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Published online before print October 17, 2006
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Center for Preclinical Investigation, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy
1 Correspondence: Centro di Sperimentazione Preclinica, Padiglione Granelli, Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Via F. Sforza 35, Milano 20122, Italy. E-mail: anna.catania{at}unimi.it
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ABSTRACT |
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-, ß-, and 
-melanocyte-stimulating hormone, the melanocortin receptors (MCRs), and the endogenous antagonists agouti- and agouti-related protein. Melanocortin peptides exert multiple effects upon the host, including anti-inflammatory and immunomodulatory effects. Leukocytes are a source of melanocortins and a major target for these peptides. Because of reduced translocation of the nuclear factor NF-
B to the nucleus, MCR activation by their ligands causes a collective reduction of the most important molecules involved in the inflammatory process. This review examines how melanocortin peptides and their receptors participate in leukocyte biology.
Key Words: adrenocorticotropic hormone • -melanocyte-stimulating hormone • melanocortin receptors • melanocortin peptides • nuclear factor-B • neuroimmunomodulation • pro-opiomelanocortin
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INTRODUCTION |
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Leukocytes are a source of melanocortins and a major target for these molecules. This review examines how the melanocortin system influences leukocyte biology.
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PRO-OPIOMELANOCORTIN PROCESSING AND MELANOCORTIN PRODUCTION BY LEUKOCYTES |
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-, ß-, and -melanocyte-stimulating hormone (-, ß-, -MSH) derive from post-translational processing of the precursor molecule pro-opiomelanocortin (POMC) [12
] (Fig. 1
). The secretory enzymes responsible for intracellular cleavage of POMC are precursor or proprotein convertases (PCs) cleaving at single and/or pairs of basic residues [13
]. PC1 generates ACTH and ß-lipotropin, whereas PC2 is required for production of -MSH and ß-endorphin [14
]. Consequently, relative expression of convertases determines tissue-specific processing of POMC. In the corticotrophs, where PC1 predominates, ACTH and ß-lipotropin are the final POMC-processing products. Expression of PC2 in the pituitary pars intermedia accounts for production of -MSH and ß-endorphin [15
, 16
]. PC1 and PC2 as well as other convertases are expressed in extrapituitary tissues including the immune system [17
] and the skin [18
].
|
Although ectopic POMC syndrome associated with malignancies has been known for decades [21
], the finding that POMC is also expressed in normal blood cells is more recent [17
, 22
]. Identification of POMC in immune cells was of great importance to molecular understanding of neuroimmunomodulation. Indeed, this observation promoted discovery of the bidirectional communication between the immune and neuroendocrine systems based on common signal molecules and receptors [22
]. POMC mRNA occurs in lymphocytes, monocytes, keratinocytes, and melanocytes, where POMC peptides exert regulatory functions [22
23
24
25
26
]. Melanocortin production by cells of the immune system is enhanced by various stimuli, including bacterial endotoxin [27
], Newcastle disease virus [28
], HIV [29
], and TNF- [24
, 30
]. Further, there is evidence that leukemia inhibitory factor stimulates POMC expression via phosphorylation of STAT1 and STAT3 proteins [31
]. Therefore, activation of the STAT signaling pathway by cytokines, IFNs, or hormones can increase POMC expression and melanocortin peptide production at sites of infection or inflammation.
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DISTRIBUTION OF MELANOCORTIN RECEPTOR (MCR) SUBTYPES AND SIGNAL TRANSDUCTION |
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The five MCRs have differing affinities for the melanocortins. However, MCR distinction based on ligand affinity is largely artificial. With the exception of the MC2R, which is activated selectively by ACTH, the other receptor subtypes recognize all the natural melanocortins. Similarly, although there are differences in tissue distribution, occurrence is redundant, and there is large overlap.
MC1R was the first member of the MCR gene family to be cloned [34
, 35
]. The relative affinity of the human MC1R for the natural melanocortins is -MSH 
ACTH > -MSH [34
, 36
]. MC1R is expressed by melanocytes and by virtually all human cells involved in the inflammatory response, including neutrophils [37
, 38
], monocytes [39
40
41
], dendritic cells (DC) [42
], endothelial cells [43
], and B lymphocytes [40
]. Further, the MC1R occurs in murine macrophages [24
, 44
].
