Corticotropin-Releasing Hormone Skin Signaling is Receptor-Mediated and is Predominant in the Sebaceous Glands

Abstract

There is increasing evidence that the sebaceous gland expresses receptors for several neuropeptides and is involved in responses to stress. Among them, corticotropin-releasing hormone (CRH) was currently found to be produced also in the skin. In this study, the distribution of CRH, CRH receptors 1 and 2 (CRH-R1 and CRH-R2), and CRH binding protein (CRH-BP) in cultured human (SZ95) sebocytes was further characterized. Moreover, the effects of CRH and CRH-like peptides on proliferation and inflammatory signaling of CRH receptor-expressing SZ95 sebocytes in vitro were investigated. Urocortin (Uct), urotensin and sauvagine are recently described members of the family of structurally related CRH-like peptides, whereas Uct shares a 45% homology with CRH. CRH and Uct inhibited SZ95 sebocyte proliferation with CRH also stimulating interleukin-6 (IL-6) and interleukin-8 (IL-8) release from SZ95 sebocytes. However, CRH had no effect on interleukin-1α and interleukin-1β production in these cells. α-Helical-CRF, a CRH antagonistic peptide, annulled the CRH effect on SZ95 sebocyte proliferation and interleukin secretion, while the non-peptidic CRH-R1 selective antagonist antalarmin inhibited the increased production of neutral lipids caused by CRH. In conclusion, CRH, and to a lesser extent Uct, may be involved in signaling of stress pathophysiology in the skin. However, further investigations into the downstream effects of CRH and Uct are required to elucidate the mechanism by which these neuropeptides could establish a stress-related pathophysiological condition in the skin.

