Expression and effects of cardiotrophin-1 (CT-1) in human airway smooth muscle cells.
1. 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). 2. CT-1 was detected in abundance in normal adult human lung and was expressed in both fetal and adult HBSMC. 3. Following serum deprivation, CT-1 was released by reintroduction of serum and by TGF-beta 2/IL-4 in fetal but not adult cells. TGF-beta 2/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. 4. CT-1 reduced the apoptosis induced both by serum deprivation and by Fas antibody/TNF-alpha treatment in adult cells, with greater efficacy than other members of the IL-6 superfamily. The MAPK/ERK kinase inhibitor PD98059 (1-10 microM) reduced the effect of CT-1. Fetal cells were more resistant to apoptosis. 5. 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 alpha-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. 6. 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.
University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6.
Danyi
D
Zhou
Xueyan
X
Zheng
Lu
L
Wang
Gerald
G
Stelmack
Andrew J
AJ
Halayko
Delbert
D
Dorscheid
Tony R
TR
Bai
D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D001980:Bronchi / Q000166:cytology*; D002308:Cardiolipins / Q000378:metabolism / Q000494:pharmacology*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D005419:Flavonoids / Q000494:pharmacology; D019085:Fluorescent Antibody Technique, Direct; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002308:Cardiolipins; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D005419:Flavonoids; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one