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-MSH and its receptors in regulation of tumor necrosis
factor- production by human monocyte/macrophages
Departments of 1 Physiology and 5 Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9040; 2 Astra Hassle, 431 83 Molndal, Sweden; 3 Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0682; and 4 Third Division of Internal Medicine, IRCCS Ospedale Maggiore, Milan, Italy 20122
The
hypothesis that macrophages contain an autocrine circuit based on
melanocortin [ACTH and 
-melanocyte-stimulating hormone (-MSH)] peptides has major implications for
neuroimmunomodulation research and inflammation therapy. To test this
hypothesis, cells of the THP-1 human monocyte/macrophage line were
stimulated with lipopolysaccharide (LPS) in the presence and absence of
-MSH. The inflammatory cytokine tumor necrosis factor (TNF)- was
inhibited in relation to -MSH concentration. Similar inhibitory
effects on TNF- were observed with ACTH peptides that contain the
-MSH amino acid sequence and act on melanocortin receptors. Nuclease protection assays indicated that expression of the human melanocortin-1 receptor subtype (hMC-1R) occurs in THP-1 cells; Southern blots of
RT-PCR product revealed that additional subtypes, hMC-3R and hMC-5R,
also occur. Incubation of resting macrophages with antibody to hMC-1R
increased TNF- concentration; the antibody also markedly reduced the
inhibitory influence of -MSH on TNF- in macrophages treated with
LPS. These results in cells known to produce -MSH at rest and to
increase secretion of the peptide when challenged are consistent with
an endogenous regulatory circuit based on melanocortin peptides and
their receptors. Targeting of this neuroimmunomodulatory circuit in
inflammatory diseases in which myelomonocytic cells are prominent
should be beneficial.
melanocortin peptides; melanocortin receptors; inflammation; autocrine regulation; neuroimmunomodulation; THP-1 cells; melanocortin-1 receptor antibody; -melanocyte-stimulating hormone
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