MC2R is the ACTH receptor in the adrenal cortex [35 ]. This receptor subtype is the only MCR that shows binding selectivity for a specific melanocortin peptide [45 ].
The MC3R is the only MCR activated by -MSH with potency similar to that of other melanocortins (-MSH=ACTH-MSH) [46
]. MC3R is expressed mainly in the CNS [47
], but it also occurs in human B lymphocytes [40
] and in murine macrophages [48
].
MC4R (-MSH=ACTH>-MSH) is the prevalent MCR in the brain. It is highly expressed in the hypothalamus, spinal cord, and cortex [49
]. Although the best-characterized effects of this receptor subtype concern control of food intake, energy expenditure, and sexual function, it likewise mediates several of the central effects of melanocortins [2
].
MC5R (-MSHACTH>>-MSH) is a relatively ubiquitous receptor in peripheral tissues [50
]. There is evidence that this receptor subtype participates in control of exocrine secretions [51
, 52
]. However, data also indicate immunomodulatory functions in B [53
] and T [54
] lymphocytes and in mast cell lines [55
].
MCRs are functionally coupled to adenylyl cyclase and mediate their effects primarily by activating a cAMP-dependent signaling pathway [48 , 56 57 58 ]. Stimulation of cAMP production by the MCRs causes activation of PKA, the catalytic subunit of which, PKAc, phosphorylates the CREB that then binds to CREs in the DNA. Ca2+ plays a key role in melanocortin/receptor binding and signal transduction, as affinity of the ligand to the receptor and signaling are markedly enhanced under physiological concentrations of extracellular Ca2+ relative to Ca2+-free conditions [59 ].
Similar to other G-protein-linked receptors, melanocortin signaling is conveyed through additional pathways, different from cAMP generation. MCR signaling has been associated with increases in intracellular-free Ca2+ concentration through mobilization from intracellular stores [60 ] or increased inositol phosphate concentration [61 ]. Another reported signaling mechanism involves activation of the MAPK [62 , 63 ]. Activation of the p42/p44 MAPK pathway by MC4R appears to occur through PI-3K [62 ]. Finally, research on MC5R in B lymphocytes indicated activation of JAK/STAT [53 ].
The base for the remarkably broad effects of -MSH on inflammatory mediator production was clarified by the discovery that the peptide inhibits activation of the nuclear factor NF-B (Fig. 2
) [64
65
66
67
68
69
70
71
]. This essential nuclear factor induces transcription of most of the molecules involved in the inflammatory process, including those for cytokines, chemokines, growth factors, major histocompatibility system, and inducible NO synthase (NOS). Therefore, its inhibition has broad consequences for mediator production and cell functions. NF-B is retained in an inactive form in the cytoplasm, bound to members of the IB inhibitory protein family [72
]. Phosphorylation of IB by various agents such as cytokines, bacterial products, and viruses causes IB degradation. Subsequently, the free NF-B is translocated to the nucleus, where it binds to sequences of DNA encoding NF-B-responsive elements and triggers the transcription of target genes.
|
-MSH down-regulated NF-B activation induced by inflammatory stimuli, including TNF, endotoxin, ceramide, and okadaic acid [64
]. Suppression of NF-B translocation occurred through generation of cAMP, activation of PKA, and protection of IB from phosphorylation [64
]. Similar results were obtained in human glioma cells [73
], macrophages [71
], fibroblasts [74
, 75
], endothelial cells [76
], keratinocytes [77
], and melanocytes [68
].
Experiments on cells transfected with a plasmid vector encoding -MSH indicate that the peptide can inhibit NF-B activation in an autocrine manner [69
, 70
, 78
].
A further contribution to clarification of the mechanism of action of melanocortins comes from the observation that in macrophages treated with -MSH, the kinase IL-1 receptor-associated kinase 1 (IRAK-1) is bound to the inhibitory molecule IRAK-M, a negative regulator of TLR signaling [79
]. Therefore, it appears that inhibition of NF-B activation occurs at an early step of signal transduction.
