ALPHA-MSH PRODUCTION, RECEPTORS, AND INFLUENCE ON NEOPTERIN IN A HUMAN MONOCYTE-MACROPHAGE CELL-LINE

alpha-Melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide der ived from proopiomelanocortin, has potent antiinflammatory activity in laboratory animals. alpha-MSH inhibits nitric oxide production by mur ine macrophages, an influence believed to reflect activation of an aut ocrine circuit in these cells, one that is based on production and rel ease of alpha-MSH and subsequent stimulation of melanocortin receptors . We found that THP-1 cells, human monocytic cells, produced alpha-MSH ; this prodnction was increased by interleukin-6, tumor necrosis facto r a, or concanavalin A. These cells also expressed the gene for the hu man alpha-MSH receptor MC1. Unlike murine macrophages, THP-1 cells pro duced little nitrite in response to interferon-gamma (IFN-gamma) and L ipopolysaccharide, and a-MSH inhibited this production only slightly, However, production of neopterin, a presumed primate homologue of nitr ic oxide in lower animals, was increased in THP-1 cells stimulated wit h IFN-gamma plus TNF-alpha and alpha-MSH significantly inhibited this production. The evidence indicates that an autocrine regulatory circui t based on alpha-MSH occurs in human monocyte/macrophages much as in m urine macrophages, alpha-MSH-induced modulation of specific inflammato ry mediators/cytotoxic agents appears to differ depending on the impor tance of the mediators in the myelomonocytic cells of different specie s.