The Self-Similarity of the Melanocortin System
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内分泌学杂志 2005年第2期
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 Universit?t zu Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. E-mail: achim.peters@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.
FIG. 1. Hypothalamic CRH from the paraventricular nucleus stimulates POMC production in the pituitary and is involved in the activation of the sympathetic nervous system (SNS). ACTH is enzymatically released from POMC, which then reaches the adrenal gland via the blood and binds to the MC2 receptor. The activation of the central nervous-CRH-POMC system leads to a restriction of the stressor-induced damage. Cytokines mediate a positive feedback signal to the paraventricular nucleus and stimulate further CRH-production. Adrenal cortisol transmits a negative feedback signal to the hypothalamic CRH production. In this way the system strives for a balance whereby the opposing effects of the stimulatory and inhibitory feedback of stressors and stress responses are of the same scale.
At the local level of the hair follicles and the epidermal melanin units, the regulation principle looks similar (Fig. 2). 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.
FIG. 2. Melanocyte CRH and POMC stimulate the MC1 receptor via -MSH, which leads to the increased formation of the pigment melanin. Melanin restricts stressor-induced damage, e.g. that caused by UV radiation. Cytokines convey the extent of the prevailing damage as a feedback signal and stimulate additional CRH and POMC production. A feedback signal that conveys the scale of the local stress reaction and inhibits additional CRH production could in theory be provided by locally produced peptides or steroids. This hypothesis can be derived by comparing the systemic regulation principle and can be tested experimentally.
There is clearly a remarkable self-similarity of melanocortin systems at the systemic and local levels. It would not be surprising if a defense system that has proven itself at the local level during evolution should also be encountered with exactly the same components in phylogenetically more highly developed organisms with a central nervous system. Neurons, just like melanocytes, are of ectodermal origin. Irrespective of whether neuronal populations then produce and release CRH and POMC, evolution might have ensured that the structural regulation mechanisms are maintained and adopted in complete form. As expected, a third melanocortin system (with POMC neurons of the arcuate nucleus and MC4 receptors) operates in the very same way. It also appears that such control systems with dual feedback input, i.e. a stimulatory and an inhibitory feedback signal, frequently reoccur in biology, e.g. in the regulation of energy metabolism (11). This reoccurrence of a tried and tested defense system at a hierarchically higher level could therefore be seen as an expression of the "self-similarity phenomenon."
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.
References
Slominski A, Tobin DJ, Shibahara S, Wortsman J 2004 Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 84:1155–1228
Kauser S, Thody AJ, Schallreuter KU, Gummer C, Tobin DJ 2005 A fully functional proopiomelanocortin/melanocortin-1 receptor system regulates the differentiation of human scalp hair follicle melanocytes. Endocrinology 146:532–543
Mandelbrot BB 1983 The fractal geometry of nature. New York: W. H. Freeman and Co.
Chrousos GP, Gold PW 1992 The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267:1244–1252
Slominski A, Wortsman J, Luger T, Paus R, Solomon S 2000 Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol Rev 80:979–1020
Saavedra JM, Ando H, Armando I, Baiardi G, Bregonzio C, Jezova M, Zhou J 2004 Brain angiotensin II, an important stress hormone: regulatory sites and therapeutic opportunities. Ann NY Acad Sci 1018:76–84
Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES 2000 The sympathetic nerve-an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52:595–638
Pedersen BK, Steensberg A, Schjerling P 2001 Muscle-derived interleukin-6: possible biological effects. J Physiol 536:329–337
Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG 1996 Identification of targets of leptin action in rat hypothalamus. J Clin Invest 98:1101–1106
Peters EM, Handjiski B, Kuhlmei A, Hagen E, Bielas H, Braun A, Klapp BF, Paus R, Arck PC 2004 Neurogenic inflammation in stress-induced termination of murine hair growth is promoted by nerve growth factor. Am J Pathol 165:259–271
Peters A, Schweiger U, Pellerin L, Hubold C, Oltmanns KM, Conrad M, Schultes B, Born J, Fehm HL 2004 The selfish brain: competition for energy resources. Neurosci Biobehav Rev 28:143–180(Achim Peters)
Address all correspondence and requests for reprints to: Achim Peters, M.D., Medical Clinic 1, Medizinische Universit?t zu Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. E-mail: achim.peters@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.