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ANTI-INFLAMMATORY CIRCUITS BASED ON MELANOCORTIN PEPTIDES AND THEIR RECEPTORS |
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Researchers dealing with the anti-inflammatory effects of -MSH and related peptides are familiar with the observation that effects in vivo are often much greater and more consistent than those obtained in vitro on individual cell types. This is not surprising, as the anti-inflammatory effects of melanocortins involve signaling through descending, anti-inflammatory, neural pathways induced by stimulation of MCRs within the brain (Fig. 3
) [81
82
83
84
85
86
87
]. In animals with spinal cord transection, the anti-inflammatory effects of -MSH were much less than in intact animals [81
, 82
]. In this perspective, a receptor-selective agonist, despite greater potency at a receptor subtype, may not produce a complete effect, i.e., an effect that combines central and peripheral actions. Indeed, although stimulation of MC1R in neutrophils and macrophages inhibits production of inflammatory mediators [8
, 30
, 37
, 38
], neurogenic, anti-inflammatory influences on peripheral inflammation are independent of a central MC1R [82
] and require MC3R and/or MC4R activation within the brain [83
, 87
]. Conversely, MC4R is not expressed by macrophages.
|
Major endogenous, melanocortin, receptor-mediated, anti-inflammatory circuits are based on ACTH (Fig. 4 ). Through activation of the MC2R in the adrenal cortex, the peptide induces production of glucocorticoids and consequently, a systemic, anti-inflammatory response. Further, ACTH recognizes MCRs within the brain and in peripheral cells. Therefore, upon activation of the HPA, the glucocorticoid-mediated, anti-inflammatory effects are associated with direct, local and central, neurogenic influences mediated by the other MCRs.
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MCR EXPRESSION BY LEUKOCYTES |
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Recent investigations based on flow cytometry improved knowledge of MCR expression in human blood cell subsets [40 , 92 ]. The MC1R was found to be expressed constitutively in monocytes/macrophages, B lymphocytes, NK cells, and a subset of cytotoxic T cells, whereas Th cells appeared to be devoid of MCR [92 ]. Another analysis of MCR expression in PBMC indicated the presence of MC1R expression in monocytes and macrophages and that of MC1R and MC3R in B lymphocytes; no MCR expression was found in T lymphocytes [40 ].
Immunoneutralization studies support the idea that MC1R activation contributes to the anti-inflammatory influences of melanocortins in human leukocytes. Neutralization of MC1R with specific antibodies increased basal and LPS-stimulated production of TNF- by the monocytic cell line THP-1 [41
]. Preincubation of cells with an anti-MC1R antibody likewise prevented the inhibitory influences of synthetic -MSH on TNF- production.
MC1R expression in monocytes is linked to cell activation [39
]. Receptor expression was low in nonstimulated monocytes. and it was enhanced by treatment with endotoxin or a mitogen and by cytokines such as IL-2, IL-4, IL-10, and IFN-.
An interesting observation is that although MC1R density in inflammatory cells is less than in melanocytes, receptor affinity is much greater. Indeed, MC1R in immunocytes and endothelial cells is activated by picomolar concentrations of -MSH, whereas MC1R activation in melanocytes requires nanomolar concentrations of the peptide [36
, 76
, 93
].
A still-open question regards whether the anti-inflammatory effects exerted by the C-terminal tripeptide -MSH (11-13) Lys-Pro-Val are mediated by any of the known MCRs. This synthetic -MSH fragment exerts anti-inflammatory effects in vivo and in vitro, similar to those of the full-length precursor, although potency is lesser [10
]. Further, -MSH (11-13) reduces NF-B translocation to the nucleus, much as the full-length -MSH [29
, 71
, 94
]. However, several observations indicate that this molecule does not compete with -MSH for receptors expressed by the B16 mouse melanoma cells [95
] and does not recognize any of the known MCRs [32
, 71
, 96
, 97
]. Therefore, the existence of a cell receptor for Lys-Pro-Val is still uncertain, as the potential non-MCR-mediated effects of melanocortins are unsolved.
