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- Title
TNF-R55-Specific Form of Human Tumor Necrosis Factor-α Induces Collagenase Gene Expression By Human Skin Fibroblasts.
- Authors
Westermarck, Jukka; Häkkinen, Lari; Fiers, Walter; Kähäri, Veli-Matti
- Abstract
Tumor necrosis factor-α(TNF-α) is a potent inhibitor of connective tissue formation. The cellular effects of TNF-α are mediated by two distinct cell-surface receptors, TNF-R55 and TNF-R75, both present on various types of cells, including fibroblasts. In this study we wanted to elucidate the role of TNF-R55 as a mediator of the connective tissue effects of TNF-α by using a mutant, TNF-R55-specific form of human TNF-α. This mutant TNF-α markedly induced collagenase and stromelysin-1 gene expression in dermal fibroblasts, the maximal activation (up to 42-fold) being 65%-89% of that noted with wild-type human TNF-α. In addition, TNF-R55-specific TNF-α suppressed type I collagen mRNA levels as potently as wild-type TNF-α (by 60%). The enhancement of collagenase gene expression by TNF-R55-specific TNF-α was augmented by simultaneous treatment of normal and scleroderma skin fibroblasts with interferon-γ, indicating specific enhancement of TNF- R55 signaling pathway by interferon-α. These results show that stimulation of the TNF-R55 signaling pathway is sufficient for the inhibitory effects of TNF-α on extracellular matrix formation by dermal fibroblasts. It is conceivable that due to reduced systemic toxicity, TNF-R55-specific forms of human TNF-α may prove to be feasible in the therapy of fibrotic disorders.
- Subjects
TUMOR necrosis factors; COLLAGENASES; GENE expression; FIBROBLASTS; MACROPHAGES; PROTEOLYTIC enzymes
- Publication
Journal of Investigative Dermatology, 1995, Vol 105, Issue 2, p197
- ISSN
0022-202X
- Publication type
Article
- DOI
10.1111/1523-1747.ep12317114