Role of CRH in skin physiology and pathology

Summary

Principal Investigator: Andrzej T Slominski
Abstract: The skin is both target and source for proopiomelanocortin (POMC)-derived neuropeptides. Corticotropin releasing hormone (CRH) and CRH receptors (CRH-R) are also expressed and fully functional in rodent and human skin, but its significance is not known. CRH and CRH receptors are recognized as main central regulators in the response to systemic stress and CRH peptide has pleiotropic role in regulation of local homeostasis. Therefore, we will investigate whether CRH can regulate local expression of POMC gene, mimicking therefore pituitary physiology, and/or to clarify its specific actions in the skin. Within this context, CRH itself is a potent immunomodulatory factor, acts on vascular function, and is also a local growth factor. These actions suggest that in the skin the role of CRH peptide could be pleiotropic in the regulation of local homeostasis. Our initial objective is the biochemical and functional characterization of the CRH-CRH receptor system in mammalian skin. The specific aims are as follow: 1. To define local mechanisms regulating the expression of CRH in normal melanocytes and keratinocytes; 2. To fully characterize the CRH-R1 receptors in normal melanocytes and keratinocytes by a) defining CRH binding site properties, b) measuring production of second messengers including cAMP, IP3 and Ca, c) testing whether postreceptor CRH signal transduction includes activation transcriptional regulators such as NF-kappa beta, CRE, AP1 and STAT; 3. To test the effect of CRH on the production of the POMC mRNA and POMC-derived peptides in normal melanocytes and keratinocytes; 4. To test the phenotypic effect of CRH on normal epidermal melanocytes and keratinocytes; 5. To test CRH participation in regulation of human hair growth and pigmentation. This will be evaluated in human hair follicle grown ex vivo and in isolated sub-populations of hair follicle-derived follicular melanocytes and keratinocytes and dermal papilla cells. To accomplish these goals we will use standard molecular, biochemical, and cell biology tools, which are currently available in our laboratory. As experimental models we will use epidermal and follicular keratinocytes and melanocytes as well as dermal papilla cells. The realization of the above aims should clarify the role of CRH and CRH receptors in the peripheral (skin) response to stress. The core of the project is the realization of the functional biochemical overlap between the cutaneous and hypothalamic CRH-activating systems. Whereas the central interactions between CRH together with CRH-Rs coordinates the behavioral, autonomic and endocrine responses to systemic stress, the present work will test whether that role extends to peripheral organs. Thus, we will test the effects of common stressors on expression of CRH and CRH-Rs, CRH effect on POMC expression. Moreover, we will characterize these CRH receptors and define their role in the regulation of phenotype in the most important components of the epidermis, e.g., melanocytes and keratinocytes, and test the role of CRH/CRH-R1 axis in the regulation of human hair growth.
Funding Period: 2002-09-01 - 2006-08-31
more information: NIH RePORT