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EFFECTS OF MELANOCORTINS ON LEUKOCYTE FUNCTIONS IN VITRO |
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In monocyte-derived macrophages (MDM), -MSH inhibited LPS-induced proteolytic enzyme release, oxidative burst response, reactive oxygen intermediate generation, NO production, and adhesion molecule expression [98
]. Further, -MSH reduced CD14 expression on the macrophage surface. Therefore, it appears that -MSH exerts part of its anti-inflammatory effect through reduction of the endotoxin receptor CD14. CD86, a major T cell costimulatory molecule, was reduced by -MSH in LPS-stimulated monocytes [39
]. -MSH increased the production and expression of IL-10 in human peripheral blood monocytes and in monocytes in culture [99
]. As IL-10 reduces proinflammatory cytokine production in macrophages, its enhancement has anti-inflammatory influences. In the human monocytic cell line THP-1, stimulated with TNF- and IFN-, -MSH inhibited neopterin production [30
]. Treatment of THP-1 cells with -MSH also blocked LPS-induced TNF- production through inhibition of p38 kinase and NF-B activation [100
].
Consistent with observations in human cells, research on murine macrophages showed anti-inflammatory effects of melanocortins. -MSH inhibited steady-state NOS2 mRNA abundance and NO production in the macrophage cell line RAW264.7 stimulated with bacterial LPS and IFN- [24
]. In RAW264.7 stimulated with LPS plus IFN-, -MSH likewise inhibited induction of DNA-binding activity of C/EBPß and NOS2 gene transcription [65
]. Incubation of RAW264.7 and primary peritoneal macrophages with ACTH or the synthetic melanocortin melanotan II caused a time-dependent and concentration-related induction of heme oxygenase [44
].
Similar to macrophages, melanocortins reduced production of inflammatory mediators by microglia. Inhibitory effects of -MSH and other melanocortins on production of TNF-, IL-6, and NO were demonstrated in a murine microglial cell line stimulated with LPS plus IFN- [101
]. Another observation in this research was that production of TNF-, IL-6, and NO was greater in activated microglia after immunoneutralization of endogenous -MSH. This effect suggests that -MSH is an autocrine, anti-inflammatory factor in microglia, much as in macrophages. In subsequent experiments, -MSH inhibited TNF- and NO production by murine microglia stimulated with ß-amyloid, a main actor in development of Alzheimer’s disease [102
].
-MSH inhibited migration of human neutrophils induced by the chemotactic tripeptide N-fMLP and by IL-8 [37
]. The inhibitory effect could be traced to alterations in cAMP in neutrophils. Another investigation on human neutrophils treated with -MSH showed inhibition of several IL-8-induced biological responses [38
]. Through an action on MC1R, the peptide down-regulated the IL-8R type 1 and 2. Receptor restoration by specific elastase inhibitors indicates involvement of this enzyme in the -MSH-induced down-regulation of IL-8R.
Research on human lymphocytes showed inhibitory effects of -MSH on antigen-stimulated lymphocyte proliferation [40
]. Of interest, the research also showed that the immunosuppressive effects of -MSH were independent of MC1R gene status and were exerted also in the presence of the MC1R variants associated with red hair and fair skin, which cause lack of cAMP stimulation in melanocytes.
Inhibitory effects of melanocortins were also shown in cells obtained from patients with infectious or inflammatory disorders. Research in septic patients showed that addition of small concentrations of -MSH to LPS-stimulated whole blood samples inhibited TNF- and IL-1ß production by 30–40% [103
]. Inhibitory effects of -MSH on TNF- production were also observed in whole blood from HIV-positive patients stimulated with endotoxin [104
]. In experiments on PBMCs, -MSH inhibited the production of IL-1 ß and TNF- induced by the HIV envelope glycoprotein gp 120 [104
].
Research on chronically HIV-1-infected, promonocytic U1 cells indicated that these cells produce -MSH, and immunoneutralization of the peptide enhances HIV expression [29
]. As U1 cells express MC1R, an autocrine-inhibitory circuit based on the peptide and its receptors likely occurs in these cells. Further, addition of synthetic -MSH to TNF--stimulated U1 cells reduced HIV p24 antigen release. HIV replication was likewise inhibited in acutely HIV-infected MDM. The basis for the peptide influence on HIV replication was traced to blockade of NF-B activation.
