Hypoxia induces expression of the chemokines monocyte chemoattractant protein-1 (MCP-1) and IL-8 in human dermal fibroblasts

Hypoxia is an important factor in the pathophysiology of vascular and infla mmatory diseases. Leucocyte infiltration, as a consequence of adhesion mole cule up-regulation and chemokine release, is a prominent feature of these d iseases. The objective of our study was to investigate the potential role o f resident fibroblasts in hypoxia-induced chemotactic responses. We show th at MCP-1 and IL-8 mRNA are specifically induced by hypoxia in dermal fibrob lasts. This response is paralleled by increased NF-kappaB p65/p50 binding a ctivity, and it is inhibited by pretreatment with N-acetyl-L-cysteine. MCP- 1 secreted by fibroblasts is chemotactic for monocytic cells and this activ ity is significantly increased by hypoxia. Chemotactic index correlates wit h MCP-1 protein levels and is significantly decreased by neutralizing anti- MCP-1 MoAb. These findings demonstrate the ability of resident fibroblasts to mediate chemotaxis of leucocytes through the release of chemokines in re sponse to hypoxia. Our data point to MCP-1 as an important component in thi s response, and therefore it may be a potential target in inflammatory resp onses associated with hypoxia.