Abstract
The skin, as the largest organ of the body, is strategically located as a barrier between the external and internal environments, being permanently exposed to noxious stressors such as bursts of radiation (solar, thermal), mechanical energy, or chemical and biological insults. Because of its functional domains and structural diversity, the skin must have a constitutive mechanism for dealing with the stressors. Activities of the skin are mostly regulated by local cutaneous factors and stressed skin can generate signals to produce rapid (neural) or slow (humoral) responses to local or systemic levels. Thus, the skin neuroendocrine system is comprised of locally produced neuroendocrine mediators that interact with corresponding specific receptors through para- or autocrine mechanisms. Furthermore, it is known for several years that the corticotropin-releasing hormone (CRH)/ pro-opiomelanocorticotropin (POMC) skin system fulfils analogous functions to the hypothalamic-pituitary-adrenal (HPA) stress axis. Additionally, skin cells produce hormones, neurotansmitters and neuropeptides, having the corresponding receptors and the skin itself is able to fulfill a multidirectional communication between endocrine, immune and central nervous systems as well as other internal organs. In summary, the skin expresses an equivalent of the prominent hypothalamic-pituitary-adrenal stress axis that may act as a cutaneous defense system, operating as a coordinator and executor of local responses to stress, in addition to its normal function: the preservation of body homeostasis.
Keywords
cutaneous HPA axis - CRH - skin
References
1
Slominski A, Mihm MC.
Potential mechanism of skin response to stress.
Int J Dermatol.
1996;
35
849-851
2
Slominski A, Wortsman J.
Neuroendocrinology of the skin.
Endocr Rev.
2000;
21
457-487
3
Slominski A.
Neuroendocrine system of the skin.
Dermatology.
2005;
211
199-208
4
Slominski A, Szczesniewski A, Wortsman J.
Liquid chromatography-mass spectrometry detection of corticotropin-releasing hormone and proopiomelanocortin-derived peptides in human skin.
J Clin Endocrinol Metab.
2000;
85
3582-3588
5
Slominski A, Wortsman J, Luger T, Paus R, Solomon S.
Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress.
Physiol Rev.
2000;
80
979-1020
6
Slominski AT, Roloff B, Zbytek B, Wei ET, Fechner K, Curry J, Wortsman J.
Corticotropin releasing hormone and related peptides can act as bioregulatory factors in human keratinocytes.
In Vitro Cell Dev Biol Anim.
2000;
36
211-216
7
Zouboulis CC.
Human skin: an independent peripheral endocrine organ.
Horm Res.
2000;
54
230-242
8
Slominski A, Ermak G, Mihm MC.
ACTH receptor, CYP11A1, CYP17 and CYP21A2 genes are expressed in skin.
J Clin Endocrinol Metab.
1996;
7
2746-2749
9
Slominski A, Zbytek B, Szczesniewski A, Semak I, Kaminski J, Sweatman T, Wortsman J.
CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH.
Am J Physiol Endocrinol Metab.
2005;
288
E701-E706
, [Epub 2004 Nov 30. Erratum in: Am J Physiol Endocrinol Metab. 2006; 290: E204]
10
Chrousos GP.
The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.
N Engl J Med.
1995;
332
1351-1362
11
Grammatopoulos DK, Chrousos GP.
Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists.
Trends Endocrinol Metab.
2002;
13
436-444
12
Smith AI, Funder JW.
Proopiomelanocortin processing in the pituitary, central nervous system, and peripheral tissues.
Endocr Rev.
1988;
9
159-179
13
Shibahara S, Morimoto Y, Furutani Y, Notake M, Takahashi H, Shimizu S, Horikawa S, Numa S.
Isolation and sequence analysis of the human corticotropin-releasing factor precursor gene.
Embo J.
1983;
2
775-779
14
Thompson RC, Seasholtz AF, Herbert E.
Rat corticotropin-releasing hormone gene: sequence and tissue-specific expression.
Mol Endocrinol.
1987;
1
363-370
15
Orth DN.
Corticotropin-releasing hormone in humans.
Endocr Rev.
1992;
13
164-191
16
Stephanou A, Jessop DS, Knight RA, Lightman SL.
Corticotrophin-releasing factor-like immunoreactivity and mRNA in human leukocytes.
Brain Behav Immun.
1990;
4
67-73
17
Jones KL.
The Cushing syndromes.
Pediatr Clin North Am.
1990;
37
1313-1332
18
Sarnyai Z, Shaham Y, Heinrichs SC.
The role of corticotropin-releasing factor in drug addiction.
Pharmacol Rev.
2001;
53
209-243
19
Heinrichs SC, De Souza EB.
Corticotropin-releasing factor antagonists, binding-protein and receptors: implications for central nervous system disorders.
Baillieres Best Pract Res Clin Endocrinol Metab.
1999;
13
541-554
20
Chrousos GP.
The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes.
Int J Obes Relat Metab Disord.
2000;
24
((Suppl 2))
S50-S55
21
Gold PW, Chrousos GP.
Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states.
Mol Psychiatry.
2002;
7
254-275
22
Wahle M, Krause A, Pierer M, Hantzschel H, Baerwald CG.
Immunopathogenesis of rheumatic diseases in the context of neuroendocrine interactions.
Ann N Y Acad Sci.
2002;
966
355-364
23
Hiroi N, Wong ML, Licinio J, Park C, Young M, Gold PW, Chrousos GP, Bornstein SR.
Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls.
Mol Psychiatry.
2001;
6
540-546
24
Zouboulis CC, Seltmann H, Hiroi N, Chen W, Young M, Oeff M, Scherbaum WA, Orfanos CE, McCann SM, Bornstein SR.
