α-MSH production, receptors, and influence on neopterin in a human monocyte/macrophage cell line

Abstract

alpha-Melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide derived from pro-opiomelanocortin, has potent antiinflammatory activity in laboratory animals. alpha-MSH inhibits nitric oxide production by murine macrophages, an influence believed to reflect activation of an autocrine circuit in these cells, one that is based on production and release of alpha-MSH and subsequent stimulation of melanocortin receptors. We found that THP-1 cells, human monocytic cells, produced alpha-MSH; this production was increased by interleukin-6, tumor necrosis factor a, or concanavalin A. These cells also expressed the gene for the human alpha-MSH receptor MC1. Unlike murine macrophages, THP-1 cells produced little nitrite in response to interferon-gamma (IFN-gamma) and lipopolysaccharide, and a-MSH inhibited this production only slightly. However, production of neopterin, a presumed primate homologue of nitric oxide in lower animals, was increased in THP-1 cells stimulated with INF-gamma plus TNF-alpha and alpha-MSH significantly inhibited this production. The evidence indicates that an autocrine regulatory circuit based on alpha-MSH occurs in human monocyte/macrophages much as in murine macrophages. alpha-MSH-induced modulation of specific inflammatory mediators/cytotoxic agents appears to differ depending on the importance of the mediators in the myelomonocytic cells of different species.

Tissue distribution and differential expression of melanocortin 1 receptor, a malignant melanoma marker

“…We also confirmed (Bhardwaj et al, 1997) that monocytes activated by short term culture with LPS or with GM-CSF alone or in combination with IL-4, showed enhanced binding of a-MSH (30% for IL-4/GM-CSF and 2 -3-fold for GM-CSF or LPS treated monocytes) as compared to control monocytes cultured in medium only. The macrophage/monocyte line THP-1 showed the same levels of a-MSH binding as LPS-or cytokine stimulated monocytes (Figure 5A), confirming the MC1R expression in this line (Rajora et al, 1996), while an ovarian and a colon carcinoma (OV3507, SW480) included as controls only bound low to insignificant levels of a-MSH.…”

“…Of these, the melanocortin 1 receptor (MC1R) was originally described to be mainly located on melanoma and melanocytes (Varga et al, 1976;Tatro et al, 1990;Chhajlani, 1996;Suzuki et al, 1996;Xia et al, 1996). MC1R was, however, subsequently shown also to be expressed in various human tissues including human keratinocytes and monocytes (Chhajlani ans Wikberg, 1992;Rajora et al, 1996;Thörnwall et al, 1997;Chakraborty et al, 1999;Curry et al, 2001).…”

“…Although there is evidence that MC1R has a broad distribution in various normal tissues including normal melanocytes, activated macrophages, and keratinocytes (Chhajlani, 1996;Rajora et al, 1996;Thörnwall et al, 1997;Chakraborty et al, 1999;Curry et al, 2001), this assessment is based mainly on qualitative or semi-quantitative methods. There is experimental and clinical evidence that immunotherapy based on administration of monoclonal antibodies or on specific tumour vaccines can also have an effect when based on non-mutated 'self-proteins' over-expressed in tumours, such as non-mutated p53, HER-2/neu, and gp100 (Ropke et al, 1996;Nagata et al, 1997;Rosenberg et al, 1998;Buchler et al, 2001;Slamon et al, 2001).…”

α-MSH Modulates Local and Circulating Tumor Necrosis Factor-α in Experimental Brain Inflammation

“…To test the idea that the primary ␣-MSH receptor MC-1, recently found in murine macrophages and in human macrophages and neutrophils (Star et al, 1995;Rajora et al, 1996;Catania et al, 1996), likewise occurs in brain tissue, normal mouse brain was subjected to RT-PCR and Southern analysis. This analysis revealed a substantial signal at 529 bp, consistent with the size of the cDNA for the murine MC-1 receptor (Fig.…”

Cutting Edge: Is Vasoactive Intestinal Peptide a Type 2 Cytokine?

“…An important clue was the discovery that lymphocytes produce hormones and neuropeptides that act as endogenous immunomodulators. For example, immune cells produce substance P (1), corticotropin releasing factor (CRF) (2), ␣-melanocyte stimulating factor (␣-MSH) (3), adrenocorticotropin hormone (4), ␤-endorphins (5), somatostatin (6), calcitonin gene-related peptide (CGRP) (7), neuropeptide Y (NPY) (8), atrial natriuretic peptide (ANP) (9), and vasoactive intestinal peptide (VIP) 3 (10 -13).…”