Chemokine expression by systemic sclerosis fibroblasts - Abnormal regulation of monocyte chemoattractant protein 1 expression

Objective. Chemokines are important mediators in the chemoattraction of leu kocytes to sites of inflammation. This study investigated the potential con tribution of systemic sclerosis (SSc) fibroblasts to chemokine production a nd its potential relevance to the pathogenesis of SSc. Methods. The expression of messenger RNA (mRNA) for different C-C and C-X-C chemokines by SSc and normal fibroblasts was studied by RNase protection a ssay. Monocyte chemoattractant protein 1 (MCP-1) protein production was ana lyzed by enzyme-linked immunosorbent assay. The chemotactic effect of fibro blast-derived MCP-1 on monocytic cells was analyzed in a transmigration ass ay. Nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) activa tion in fibroblasts was studied by electromobility shift analysis. MCP-1 ex pression in SSc skin sections was studied by immunohistochemistry. Results. Among all chemokine genes studied, only MCP-1 and interleukin-8 mR NA were expressed by nonstimulated normal and SSc fibroblasts. SSc fibrobla sts displayed increased constitutive expression of MCP-1 mRNA and protein a nd showed a blunted response to oxidative stress. Increased MCP-1 productio n was associated with higher chemotactic activity for monocytic cells. Incr eased NF-kappaB or AP-1 activation was not responsible for the constitutive overexpression of MCP-1 by SSc fibroblasts. In SSc skin sections, MCP-1 ex pression was detected in fibroblasts, keratinocytes, and mononuclear cells, whereas it was undetectable in normal skin. Conclusion. SSc fibroblasts display a specific pattern of chemokine gene ex pression that is characterized by constitutively increased and abnormally r egulated expression of MCP-1 in vitro. MCP-1 is also expressed in lesional skin and can participate in the pathogenesis of SSc.