Proopiomelanocortin Signaling System Is Operating in Mast Cells

Abstract

The proopiomelanocortin (POMC) system is the central coordinator of the systemic endocrine responses to sustained stress. It has been recently discovered that mast cells also display regulated production of POMC peptides. Since at the tissue level mast cells integrate stress responses into the neuroimmune regulatory network, it is likely that the POMC system is involved in mast cells' functions in tissue homeostasis.

The proopiomelanocortin system

Proopiomelanocortin (POMC) is predominantly produced in the anterior pituitary, where it is a mediator in the hypothalamic–pituitary–adrenal axis, the main adaptive response to systemic stress. The hypothalamic–pituitary–adrenal axis is activated by the stress-induced production and release of hypothalamic corticotropin-releasing hormone (CRH), which, in turn, activates the anterior pituitary CRH receptor type 1 to stimulate production and release of POMC-derived ACTH. ACTH directly stimulates adrenocortical production and secretion of cortisol (in humans) or corticosterone (in rodents); these steroids counteract the effects of the stressor and suppress the hypothalamic–pituitary–adrenal axis through negative-feedback inhibition. Besides the pituitary, the POMC system is also expressed in the brain and peripheral tissues that include the skin (Slominski et al., 2000). The POMC gene contains three exons, separated by two introns that are spliced out in the pituitary and brain to generate POMC mRNA of approximately 1.1 kb (Slominski et al., 2000; Smith and Funder, 1988). Shorter and longer POMC transcripts have also been found predominantly in extrapituitary tissues, and the size heterogeneity has been explained by alternative splicing, variation in the length of the poly(A)⁺ tail, or use of alternate transcription initiation sites. Moreover, smaller mRNAs are also translatable despite lack of the signal peptide sequence (Slominski et al., 2000).

POMC yields different neuropeptides (for example, ACTH, α-melanocyte-stimulating hormone (α-MSH), γ1-3-MSH, β-MSH, and β-endorphin), generated through processing mechanisms that are cell and tissue specific, including post-translational modifications of the POMC precursor with endo- and exopeptidase cleavage, amidation, and acetylation (Smith and Funder, 1988). In general, the POMC precursor is selectively cleaved at the dibasic amino acid residues by prohormone convertase 1 (PC1) and PC2 (and perhaps furin convertase (FC) and paired basic amino acid converting enzyme 4 (PACE4)) in a process affected by O-glycosylation of the prohormone (Smith and Funder, 1988; Wilkinson, 2006). PC1 sequentially cleaves POMC to produce a 16 kilodalton N-terminal peptide, a join peptide, and the carboxy-terminal peptides ACTH and β-LPH (β-lipotropin) with some β-endorphin (Smith and Funder, 1988). PC2 then cleaves ACTH to generate ACTH(1–17) CLIP; β-LPH to generate β-endorphin and γ-LPH (further cleaved to β-MSH); and pro-γ-MSH to generate γ1-3-MSH (Smith and Funder, 1988). Sequential actions of carboxypeptidase E on ACTH(1–17), together with C-terminal peptide amidation by peptidyl α-amidating mono-oxygenase, and α-N-acetylation at the N-terminus produce mature α-MSH (Wilkinson, 2006). In addition, segments of POMC can undergo differential N- and O-glycosylation, sulfatation and phosphorylation, and post-translational modification to generate N-acetylated and truncated forms of β-endorphin, truncated forms of ACTH, and variant forms of α-MSH (Smith and Funder, 1988; Wilkinson, 2006).

POMC-derived peptides (and perhaps POMC precursor proteins themselves) can act as neurotransmitters, neurohormones, hormones, cytokines, growth factors, and immunomodulators, depending on the site of production, form of delivery, and target-cell function. In skin cells the peptides are involved in melanin pigmentation (predominantly ACTH and α-MSH), immune activity (predominantly immunosuppression), functions of adnexal structures (hair follicle, sebaceous and eccrine glands), secretory activities, differentiation level and potential, migratory capabilities, and proliferation (Slominski, 2005; Slominski et al., 2004; Slominski et al., 2000). POMC peptide receptors have been shown for the main skin cellular populations, including keratinocytes, melanocytes, fibroblasts, sebocytes, and immune cells (Slominski, 2005; Slominski et al., 2000). It has been therefore proposed that the cutaneous POMC system, being highly organized and encoding mediators and receptors coupled differentially to signal transduction systems and endowed with stress-neutralizing activity, is addressed at maintaining skin integrity to restrict stress-dependent disruptions of internal homeostasis with potential effects on global homeostasis (Slominski et al., 2004; Slominski and Wortsman, 2000; Slominski et al., 2000).