FIG. 1. Hypothalamic CRH from the paraventricular nucleus stimulates POMC production in the pituitary and is involved in the activation of the sympathetic nervous system (SNS). ACTH is enzymatically released from POMC, which then reaches the adrenal gland via the blood and binds to the MC2 receptor. The activation of the central nervous-CRH-POMC system leads to a restriction of the stressor-induced damage. Cytokines mediate a positive feedback signal to the paraventricular nucleus and stimulate further CRH-production. Adrenal cortisol transmits a negative feedback signal to the hypothalamic CRH production. In this way the system strives for a balance whereby the opposing effects of the stimulatory and inhibitory feedback of stressors and stress responses are of the same scale.
At the local level of the hair follicles and the epidermal melanin units, the regulation principle looks similar (Fig. 2). 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.
FIG. 2. Melanocyte CRH and POMC stimulate the MC1 receptor via -MSH, which leads to the increased formation of the pigment melanin. Melanin restricts stressor-induced damage, e.g. that caused by UV radiation. Cytokines convey the extent of the prevailing damage as a feedback signal and stimulate additional CRH and POMC production. A feedback signal that conveys the scale of the local stress reaction and inhibits additional CRH production could in theory be provided by locally produced peptides or steroids. This hypothesis can be derived by comparing the systemic regulation principle and can be tested experimentally.
There is clearly a remarkable self-similarity of melanocortin systems at the systemic and local levels. It would not be surprising if a defense system that has proven itself at the local level during evolution should also be encountered with exactly the same components in phylogenetically more highly developed organisms with a central nervous system. Neurons, just like melanocytes, are of ectodermal origin. Irrespective of whether neuronal populations then produce and release CRH and POMC, evolution might have ensured that the structural regulation mechanisms are maintained and adopted in complete form. As expected, a third melanocortin system (with POMC neurons of the arcuate nucleus and MC4 receptors) operates in the very same way. It also appears that such control systems with dual feedback input, i.e. a stimulatory and an inhibitory feedback signal, frequently reoccur in biology, e.g. in the regulation of energy metabolism (11). This reoccurrence of a tried and tested defense system at a hierarchically higher level could therefore be seen as an expression of the "self-similarity phenomenon."
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.
References
Slominski A, Tobin DJ, Shibahara S, Wortsman J 2004 Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 84:1155–1228
Kauser S, Thody AJ, Schallreuter KU, Gummer C, Tobin DJ 2005 A fully functional proopiomelanocortin/melanocortin-1 receptor system regulates the differentiation of human scalp hair follicle melanocytes. Endocrinology 146:532–543
Mandelbrot BB 1983 The fractal geometry of nature. New York: W. H. Freeman and Co.
Chrousos GP, Gold PW 1992 The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267:1244–1252
Slominski A, Wortsman J, Luger T, Paus R, Solomon S 2000 Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol Rev 80:979–1020
Saavedra JM, Ando H, Armando I, Baiardi G, Bregonzio C, Jezova M, Zhou J 2004 Brain angiotensin II, an important stress hormone: regulatory sites and therapeutic opportunities. Ann NY Acad Sci 1018:76–84
Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES 2000 The sympathetic nerve-an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52:595–638
Pedersen BK, Steensberg A, Schjerling P 2001 Muscle-derived interleukin-6: possible biological effects. J Physiol 536:329–337
Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG 1996 Identification of targets of leptin action in rat hypothalamus. J Clin Invest 98:1101–1106
Peters EM, Handjiski B, Kuhlmei A, Hagen E, Bielas H, Braun A, Klapp BF, Paus R, Arck PC 2004 Neurogenic inflammation in stress-induced termination of murine hair growth is promoted by nerve growth factor. Am J Pathol 165:259–271
Peters A, Schweiger U, Pellerin L, Hubold C, Oltmanns KM, Conrad M, Schultes B, Born J, Fehm HL 2004 The selfish brain: competition for energy resources. Neurosci Biobehav Rev 28:143–180(Achim Peters)