Overexpression of monocyte chemoattractant protein 1 in systemic sclerosis- Role of platelet-derived growth factor and effects on monocyte chemotaxis and collagen synthesis

Objective. In addition to its chemotactic properties, recent evidence sugge sts that monocyte chemoattractant protein 1 (MCP-1) might participate in th e fibrotic process by inducing the secretion of extracellular matrix (ECM) components. Since the factors that initiate the accumulation of inflammator y infiltrates and ECM deposits in systemic sclerosis (SSc) skin lesions are still unknown, this study was undertaken to examine the role of MCP-1 in S Sc. Methods. In situ hybridization and immunohistochemistry studies for MCP-1 w ere performed on skin biopsy specimens from patients with SSc and healthy c ontrols. To identify possible stimulators of MCP-1 overexpression in SSc le sions, cultured dermal fibroblasts were incubated with recombinant platelet -derived growth factor (PDGF) and analyzed by real-time polymerase chain re action (PCR) and enzyme-linked immunosorbent assay. The chemotactic effects of SSc fibroblasts were examined using a modified Boyden chamber assay. To analyze the fibrotic potential of MCP-1, cultured dermal fibroblasts were incubated with recombinant MCP-1, and type I procollagen was measured by ra dioimmunoassay and real-time PCR. Results. MCP-1 was expressed by fibroblasts, keratinocytes, and perivascula r infiltrates throughout the skin, in involved as well as uninvolved skin a reas, from 10 of 11 SSc patients, whereas no expression of MCP-I was found in healthy controls. Stimulation with PDGF resulted in a significant increa se in MCP-1 messenger RNA and protein, with differences between healthy con trol fibroblasts and fibroblasts from SSc patients. The chemotactic activit y for peripheral blood mononuclear cells of SSc fibroblast supernatants inc reased in a time-dependent manner. Antibodies blocking MCP-1 decreased the chemotactic activity of SSc fibroblasts by a mean +/- SD of 37 +/- 12%. Des pite an increase in type I collagen levels over time, no effect of recombin ant MCP-1 on the synthesis of type I collagen was observed. Conclusion. These data indicate that MCP-1 might contribute to the initiati on of inflammatory infiltrates in SSc. Possible stimuli of MCP-1 in dermal SSc lesions include PDGF, which is known to be expressed in SSc. In contras t to previous findings in fibrotic lung diseases, no effect of MCP-1 on col lagen synthesis was observed in SSc dermal fibroblasts in vitro.