Corticotropin-releasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes.
Proc Natl Acad Sci USA.
2002;
99
7148-7153
25
Krause K, Schnitger A, Fimmel S, lass E, Zouboulis CC.
Corticotropin-releasing hormone skin signalling is receptor-mediated and is predominant in the sebaceous glands.
Horm Metab Res.
, in press
26
Slominski A, Zbytek B, Pisarchik A, Slominski RM, Zmijewski M A, Wortsman J.
CRH functions as a growth factor/cytokine in the skin.
J Cell Physiol.
2006;
206
780-791
27
Zbytek B, Pikula M, Slominski RM, Mysliwski A, Wei E, Wortsman J, Slominski AT.
Corticotropin-releasing hormone triggers differentiation in HaCaT keratinocytes.
Br J Dermatol.
2005;
152
474-480
28
Quevedo ME, Slominski A, Pinto W, Wei E, Wortsman J.
Pleiotropic effects of corticotropin releasing hormone on normal human skin keratinocytes.
In Vitro Cell Dev Biol Anim.
2001;
37
50-54
29
Slominski A, Wortsman J, Pisarchik A, Zbytek B, Linton EA, Mazurkiewicz JE, Wei ET.
Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors.
FASEB J.
2001;
10
1678-1693
30
Willenberg HS, Haase M, Papewalis C, Schott M, Scherbaum WA, Bornstein SR.
Corticotropin-releasing hormone receptor expression on normal and tumorous human adrenocortical cells.
Neuroendocrinology.
2005;
82
((5-6))
274-281
31
Seres J, Bornstein SR, Seres P, Willenberg HS, Schulte KM, Scherbaum WA, Ehrhart-Bornstein M.
Corticotropin-releasing hormone system in human adipose tissue.
J Clin Endocrinol Metab.
2004 Feb;
89
((2))
965-970
32
Ganceviciene R, Graziene V, Fimmel S, Zouboulis CC.
Involvement of the Corticotropin-releasing hormone system in the pathogenesis of acne vulgaris.
, Submitted for publication
33
Slominski A, Pisarchik A, Tobin DJ, Mazurkiewicz JE, Wortsman J.
Differential expression of a cutaneous corticotropin-releasing hormone system.
Endocrinology.
2004;
145
941-950
34
Zbytek B, Pfeffer LM, Slominski AT.
Corticotropin-releasing hormone stimulates NF-kappaB in human epidermal keratinocytes.
J Endocrinol.
2004;
181
R1-R7
35
Papadopoulou N, Kalogeromitros D, Staurianeas NG, Tiblalexi D, Theoharides TC.
Corticotropin-releasing hormone receptor-1 and histidine decarboxylase expression in chronic urticaria.
J Invest Dermatol.
2005;
125
952-955
36
Bienenstock J, Tomioka M, Matsuda H, Stead RH, Quinonez G, Simon GT, Coughlin, MD, Denburg JA.
The role of mast cells in inflammatory processes: evidence for nerve/mast cell interactions.
Int Arch Allergy Appl Immunol.
1987;
82
238-243
37
Maurer M, Theoharides T, Granstein RD, Bischoff SC, Bienenstock J, Henz B, Kovanen P, Piliponsky AM, Kambe N, Vliagoftis H, Levi-Schaffer F, Metz M, Miyachi Y, Befus D, Forsythe P, Kitamura Y, Galli S.
What is the physiological function of mast cells?.
Exp Dermatol.
2003;
12
886-910
38
Ito N, Ito T, Kromminga A, Bettermann A, Takigawa M, Kees F, Straub RH, Paus R.
Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol.
FASEB J.
2005;
19
1332-1334
39
Itoi K, Seasholtz AF, Watson SJ.
Cellular and extracellular regulatory mechanisms of hypothalamic corticotropin-releasing hormone neurons.
Endocr J.
1998;
45
13-33
40
Böhm M, Schiller M, Ständer S, Seltmann H, Li Z, Brzoska T, Metze D, Schiöth HB, Skottner A, Seiffert K, Zouboulis CC, Luger TA.
Evidence for expression of melanocortin-1 receptor in human sebocytes in vitro and in situ. Evidence for expression of melanocortin-1 receptor in human sebocytes in vitro and in situ.
J Invest Dermatol.
2002;
118
533-539
41
Kane MO, Murphy EP, Kirby B.
The role of corticotropin-releasing hormone in immune-mediated cutaneous inflammatory disease.
Exp Dermatol.
2006;
15
143-153
42
Biro T, Ko MC, Bromm B, Wei ET, Bigliardi P, Siebenhaar F, Hashizume H, Misery L, Bergasa NV, Kamei C, Schouenborg J, Roostermann D, Szabo T, Maurer M, Bigliardi-Qi M, Meingassner JG, Hossen MA, Schmelz M, Steinhoff M.
How best to fight that nasty itch - from new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus to novel therapeutic approaches.
Exp Dermatol.
2005;
14
225-240
43
Theoharides TC, Donelan JM, Papadopoulou N, Cao J, Kempuraj D, Conti P.
Mast cells as targets of corticotropin-releasing factor and related peptides.
Trends Pharmacol Sci.
2004;
25
563-568
Correspondence
S. R. Bornstein
Medical Clinic III, Technical University of Dresden, Department of Endocrinology, Diabetology and Metabolism
Fetscherstrasse 74
01307 Dresden
Germany
Phone: +49/351/458 59 55
Fax: +49/351/458 63 98
Email: Stefan.Bornstein@uniklinikum-dresden.de