Mechanisms of the antiinflammatory effects of alpha-MSH. Role of transcription factor NF-kappa B and adhesion molecule expression.

The recruitment of leukocytes from the circulation to inflamed tissue is regulated by the expression of adhesion molecules on both leukocytes and endothelial cells. The proopiomelanocortin-derived peptide alpha-melanocyte stimulating hormone (alpha-MSH) is known to modulate inflammation. Thus, we investigated the influence of alpha-MSH on the LPS-induced expression of the adhesion molecules E-selectin and VCAM-1 on endothelial cells. Human microvascular endothelial cells (HMEC-1) were treated with LPS (100 ng/ml) alone or in the presence of alpha-MSH (10(-8) to 10(-16) M). RT-PCR analysis showed that alpha-MSH significantly reduced LPS-induced expression of VCAM-1 and E-selectin. Since many adhesion molecules contain regulatory NF-kappa B sites in their promoter region, the role of alpha-MSH in the activation of the transcription factor NF-alpha B was also investigated. alpha-MSH significantly downregulated the LPS-mediated activation of NF-kappa B, in a dose-dependent manner. These findings indicate that modulation of the transcription factor NF-kappa B is a crucial molecular event, one that seems to be responsible for the antiinflammatory effects of alpha-MSH.