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Melanocortin 1 Receptor Gene Status Proliferation in Humans

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Melanocortin 1 Receptor Gene Status Proliferation in Humans α-Melanocyte-Stimulating Hormone Suppresses Antigen-Induced Lymphocyte Proliferation in Humans Independently of Melanocortin 1 Receptor Gene Status This information is current as of September 24, 2021. Ashley Cooper, Samantha J. Robinson, Chris Pickard, Claire L. Jackson, Peter S. Friedmann and Eugene Healy J Immunol 2005; 175:4806-4813; ; doi: 10.4049/jimmunol.175.7.4806 http://www.jimmunol.org/content/175/7/4806 Downloaded from References This article cites 36 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/175/7/4806.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology ␣-Melanocyte-Stimulating Hormone Suppresses Antigen-Induced Lymphocyte Proliferation in Humans Independently of Melanocortin 1 Receptor Gene Status1 Ashley Cooper,2 Samantha J. Robinson,2 Chris Pickard,2 Claire L. Jackson, Peter S. Friedmann, and Eugene Healy3 Studies in mice indicate that ␣-melanocyte-stimulating hormone (␣MSH) is immunosuppressive, but it is not known whether ␣MSH suppresses human immune responses to exogenous Ags. Human PBMCs, including monocytes, express the melanocortin 1 receptor (MC1R), and it is thought that the ability of ␣MSH to alter monocyte-costimulatory molecule expression and IL-10 release is mediated by this receptor. However, the MC1R gene is polymorphic, and certain MC1R variants compromise receptor signaling via cAMP, resulting in red hair and fair skin. Here, we have investigated whether ␣MSH can suppress Ag-induced Downloaded from lymphocyte proliferation in humans and whether these effects are dependent on MC1R genotype. ␣MSH suppressed streptokinase- streptodornase-induced lymphocyte proliferation, with maximal inhibition at 10؊13–10؊11 M ␣MSH. Anti-IL-10 Abs failed to prevent suppression by ␣MSH, indicating that it was not due to MC1R-mediated IL-10 release by monocytes. Despite variability in the degree of suppression between subjects, similar degrees of ␣MSH-induced immunosuppression were seen in individuals with wild-type, heterozygous variant, and homozygous/compound heterozygous variant MC1R alleles. RT-PCR of streptokinase- streptodornase-stimulated PBMCs for all five melanocortin receptors demonstrated MC1R expression by monocytes/macro- http://www.jimmunol.org/ phages, MC1R and MC3R expression by B lymphocytes, but no melanocortin receptor expression by T lymphocytes. In addition, ␣MSH did not significantly inhibit anti-CD3 Ab-induced lymphocyte proliferation, whereas ␣MSH and related analogs (SHU9119 and MTII) inhibited Ag-induced lymphocyte proliferation in monocyte-depleted and B lymphocyte-depleted assays. These findings demonstrate that ␣MSH, acting probably via MC1R on monocytes and B lymphocytes, and possibly also via MC3R on B lym- phocytes, has immunosuppressive effects in humans but that suppression of Ag-induced lymphocyte proliferation by ␣MSH is independent of MC1R gene status. The Journal of Immunology, 2005, 175: 4806–4813. he ␣-melanocyte-stimulating hormone (␣MSH)4 is a induce hapten-specific tolerance in murine skin (7–9). ␣MSH ex- by guest on September 24, 2021 tridecapeptide that is synthesized, through cleavage of the erts its effects by signaling through a family of five separate seven- T precursor pro-opiomelanocortin peptide, by several cell pass transmembrane G protein-coupled receptors, known as mela- types in various organs, including the pituitary and skin (1). Al- nocortin receptors (MC1R, MC2R, MC3R, MC4R, and MC5R) though originally identified for its effects on pigmentation, ␣MSH (10). In inflammatory/immune responses where the monocyte is of has since been recognized as having anti-inflammatory and immu- central importance, previous work has suggested that the melano- nomodulatory actions (2, 3). For example, in animal models, cen- cortin 1 receptor (MC1R) mediates the anti-inflammatory and im- tral administration of ␣MSH can inhibit fever and other effects munomodulatory effects of ␣MSH on/via this cell. ␣MSH, through induced by proinflammatory molecules (IL-1, TNF-␣) including its binding to MC1R, can down-regulate CD86 expression on increases in circulating blood neutrophils and plasma acute phase monocytes and can induce the release of IL-10 by these cells, with proteins, and inflammation (4–6). In addition, the epicutaneous a maximum effect on IL-10 release at 10Ϫ13 M ␣MSH (11, 12). ␣ application of MSH can suppress the sensitization and elicitation Furthermore, it has been reported that ␣MSH also reduces CD86 phases of immune responses to contact sensitizers in mice and can and CD40 expression on monocyte-derived dendritic cells through MC1R (13). However, the consequences of these observations re- main unclear, because to date no investigations have documented Dermatopharmacology Unit, University of Southampton, Southampton, United ␣ Kingdom whether MSH can suppress Ag presentation/lymphocyte prolif- Received for publication October 8, 2004. Accepted for publication July 18, 2005. eration responses in human subjects, including those where the The costs of publication of this article were defrayed in part by the payment of page monocyte/macrophage act as the APC, and therefore whether charges. This article must therefore be hereby marked advertisement in accordance ␣MSH is capable of inhibiting human cell-mediated immune re- with 18 U.S.C. Section 1734 solely to indicate this fact. sponses to exogenous Ags. 1 E.H. is a Medical Research Council Senior Clinical Fellow. A.C. was supported by In human skin, MC1R is expressed on melanocytes, the function a Wellcome Trust Entry Level Fellowship. C.L.J. is a British Skin Foundation Post- Graduate Student. of which is to synthesize melanin pigment to protect the skin from 2 A.C., S.J.R., and C.P. contributed equally to the project. UV radiation-induced damage. However, human skin and hair color varies greatly among subjects as a result of differences in the 3 Address correspondence and reprint requests to Dr. Eugene Healy, Mailpoint 825, Level F, South Block, Southampton General Hospital, Southampton, SO16 6YD, total amount and ratio of the two types of melanin (brown/black United Kingdom. E-mail address: [email protected] eumelanin and red/yellow phaeomelanin) at these sites (14, 15). 4 Abbreviations used in this paper: ␣MSH, ␣-melanocyte-stimulating hormone; The human MC1R gene is highly polymorphic, with Ͼ35 genetic MC[1–5]R, melanocortin [1–5] receptor (human, MC[1–5]R; murine, Mc[1–5]r); SK/ SD, streptokinase-streptodornase; SI, stimulation index; fw, forward; rev, reverse; variants identified at present, and research into the genetic control infw, inner forward. of normal human pigmentation during the last several years has Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 4807 comprehensively shown that human MC1R variants are causally MgCl2, and 200 mM dNTPs in a PerkinElmer Cetus 9700 thermal cycler associated with red hair, fair skin type, and an increased suscep- and consisted of a single denaturation cycle of 94°C for 5 min followed by tibility to skin cancer (16). Case control, kindred and population 35 cycles of 94°C for 1 min, 62°C for 1 min, and 72°C for 2 min with a final extension of 72°C for 7 min. The 1148-bp amplicons were purified studies have demonstrated that, in general, two variant MC1R al- using a Qiagen PCR cleanup column (Qiagen), and the nucleotide sequence leles result in red hair whereas a single variant allele gives rise to was determined with primers MC1R332fw (5Ј-GCGGTGCTGCAG fairer skin type (17–22). Cell transfection assays and transgenic CAGCTGG-3Ј), MC1R344rev (5Ј-TGCTGCAGCACCGCAGCC-3Ј), mouse work have indicated that a number of the variant receptors, MC1R581rev (5Ј-ACCACGAGGCACAGCAGG-3Ј), and MC1R715fw (5Ј-GGCGCTGTCACCCTCACC-3Ј). Sequencing was performed using a in particular the Arg151Cys, Arg160Trp, and Asp294His variants, dye terminator cycle sequencing kit (Amersham Pharmacia Biotech) and a which are frequently associated with red hair and fair skin, are model ABI 377 automated DNA sequencer (Applied Biosystems). significantly functionally compromised in their ability to signal intracellularly via cAMP, leading to a lighter/phaeomelanic pig- Generation of adherent and nonadherent PBMC fractions, mentation phenotype (23–25). It is therefore possible that human monocytes/macrophages, B and T cell lines, and monocyte- MC1R variants could have consequences on the anti-inflammatory depleted and B lymphocyte-depleted cultures ␣ and/or immunomodulatory actions of MSH in humans, especially PBMCs were purified from venous blood by centrifugation using Lym- in cases where the monocyte/macrophage plays an important role. phoprep
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