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Medical Clinic 1 University of Luebeck Luebeck D-23538, Germany
Address all correspondence and requests for reprints to: Achim Peters, M.D., Medical Clinic 1, Medizinische Universität zu Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. E-mail: achim.peters{at}uni-luebeck.de.
The skin protects the organism against radiation, chemical agents, and microorganisms by activating its own stress defense system. The local melanocortin system in the skin serves to neutralize external noxious stimuli. Major players of this local defense system are the peptides CRH, proopiomelanocortin (POMC), the 
-MSH with its melanocortin-1 (MC1) receptor, and finally the cutaneous pigment melanin. UV irradiation represents the main stimulus for the activation of cutaneous melanogenesis. In melanocytes, UV irradiation stimulates CRH and POMC formation, which then results in the release of peptides that are cleaved from the POMC molecule, i.e. -MSH, ACTH, and others. -MSH binds to the MC1 receptor localized on neighboring melanocytes and other cutaneous cells, and melanin formation is then increased via an intracellular signal cascade. The melanin pigment represents a buffer molecule that antagonizes the noxious effects of physical, biological, and chemical insults (1).
The epidermal melanocortin system has been characterized in detail over the last several years. In contrast, the follicular (hair) melanocortin system is only poorly characterized. The paper by Kauser et al. (2) in this issue represents a decisive step toward understanding how the same melanocortin system functions within the human follicular pigmentary unit. The paper reliably presents new data on the role of the melanocortin system in the development and pigmentation of the human hair follicle. The authors also show that different components of the melanocortin system are present in the human hair follicle (a continuation of their earlier work) and demonstrate the phenotypic effects that -MSH and ACTH peptides have on human follicular melanocytes. These new experiments are particularly welcome because most earlier studies were only conducted on rodent skin (which is fundamentally different from human skin) or isolated human epidermal or neonatal melanocytes (which also differ from follicular melanocytes). The main findings of this study were obtained by immunohistochemical photomicrographs, which very vividly and clearly reveal where the corresponding peptides and receptors are localized intracellularly. The authors were able to show that a completely functional melanocortin system can drive follicular melanocyte differentiation by up-regulating melanogenesis, dendricity, and proliferation in a poorly differentiated melanocyte population. This paper not only shows that the functional regulation of follicular (hair) and epidermal melanin units is symmetrical, but also suggests a broader fundamental principle that is of interest for the entire endo-crinological community, i.e. the "self-similarity" of the melanocortin systems at the local and systemic level. In a mathematical sense, an object is said to be self-similar if it looks roughly the same at any scale (3).
The systemically active melanocortin system is localized in the brain. CRH is found in the neuronal populations of the paraventricular nucleus in the hypothalamus. These neurons release CRH, which then stimulates the formation of POMC in hypophyseal cells. ACTH, -MSH, and other peptides are cleaved from the precursor molecule POMC. ACTH reaches the adrenal gland via the blood where it stimulates the synthesis and release of cortisol via the MC2 receptor on the adrenal cortical cells. Coincidentally, with the activation of these CRH neurons in the paraventricular nucleus, there is also an activation of the sympathetic nervous system. Both the sympathetic nervous system and the CRH-ACTH-cortisol systems are ultimately subject to the control of the limbic system (amygdala and hippocampus) and the neocortex. This systemic stress system is also a defense system that controls and restricts the harmful influence of multiple stressors such as major hemorrhage, systemic infections, excessive physical effort, and psychological stress (traumas) (4). Via concerted action it strives to maintain homeostasis in the entire organism.
Slominski et al. (5) pointed out the similarity of the local and systemic stress systems and showed in detail that the essential components such as CRH, POMC, -MSH, ACTH, and the melanocortin receptor are present to the same extent both at a local and a systemic level. Also, these authors were able to show quite impressively that the various components are adjusted by the same factors at both levels. Not only are the components the same, but there is also a remarkable similarity in regulatory principles at the local and systemic levels.
The activation of cerebral CRH restricts stressor induced damage via various intermediary steps (Fig. 1
). Conversely, the brain is also informed of the extent of prevailing damage, particularly in its hypothalamic centers. For this purpose, feedback signals are transmitted from the location of the problem to the hypothalamus: these signals include angiotensin II with systemic loss of blood (6), cytokines such as TNF and IL-1 with inflammation and toxic damage (7), molecules such as IL-6 with excessive physical effort (8), and the adipocytokine leptin in which there is an excessively large body mass (9). All these feedback signals exert a stimulatory influence on the stress system, with its magnitude depending on the extent of the damage and the problem. Correspondingly, there is also a feedback signal that provides the brain, i.e. the hypothalamic centers, with information about the extent of the systemic defense reaction. With increasing activation of the stress system, more cortisol is released from the adrenal gland. Cortisol acts as a feedback signal on the hypothalamus, the pituitary, and the adrenal cortex itself. Cortisol is inhibitory toward CRH and POMC and in this way prevents an overshoot of the body’s endogenous defense reaction.
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). Feedback signals transmit a signal to melanocytes regarding stressor-induced damage to the skin. Cytokines and many other peptide signals number among these feedback signals. These feedback signals, which report on the extent of the prevailing damage or the problem, act in a stimulatory manner on the local CRH and POMC systems. The activated local melanocortin system prevents the damage from exacerbating in a pleiotropic manner. Much research has been performed on this stimulatory portion of the feedback system. However, there is only scant knowledge regarding the feedback signals that convey information about the extent of local defense reactions. If one compares the systemic melanocortin system, one might expect that if there is a strong activation of the local melanocortin system, a signal molecule should also be produced more that acts inhibitorily on CRH and POMC—and in so doing prevents overshooting of the cutaneous defense. Speculatively, such negative feedback signals could be provided by locally produced steroids; other candidates are neuropeptides like substance P or nerve growth factor (10). Such hypotheses can be derived and tested straightforwardly by comparatively considering the local and systemic melanocortin systems.
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Against this background, the new findings of Kauser et al. (2) represent not only an increase in knowledge of the processes of cutaneous neuroimmunomodulation, but they also point toward a much more universal principle that is of importance for the entire endocrinological community.
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Footnotes |
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Received November 12, 2004.
Accepted for publication November 15, 2004.
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  H Rumie, L A Metherell, A J L Clark, V Beauloye, and M Maes Clinical and biological phenotype of a patient with familial glucocorticoid deficiency type 2 caused by a mutation of melanocortin 2 receptor accessory protein Eur. J. Endocrinol., October 1, 2007; 157(4): 539 - 542. [Abstract] [Full Text] [PDF]
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