Top Publications

  1. pmc Key role of CRF in the skin stress response system
    Andrzej T Slominski
    MD, PhD, Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center 930 Madison Avenue, Suite 500, Memphis, Tennessee 38163
    Endocr Rev 34:827-84. 2013
  2. pmc Sensing the environment: regulation of local and global homeostasis by the skin's neuroendocrine system
    Andrzej T Slominski
    University of Tennessee Health Science Center, Department of Pathology and Laboratory Medicine, Memphhis, TN, USA
    Adv Anat Embryol Cell Biol 212:v, vii, 1-115. 2012
  3. pmc Molecular cloning and initial characterization of African green monkey (Cercopithecus aethiops) corticotropin releasing factor receptor type 1 (CRF1) from COS-7 cells
    Andrzej T Slominski
    Department of Pathology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Gene 389:154-62. 2007
  4. pmc Differential expression of HPA axis homolog in the skin
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, University of Tennessee, HSC, Memphis, TN 38163, USA
    Mol Cell Endocrinol 265:143-9. 2007
  5. pmc Proopiomelanocortin (POMC), the ACTH/melanocortin precursor, is secreted by human epidermal keratinocytes and melanocytes and stimulates melanogenesis
    Karine Rousseau
    Faculty of Life Sciences, Stopford Bldg, University of Manchester, Manchester M13 9PT, UK
    FASEB J 21:1844-56. 2007
  6. pmc Expression of molecular equivalent of hypothalamic-pituitary-adrenal axis in adult retinal pigment epithelium
    Michal A Zmijewski
    Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, 930 Madison Avenue, RM525, Memphis, Tennessee 38163, USA
    J Endocrinol 193:157-69. 2007
  7. pmc Melanocyte receptors: clinical implications and therapeutic relevance
    J Andrew Carlson
    Division of Dermatopathology and Dermatology, Department of Pathology and Laboratory Medicine, Albany Medical College MC 81, 47 New Scotland Avenue, Albany, NY 12208, USA
    Dermatol Clin 25:541-57, viii-ix. 2007
  8. pmc A nervous breakdown in the skin: stress and the epidermal barrier
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, Health Science Center, University of Tennessee, Memphis, Tennessee 38163, USA
    J Clin Invest 117:3166-9. 2007
  9. pmc CRF1 receptor splicing in epidermal keratinocytes: potential biological role and environmental regulations
    Michal A Zmijewski
    Department of Pathology and Laboratory Medicine, Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    J Cell Physiol 218:593-602. 2009
  10. pmc Neuroendocrine activity of the melanocyte
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
    Exp Dermatol 18:760-3. 2009

Scientific Experts

  • J Andrew Carlson
  • Andrzej T Slominski
  • Petra Arck
  • Blazej Zbytek
  • Michal A Zmijewski
  • Sobia Kauser
  • M A Zmijewski
  • Karine Rousseau
  • Edward T Wei
  • Desmond J Tobin
  • B Zbytek
  • Anne White
  • Lynn E Pritchard
  • Robert L Oliver
  • Anne Warhurst
  • Rajesh K Sharma
  • Anthony J Thody
  • Lawrence M Pfeffer
  • Jacobo Wortsman
  • J Wortsman
  • A Mysliwski
  • R M Slominski
  • M Pikula
  • E Wei