CRH - skin - SZ95 sebocytes - interleukins - proliferation - lipogenesis

References

• 1 Aguilera G. Corticotropin releasing hormone, receptor regulation and the stress response.  Trends Endocrinol Metab. 1998;  9 329-336
• 2 Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis.  JAMA. 1992;  267 1244-1252
• 3 Dautzenberg FM, Hauger RL. The CRH peptide family and their receptors: yet more partners discovered.  Trends Pharmacol Sci. 2002;  23 71-77
• 4 Grammatopoulos DK, Chrousos GP. Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists.  Trends Endocrinol Metab. 2002;  13 436-444
• 5 Perrin MH, Vale WW. Corticotropin releasing factor receptors and their ligand family.  Ann N Y Acad Sci. 1999;  885 312-328
• 6 Linton EA, Woodman JR, Asboth G, Glynn BP, Plested CP, Bernal AL. Corticotrophin releasing hormone: its potential for a role in human myometrium.  Exp Physiol. 2001;  86 273-281
• 7 Slominski A, Wortsman J, Luger T, Paus R, Salomon S. Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress.  Physiol Rev. 2000;  80 979-1020
• 8 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;  15 1678-1693
• 9 Chalmers DT, Lovenberg TW, Grigoriadis DE, Behan DP, De Souza EB. Corticotropin- releasing factor receptors: from molecular biology to drug design.  Trends Pharmacol Sci. 1996;  17 166-172
• 10 Slominski A, Pisarchik A, Tobin DJ, Mazurkiewicz JE, Wortsman J. Differential expression of a cutaneous corticotropin-releasing hormone system.  Endocrinology. 2004;  145 941-950
• 11 Zouboulis CC, Seltmann H, Hiroi N, Chen WC, 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
• 12 Kono M, Nagata H, Umemura S, Kawana S, Osamura RY. In situ expression of corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) genes in human skin.  FASEB J. 2001;  15 2297-2299
• 13 Park HJ, Kim HJ, Lee JH, Lee JY, Cho BK, Kang JS, Kang H, Yang Y, Cho DH. Corticotropin-releasing hormone (CRH) downregulates interleukin-18 expression in human HaCaT keratinocytes by activation of p38 mitogen-activated protein kinase (MAPK) pathway.  J Invest Dermatol. 2005;  124 751-755
• 14 Zbytek B, Pfeffer LM, Slominski AT. Corticotropin-releasing hormone stimulates NF-kappa B in human epidermal keratinocytes.  J Endocrinol. 2004;  181 1-7
• 15 Zouboulis CC, Seltmann H, Neitzel H, Orfanos CE. Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95).  J Invest Dermatol. 1999;  113 1011-1020
• 16 Slominski AT, Botchkarev V, Choudhry M, Fazal N, Fechner K, Furkert J, Krause E, Roloff B, Sayeed M, Wei E, Zbytek B, Zipper J, Wortsman J, Paus R. Cutaneous expression of CRH and CRH-R. Is there a “skin stress response system?”.  Ann N Y Acad Sci. 1999;  885 287-311
• 17 Pisarchik A, Slominski AT. Alternative splicing of CRH-R1 receptors in human and mouse skin: identification of new variants and their differential expression.  Faseb J. 2001;  15 2754-2756
• 18 Slominski A, Zbytek B, Pisarchik A, Slominski RM, Zmijewski MA, Wortsman J. CRH functions as a growth factor/cytokine in the skin.  J Cell Physiol. 2006;  206 780-791
• 19 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
• 20 Ganceviciene R, Marciukaitiene I, Graziene V, Rimkevicius A, Zouboulis CC. New accents in the pathogenesis of acne vulgaris.  Acta Medica. , in press
• 21 Kempuraj D, Papadopoulou NG, Lytinas M, Huang M, Kandere-Grzybowska K, Madhappan B, Boucher W, Christodoulou S, Athanassiou A, Theoharides TC. Corticotropin-releasing hormone and its structurally related urocortin are synthesized and secreted by human mast cells.  Endocrinology. 2004;  145 43-48
• 22 Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, Hogenesch JB, Gulyas J, Rivier J, Vale WW, Sawchenko PE. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors.  Proc Natl Acad Sci USA. 2001;  98 2843-2848
• 23 Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, Vaughan J, Reyes TM, Gulyas J, Fischer W, Bilezikjian L, Rivier J, Sawchenko PE, Vale WW. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor.  Proc Natl Acad Sci USA. 2001;  98 7570-7575
• 24 Lawrence AJ, Krstew EV, Dautzenberg FM, Ruhmann A. The highly selective CRF(2) receptor antagonist K41498 binds to presynaptic CRF(2) receptors in rat brain.  Br J Pharmacol. 2002;  136 896-904
• 25 Zbytek B, Mysliwski A, Slominski A, Wortsman J, Wei ET, Mysliwska J. Corticotropin-releasing hormone affects cytokine production in human HaCaT keratinocytes.  Life Sci. 2002;  70 1013-1021
• 26 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
• 27 Zbytek B, Pfeffer LM, Slominski AT. Corticotropin-releasing hormone stimulates NF-kappaB in human epidermal keratinocytes.  J Endocrinol. 2004;  181 R1-R7
• 28 Fazal N, Slominski A, Choudhry MA, Wei ET, Sayeed MM. Effect of CRF and related peptides on calcium signaling in human and rodent melanoma cells.  FEBS Lett. 1998;  435 187-190
• 29 Wiesner B, Roloff B, Fechner K, Slominski A. Intracellular calcium measurements of single human skin cells after stimulation with corticotropin-releasing factor and urocortin using confocal laser scanning microscopy.  J Cell Sci. 2003;  116 1261-1268
• 30 Bohm M, Schiller M, Stander S, Seltmann H, Li Z, Brzoska T, Metze D, Schioth HB, Skottner A, Seiffert K, Zouboulis CC, Luger TA. Evidence for expression of melanocortin-1 receptor in human sebocytes in vitro and in situ.  J Invest Dermatol. 2002;  118 533-539
• 31 Dinarello CA. Interleukin-1 and interleukin-1 antagonism.  Blood. 1991;  77 1627-1652
• 32 Zouboulis CC, Eady A, Philpott M, Goldsmith LA, Orfanos C, Cunliffe WC, Rosenfield R. What is the pathogenesis of acne?.  Exp Dermatol. 2005;  14 143-152
• 33 Zouboulis CC, Xia L, Akamatsu H, Seltmann H, Fritsch M, Hornemann S, Ruhl R, Chen W, Nau H, Orfanos CE. The human sebocyte culture model provides new insights into development and management of seborrhoea and acne.  Dermatology. 1998;  196 21-31
• 34 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

1 The authors, K. Krause and A. Schnitger, contributed equally to the work.

Correspondence