TNF-R55-Specific form of human tumor necrosis factor-α induces collagenase gene expression by human skin fibroblasts

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-l 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-γ. 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.