Detail Information

Publications33

  1. pmc Key role of CRF in the skin stress response system
    Andrzej T Slominski
    MD, PhD, Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center 930 Madison Avenue, Suite 500, Memphis, Tennessee 38163
    Endocr Rev 34:827-84. 2013
    ..CRF and CRFR-1 may constitute novel targets through the use of specific agonists or antagonists, especially for therapy of skin diseases that worsen with stress, such as atopic dermatitis and psoriasis. ..
  2. pmc Sensing the environment: regulation of local and global homeostasis by the skin's neuroendocrine system
    Andrzej T Slominski
    University of Tennessee Health Science Center, Department of Pathology and Laboratory Medicine, Memphhis, TN, USA
    Adv Anat Embryol Cell Biol 212:v, vii, 1-115. 2012
    ..In conclusion, skin cells and skin as an organ coordinate and/or regulate not only peripheral but also global homeostasis...
  3. pmc Molecular cloning and initial characterization of African green monkey (Cercopithecus aethiops) corticotropin releasing factor receptor type 1 (CRF1) from COS-7 cells
    Andrzej T Slominski
    Department of Pathology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Gene 389:154-62. 2007
    ....
  4. pmc Differential expression of HPA axis homolog in the skin
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, University of Tennessee, HSC, Memphis, TN 38163, USA
    Mol Cell Endocrinol 265:143-9. 2007
    ..Thus, differential, CRH-driven responses of defined cutaneous cell populations reproduce key features of the central HPA axis at the tissue/single cell levels...
  5. pmc Proopiomelanocortin (POMC), the ACTH/melanocortin precursor, is secreted by human epidermal keratinocytes and melanocytes and stimulates melanogenesis
    Karine Rousseau
    Faculty of Life Sciences, Stopford Bldg, University of Manchester, Manchester M13 9PT, UK
    FASEB J 21:1844-56. 2007
    ..POMC also increased melanogenesis and dendricity in human pigment cells. This release of POMC from skin cells and its functional activity at the MC-1R highlight the importance of POMC processing as a key regulatory event in the skin...
  6. pmc Expression of molecular equivalent of hypothalamic-pituitary-adrenal axis in adult retinal pigment epithelium
    Michal A Zmijewski
    Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, 930 Madison Avenue, RM525, Memphis, Tennessee 38163, USA
    J Endocrinol 193:157-69. 2007
    ..Therefore, we suggest that ocular tissue expresses CRF-driven signalling system that follows organisational structure of the HPA axis...
  7. pmc Melanocyte receptors: clinical implications and therapeutic relevance
    J Andrew Carlson
    Division of Dermatopathology and Dermatology, Department of Pathology and Laboratory Medicine, Albany Medical College MC 81, 47 New Scotland Avenue, Albany, NY 12208, USA
    Dermatol Clin 25:541-57, viii-ix. 2007
    ..This article reviews the current understanding of melanocyte receptors, their agonists and inhibitors, and their potential to treat the melanocytic pathology...
  8. pmc A nervous breakdown in the skin: stress and the epidermal barrier
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, Health Science Center, University of Tennessee, Memphis, Tennessee 38163, USA
    J Clin Invest 117:3166-9. 2007
    ..Thus, this study provides what I believe to be the first mechanistic link between psychological stress and increased susceptibility to microbial infection...
  9. pmc CRF1 receptor splicing in epidermal keratinocytes: potential biological role and environmental regulations
    Michal A Zmijewski
    Department of Pathology and Laboratory Medicine, Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    J Cell Physiol 218:593-602. 2009
    ..We suggest that alternative splicing of CRF1 may play an important role in the regulation of skin cell phenotype with potential implications in pathology...
  10. pmc Neuroendocrine activity of the melanocyte
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
    Exp Dermatol 18:760-3. 2009
    ..Such capabilities have defined melanocytes as neuroendocrine cells that not only coordinate cutaneous but also can affect a global homeostasis...
  11. pmc Modulation of corticotropin releasing factor (CRF) signaling through receptor splicing in mouse pituitary cell line AtT-20--emerging role of soluble isoforms
    M A Zmijewski
    Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Gdansk, Poland
    J Physiol Pharmacol 60:39-46. 2009
    ..extracellular localization...
  12. pmc CRH mediates inflammation induced by lipopolysaccharide in human adult epidermal keratinocytes
    Blazej Zbytek
    J Invest Dermatol 127:730-2. 2007
  13. pmc CRH inhibits NF-kappa B signaling in human melanocytes
    Blazej Zbytek
    Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, 930 Madison Avenue 525, Memphis, TN 38163, USA
    Peptides 27:3276-83. 2006
    ..g. through activation of POMC. We suggest that induction of POMC by CRH serves as a feedback mechanism to self-restrict inflammatory response in the skin...
  14. pmc Proopiomelanocortin signaling system is operating in mast cells
    Andrzej T Slominski
    Department of Pathology and Laboratory Medicine, Health Science Center, University of Tennessee, Memphis, 38163, USA
