to apoptosis. CT‐1 (10 ng ml−1) induced a significant increase in cell size as judged by protein/DNA ratios and flow cytometry. No effects on smooth muscle α‐actin or vimentin proteins were noted, although CT‐1 qualitatively alters the cytostructural distribution of SM22, an actin filament‐associated protein, and increased SM22 protein abundance. No effect on proliferation or migration was evident. These data suggest CT‐1 expression primarily in fetal and synthetic HBSMC phenotypes. By reducing the rates of apoptosis and inducing hypertrophy, CT‐1 may contribute to increased smooth muscle mass in airway disease. British Journal of Pharmacology (2003) 140, 1237–1244. doi:10.1038/sj.bjp.0705562