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

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Abstract
Objective Chemokines are important mediators in the chemoattraction of leukocytes to sites of inflammation. This study investigated the potential contribution of systemic sclerosis (SSc) fibroblasts to chemokine production and 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 assay. Monocyte chemoattractant protein 1 (MCP‐1) protein production was analyzed by enzyme‐linked immunosorbent assay. The chemotactic effect of fibroblast‐derived MCP‐1 on monocytic cells was analyzed in a transmigration assay. Nuclear factor κB (NF‐κB) and activator protein 1 (AP‐1) activation in fibroblasts was studied by electromobility shift analysis. MCP‐1 expression in SSc skin sections was studied by immunohistochemistry. Results Among all chemokine genes studied, only MCP‐1 and interleukin‐8 mRNA were expressed by nonstimulated normal and SSc fibroblasts. SSc fibroblasts displayed increased constitutive expression of MCP‐1 mRNA and protein and showed a blunted response to oxidative stress. Increased MCP‐1 production was associated with higher chemotactic activity for monocytic cells. Increased NF‐κB or AP‐1 activation was not responsible for the constitutive overexpression of MCP‐1 by SSc fibroblasts. In SSc skin sections, MCP‐1 expression 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 expression that is characterized by constitutively increased and abnormally regulated expression of MCP‐1 in vitro. MCP‐1 is also expressed in lesional skin and can participate in the pathogenesis of SSc.