Abstract
Pro-opiomelanocortin (POMC)-derived peptides such as alpha-melanocyte-stimulating hormone (alpha-MSH) recently have been recognized as mediators with potent immunomodulating and anti-inflammatory properties. Their effects are mediated via different protein G-coupled melanocortin (MC) receptors that are capable to bind one or more POMC-derived peptides. Among these receptors, MC-1 is specific for alpha-MSH and adrenocorticotropin. The purpose of the present study was to investigate whether MC receptors are expressed on normal human dermal microvascular endothelial cells (HDMEC) as well as transformed human dermal microvascular endothelial cells (HMEC-1). Using semiquantitative reverse transcriptase-PCR and MC receptor-specific primers, both HDMEC and HMEC-1 were found to express MC-1 constitutively. In addition, MC-1 expression was increased upon stimulation with IL-1beta or alpha-MSH itself. Other known MC receptors were neither detectable in unstimulated nor in IL-1beta- or alpha-MSH-stimulated cells. The binding of alpha-MSH by HMEC-1 was specific and saturable as demonstrated by competitive and saturation-binding studies with 125I-labeled alpha-MSH (Kd: 1.1 nM). To evaluate the physiologic relevance of MC-1 expression, HMEC-1 were treated with various concentrations of alpha-MSH (10(-15)-10(-6) M) and were investigated for their cytokine-producing capacity. Alpha-MSH (10(-10)-10(-8) M) significantly up-regulated IL-8 release and mRNA expression by HMEC-1. In contrast, the production of IL-1 or IL-6 by HMEC-1 was not affected upon treatment with alpha-MSH. These data provide first evidence that HDMEC express functional MC receptors. Therefore, alpha-MSH, which is released in the skin during cutaneous inflammation via inducing chemokines may represent an important signal required for leukocyte-endothelial cell interaction.
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