Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts

Summary Connective tissue growth factor (CTGF) plays a role in the fibrotic process of systemic sclerosis (SSc). Because hypoxia is associated with fibrosis in several profibrogenic conditions, we investigated whether CTGF expression in SSc fibroblasts is regulated by hypoxia. Dermal fibroblasts fro...

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Bibliographic Details
Published in:Clinical and experimental immunology 2006-11, Vol.146 (2), p.362-370
Main Authors: Hong, K.‐H., Yoo, S.‐A., Kang, S.‐S., Choi, J.‐J., Kim, W.‐U., Cho, C.‐S.
Format: Article
Language:English
Subjects:
Basic Immunology
Biological and medical sciences
Cell Hypoxia - physiology
Cells, Cultured
Cobalt - pharmacology
Connective Tissue Growth Factor
CTGF
dermal fibroblasts
Fibroblasts - metabolism
Fundamental and applied biological sciences. Psychology
Fundamental immunology
HIF‐1α
Humans
hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Immediate-Early Proteins - biosynthesis
Immediate-Early Proteins - genetics
Immunopathology
Intercellular Signaling Peptides and Proteins - biosynthesis
Intercellular Signaling Peptides and Proteins - genetics
Medical sciences
NF-kappa B - physiology
RNA, Messenger - genetics
Scleroderma, Systemic - metabolism
Signal Transduction - physiology
Skin - metabolism
systemic sclerosis
Transfection
Transforming Growth Factor beta - pharmacology
Up-Regulation - drug effects
Up-Regulation - physiology
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Summary:Summary Connective tissue growth factor (CTGF) plays a role in the fibrotic process of systemic sclerosis (SSc). Because hypoxia is associated with fibrosis in several profibrogenic conditions, we investigated whether CTGF expression in SSc fibroblasts is regulated by hypoxia. Dermal fibroblasts from patients with SSc and healthy controls were cultured in the presence of hypoxia or cobalt chloride (CoCl2), a chemical inducer of hypoxia‐inducible factor (HIF)‐1α. Expression of CTGF was evaluated by Northern and Western blot analyses. Dermal fibroblasts exposed to hypoxia (1% O2) or CoCl2 (1–100 µM) enhanced expression of CTGF mRNA. Skin fibroblasts transfected with HIF‐1α showed the increased levels of CTGF protein and mRNA, as well as nuclear staining of HIF‐1α, which was enhanced further by treatment of CoCl2. Simultaneous treatment of CoCl2 and transforming growth factor (TGF)‐β additively increased CTGF mRNA in dermal fibroblasts. Interferon‐γ inhibited the TGF‐β‐induced CTGF mRNA expression dose‐dependently in dermal fibroblasts, but they failed to hamper the CoCl2‐induced CTGF mRNA expression. In addition, CoCl2 treatment increased nuclear factor (NF)‐κB binding activity for CTGF mRNA, while decreasing IκBα expression in dermal fibroblasts. Our data suggest that hypoxia, caused possibly by microvascular alterations, up‐regulates CTGF expression through the activation of HIF‐1α in dermal fibroblasts of SSc patients, and thereby contributes to the progression of skin fibrosis.
ISSN:0009-9104
1365-2249
DOI:10.1111/j.1365-2249.2006.03199.x