    J Invest Dermatol 126:1934-6. 2006
    ..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...
  15. pmc Preservation of eumelanin hair pigmentation in proopiomelanocortin-deficient mice on a nonagouti (a/a) genetic background
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, University of Tennessee, Memphis, Tennessee 38163, USA
    Endocrinology 146:1245-53. 2005
    ..Whereas the latter implies feedback control of melanogenesis, it is also possible that the two mechanisms operate jointly in hair follicles...
  16. ncbi CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, 930 Madison Ave Room 519, Memphis, TN 38103, USA
    Am J Physiol Endocrinol Metab 288:E701-6. 2005
    ..This pattern demonstrates the fractal nature of the response to stress with similar activation sequence at the single-cell and whole body levels...
  17. pmc Hair follicle pigmentation
    Andrzej Slominski
    Department of Pathology, University of Tennessee, Memphis, Tennessee 38163, USA
    J Invest Dermatol 124:13-21. 2005
    ..Melanin itself has a wide range of bioactivities that extend far beyond its determination of hair color...
  18. pmc Corticotropin-releasing hormone triggers differentiation in HaCaT keratinocytes
    B Zbytek
    Department of Histology and Immunology, Medical University of Gdansk, Gdansk, Poland
    Br J Dermatol 152:474-80. 2005
    ..These are mediated by CRH-R1alpha and represented by adenylate cyclase activation, Ca2+ influx, inhibition of cell proliferation and modifications in intracellular signal transduction by NF-kappaB...
  19. ncbi CRH stimulates POMC activity and corticosterone production in dermal fibroblasts
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, University of Tennessee, 930 Madison Avenue 519, Memphis, TN 38163, USA
    J Neuroimmunol 162:97-102. 2005
    ..However, it diverges from the HPA organization in its distal step, where CRH and ACTH stimulate production of corticosterone, instead of cortisol...
  20. pmc The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, University of Tennessee, Health Science Center, Memphis, TN 38163, USA
    FEBS J 272:4080-90. 2005
    ..Additional vitamin D3 metabolites arise from the action of other enzymes in adrenal mitochondria. These findings appear to define novel metabolic pathways involving vitamin D3 that remain to be characterized...
  21. pmc Neuroendocrine system of the skin
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, 38163, USA
    Dermatology 211:199-208. 2005
    ..These endocrine factors would represent an exquisite regulatory layer addressed at restricting maximally the effect of noxious agents in the skin to preserve local and consequently global homeostasis...
  22. pmc On the role of melatonin in skin physiology and pathology
    Andrzej Slominski
    Department of Pathology and Laboratory Medicine, Health Science Center, University of Tennessee, Memphis, TN 38103, USA
    Endocrine 27:137-48. 2005
    ..Furthermore, melatonin could have a role in protection against solar radiation or even in the management of skin diseases...
  23. pmc CRH functions as a growth factor/cytokine in the skin
    A Slominski
    Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
    J Cell Physiol 206:780-91. 2006
    ..In conclusion, CRH and related peptides can couple CRH-R1 to any of diverse signal transduction pathways; they also regulate cell viability and proliferation in cell type and growth condition-dependent manners...
  24. pmc Cultured human dermal fibroblasts do produce cortisol
    Andrzej Slominski
    J Invest Dermatol 126:1177-8. 2006
  25. pmc Modulation of the human hair follicle pigmentary unit by corticotropin-releasing hormone and urocortin peptides
    Sobia Kauser
    Department of Biomedical Sciences, University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK
    FASEB J 20:882-95. 2006
    ..This study indicates that CRH peptides can differentially influence hair follicle melanocyte behavior not only via CRH-R1 signaling but also by complex cross-talk between CRH-R1 and CRH-R2...
  26. pmc Corticotropin releasing hormone and the skin
    Andrzej Slominski
    Department of Pathology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    Front Biosci 11:2230-48. 2006
    ..The accumulated evidence indicates that cutaneous CRH is also a component of a local structure organized similarly to the hypothalamo-pituitary-adrenal axis...
  27. pmc Characterization of a ultraviolet B-induced corticotropin-releasing hormone-proopiomelanocortin system in human melanocytes
    Blazej Zbytek
    Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
    Mol Endocrinol 20:2539-47. 2006
    ..In conclusion, UVB induces CRH production in human melanocytes through stimulation of the protein kinase A pathway, with sequential involvement of CRH-CRH receptor 1 in the stimulation of POMC expression...
  28. pmc Neuroimmunology of stress: skin takes center stage
    Petra C Arck
    Biomedical Research Center, Charite, University Medicine Berlin, Berlin, Germany
    J Invest Dermatol 126:1697-704. 2006
    ....
  29. ncbi Corticotropin-releasing hormone induces keratinocyte differentiation in the adult human epidermis
    Blazej Zbytek
    Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
    J Cell Physiol 203:118-26. 2005
    ....