Mast cells

Mast cells are recognized for their pathogenic role in production of allergic and anaphylactic reactions, especially in the skin. Mast cells can rapidly induce multiple tissue effects that include vasodilation, angiogenesis, and proinflammatory activities; mast cells have also been implicated in innate immunity and autoimmune processes (Theoharides and Cochrane, 2004; Theoharides et al., 2004). The above actions are related to the capacity of mast cells to synthesize and secrete over 50 biologically powerful molecules such as histamine, heparin, kinins, neuropeptides (including vasoactive intestinal peptide), proteases (chymase and preformed tryptase), chemoattractants, cytokines (tumor necrosis factor-α and interleukin-6 in particular), growth factors, leukotrienes, prostaglandins, nitric oxide, stem-cell factor, and vascular endothelial growth factor. It is of further interest that human mast cells also produce and release relatively large amounts of CRH and the related urocortin peptide in response to chemical, physical, or psychological stimulation; mast cells also express corresponding CRH receptors (Paus et al., 2006; Theoharides et al., 2004).

Remarkably, mast cells display high selectivity in determining the mediators to be released, depending primarily on the pathophysiological context of this process (Paus et al., 2006; Theoharides and Cochrane, 2004; Theoharides et al., 2004). Also specific is the cellular structure affected; in anaphylactic reactions, thus, they can release their content through typical degranulation of the majority of secretory granules, or through secretion of the content of individual granules, or even by releasing selective mediators without degranulation (Paus et al., 2006; Theoharides and Cochrane, 2004). As mast cells are located perivascularly in close proximity to neurons, the existence of a functional association between mast cells and nerve cells has been postulated (Paus et al., 2006; Theoharides and Cochrane, 2004; Theoharides et al., 2004). Indeed, mast cells can be activated by antidromic nerve stimulation (for example, of the trigeminal nerve or the cervical ganglion) to secrete neuropeptides, and therefore release of substance P or CRH from sensory nerves to stimulate mast-cell secretion could occur in vivo (Paus et al., 2006; Theoharides and Cochrane, 2004; Theoharides et al., 2004). Thus, a role for mast cells has been proposed as coordinators of immune, neural, and endocrine activities at the central and peripheral levels (Paus et al., 2006; Theoharides and Cochrane, 2004; Theoharides et al., 2004). In the skin, mast cells would coordinate local cutaneous neuroimmune responses (Paus et al., 2006; Theoharides and Cochrane, 2004).

These findings implicate mast cell-derived α-MSH in the autocrine and paracrine regulation of local immune activity.

The POMC system in the skin mast cells

Artuc et al. (2006, this issue) demonstrate that human skin mast cells express the POMC gene and protein, and they provide evidence supporting the further processing to the secretory molecule α-MSH. Moreover, the addition of anti-IgE antibody significantly reduces intracellular α-MSH, while increasing its extracellular levels, indicating IgE-mediated secretion of the neuropeptide. Furthermore, because skin mast cells co-express the PC1, PC2, and FC genes, they have the potential to fully express the enzymatic machinery necessary to process POMC to α-MSH. These findings complement previous reports of ACTH antigen expression in mast cells and are consistent with the ability of α-MSH to stimulate the release of histamine (Artuc et al., 2006). As a clinical implication, the work may explain a well-known phenomenon of increased pigmentation of lesional skin in urticaria pigmentosa. From the experimental point of view, these findings implicate mast cell-derived α-MSH in the autocrine and paracrine regulation of local immune activity and inflammatory and allergic responses.

An immediate challenge would be to define, within the context of expected actions, the precise mechanism(s) regulating POMC expression, processing in mast cells, and release of peptide products from mast cells. Indeed, elucidation of both ligand identity and time dependence for POMC system activation should clarify the functional organization of the signaling axis involving ligand → POMC expression → processing → release of final products. Thus, if the predominant final product were ACTH, POMC activation could result in local stimulation of cortisol production (Slominski, 2005), whereas if it were instead α-MSH, the local actions on melanin pigmentation would predominate (Slominski et al., 2004). In the latter case, modifications of α-MSH molecules could be involved, playing perhaps important roles in phenotypic specificity or in attenuation of variant action (Wilkinson, 2006). Furthermore, the remaining possibility of peptide co-secretion would result in further widening of the range of regulators for mast-cell responses, with the inherent possibility of enhanced “fine-tuning” in the local reaction to cutaneous stressors. Lastly, from the evolutionary point of view, the findings of Artuc et al. (2006) provide additional evidence strengthening the concept of conservation of the central stress response algorithm at distant, local levels (Paus et al., 2006; Slominski, 2005; Slominski and Wortsman, 2000; Slominski et al., 2000; Theoharides et al., 2004).