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EFFECTS OF MELANOCORTINS ON INFLAMMATORY REACTIONS IN VIVO |
|---|
NO production was reduced in many animal models including brain inflammation [120
121
122
], uveitis [123
], inflammatory bowel diseases [124
, 125
], heart transplantation [106
], and peritonitis [126
]. TNF- was likewise reduced by melanocortin treatment in many conditions including experimental brain inflammation [127
, 128
], inflammatory bowel disease [125
], heart transplantation [106
], peritonitis [126
], hemorragic shock [87
, 129
], and several other localized or systemic inflammatory conditions [130
, 131
]. Chemokine production induced in endotoxin-induced liver inflammation [109
], experimental heart transplantation [106
, 112
], and ischemic renal injury [132
] was inhibited by systemic treatment with -MSH. In murine, LPS-induced, cutaneous vasculitis (local Shwartzman reaction), a single injection of -MSH significantly suppressed expression of E-selectin and VCAM-1. Adhesion molecule expression contributes to diapedesis and activation of leukocytes, which subsequently leads to hemorrhagic vascular damage; its inhibition can have, therefore, beneficial effects [133
]. In a model of acute pancreatitis induced by cerulein, -MSH treatment reduced plasma amylase concentration, pancreatic weight, pancreatic myeloperoxidase activity, and the severity of histological lesions [105
]. These effects were associated with a marked reduction in tissue leukocyte infiltration.
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CENTRAL NEUROGENIC ANTI-INFLAMMATORY SIGNALS ACTIVATED BY MELANOCORTINS |
|---|
Research on acute inflammation in the mouse skin indicated that -MSH can act solely within the brain to inhibit peripheral edema and NF-B activation [81
, 82
]. This effect appeared to be mediated by sympathetic signals that require a peripheral ß2 adrenergic receptor. Indeed, central anti-inflammatory influences in this model were prevented by peripheral ß2 adrenergic receptor blockade and by spinal cord transection.
Recent data indicate that the CNS exerts anti-inflammatory influences via acetylcholine-mediated, efferent signals carried through the vagus nerve [88 ]. Nicotinic, cholinergic receptors expressed on macrophages detect these signals and react with diminished cytokine production in response to LPS. Vagus nerve stimulators can mimic this response and prevent lethal endotoxemia.
Through an efferent vagal pathway, central melanocortins protected rats against myocardial ischemia/reperfusion injury [83
, 86
] and hemorrhagic shock [87
]. In myocardial ischemia followed by reperfusion or permanent occlusion of a coronary artery, intracerebroventricular treatment with ACTH (1-24) reduced the incidence of ventricular tachycardia, ventricular fibrillation, and lethality and prevented the fall in blood pressure [86
]. Complete protection occurred with an intracerebroventricular dose 10 times less than that effective by the i.v. route. Further research on this model indicated that a brain-cholinergic, MC3R-dependent, efferent pathway mediated the protective effect of ACTH [83
]. Central effects of ACTH likewise controlled hemorrhagic shock [87
]. ACTH suppressed the NF-B-dependent, inflammatory response triggered by hemorrhage and reversed the shock condition through a MC4R-activated, cholinergic, anti-inflammatory pathway. The observation that central MCRs activate the cholinergic, anti-inflammatory pathway is, therefore, important and improves knowledge of brain-immune interactions based on melanocortins.
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CONCLUSIONS |
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-MSH has potent, antipyretic properties [134
], research on the melanocortin system has expanded greatly. It is now clear that the melanocortins, considered for a long time an evolutionary remnant, participate in control of disparate, physiological functions. A major contribution to the host physiology resides in the capacity to prevent tissue injury in the presence of a harmful challenge. Beneficial effects stem from the potent modulatory properties exerted on leukocytes and other cells involved in the immune/inflammatory response. The information collected should help design of synthetic analogs to be used as a novel class of anti-inflammatory drugs.
Received July 4, 2006; revised September 1, 2006; accepted September 12, 2006.
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ABSTRACT
INTRODUCTION
