alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte macrophages

The hypothesis that macrophages contain an autocrine circuit based on melan ocortin [ACTH and alpha-melanocyte-stimulating hormone (alpha-MSH)] peptide s has major implications for neuroimmunomodulation research and inflammatio n therapy. To test this hypothesis, cells of the THP-1 human monocyte/macro phage line were stimulated with lipopolysaccharide (LPS) in the presence an d absence of alpha-MSH. The inflammatory cytokine tumor necrosis factor (TN F)-alpha was inhibited in relation to alpha-MSH concentration. Similar inhi bitory effects on TNF-alpha were observed with ACTH peptides that contain t he ol-MSH amino acid sequence and act on melanocortin receptors. Nuclease p rotection assays indicated that expression of the human melanocortin-1 rece ptor subtype (hMC-1R) occurs in THP-1 cells; Southern blots of RT-PCR produ ct revealed that additional subtypes, hMC-3R and hMC-5R, also occur. Incuba tion of resting macrophages with antibody to hMC-1R increased TNF-alpha con centration; the antibody also markedly reduced the inhibitory influence of alpha-MSH on TNF-alpha in macrophages treated with LPS. These results in ce lls known to produce alpha-MSH at rest and to increase secretion of the pep tide when challenged are consistent with an endogenous regulatory circuit b ased on melanocortin peptides and their receptors. Targeting of this neuroi mmunomodulatory circuit in inflammatory diseases in which myelomonocytic ce lls are prominent should be beneficial.