CHEMOKINE GENE-EXPRESSION AND SECRETION BY CYTOKINE-ACTIVATED HUMAN MICROVASCULAR ENDOTHELIAL-CELLS - DIFFERENTIAL REGULATION OF MONOCYTE CHEMOATTRACTANT PROTEIN-1 AND INTERLEUKIN-8 IN RESPONSE TO INTERFERON-GAMMA

The elicitation of leukocytes from the circulation to inflamed tissue depends on the activation of both the leukocyte and endothelial cell. In this study toe determined the gene expression and secretion pattern s for the chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in cytokine- and lipopolysaccharide (LPS)-treated c ultured human lung microvascular endothelial cells (HLE). HLE constitu tively ex pressed low levels of MCP-1 and IL-8. Treatment of NLE with a variety of cytokines and LPS upregulated both IL-8 mRNA expression a nd release of immunoreactive IL-8 with an order of potency tumor necro sis factor-alpha (TNF-alpha) >> IL-1 alpha > LPS, whereas interferon-g amma (IFN-gamma) had no effect on IL-8 mRNA or antigenic levels. Howev er, IFN-gamma, in combination with high doses of IL-1 alpha, resulted in a synergistic increase in IL-8 generation. MCP-1 gene expression an d secretion was induced in a dose-dependent manner after IL-1 alpha, T NF-alpha, IFN-gamma, and LPS activation of HLE. IL-1 alpha was the mos t potent inducer of MCP-1 generation and LPS was relatively ineffectiv e IFN-gamma, in combination with low doses of IL-1 alpha, resulted in a synergistic increase in MCP-1 generation by HLE. These results demon strate that although IL-8 and MCP-1 generation by NLE occurs on cytoki ne treatment, the relative ability of a given cytokine to elicit IL-8 generation is not directly parallel to effects on MCP-1 generation The se data suggest that the regulation of IL-8 and MCP-1 expression exhib it significant differences in their mechanisms. Such differences in th e expression of specific chemokines may explain the specific appearanc e of various leukocytes at sites of inflammation and injury. These dat a also directly demonstrate that the lung microvascular endothelium co ntribute to the cytokine network, of the lung, with the ability to res pond to locally generated cytokines and to produce potent mediators of the local inflammatory response.