Background: The pathogenesis of keloid and hypertrophic scar is less well understood because of the lack of animal models. The cell-surface Fas receptor, which is widely distributed in skin components, has been shown to be an important factor that induces apoptosis in human dermal fibroblasts. In this report, the authors performed a comparative study on apoptotic signal transduction in fibroblasts derived from keloids and hypertrophic scars.
Methods: Fibroblasts harvested from 10 patients with keloids and hypertrophic scars were used for this study. At first, apoptosis induction using Fas antibody and C2-ceramide were evaluated using electron microscopy and flow cytometry. Second, the expression of the apoptosis-related proteins Fas and Bcl-2 were measured by means of flow cytometry. Third, ceramide was measured by quantitative derivatization to ceramide-1-phosphate using diacylglycerol kinase and [γ-32P] ATP. Moreover, intercellular Ca2+ was investigated using confocal microscopic analyses.
Results: In contrast to hypertrophic scar–derived fibroblasts, those derived from keloids are significantly resistant to Fas-mediated apoptosis. The intercellular ceramide and Ca2+ were not activated. There were no significant differences in the level of expression of Bcl-2 between the two groups, but Fas expression was higher in keloid than in hypertrophic scar. Fibroblasts from the two groups were susceptible to ceramide-induced apoptosis.
Conclusions: Blocking of the Fas-mediated apoptotic pathway in keloids occurs upstream of the second messenger. The abnormal Fas-induced apoptosis in keloids may account for the imbalance of proliferation and apoptosis. Enhancement of Fas sensitivity could be a promising therapeutic target.