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Gene Expression Analysis of the Corticotrophin-Releasing Hormone-Proopiomelanocortin System in Psoriasis Skin Biopsies

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Gene Expression Analysis of the Corticotrophin-Releasing Hormone-Proopiomelanocortin System in Psoriasis Skin Biopsies Acta Derm Venereol 2013; 93: 400–405 INVESTIGATIVE REPORT Gene Expression Analysis of the Corticotrophin-releasing Hormone-proopiomelanocortin System in Psoriasis Skin Biopsies Ulvi LOITE1, Külli KINGO1, Ene REIMANN2, Paula REEMANN2, Eero VASAR2, Helgi SILM1 and Sulev KÕKS2 Departments of 1Dermatology and 2Physiology, University of Tartu, Tartu, Estonia The corticotrophin-releasing hormone-proopiomelano- R1 and CRH-R2)) peptides, which are the binding site cortin (CRH-POMC) system in the skin coordinates for CRH and the related urocortin peptide, suggests a pigmentation and the immune response. The aim of this potential CRH-induced neuroendocrine pathway in the study was to evaluate the regulatory role of the neuro- skin (4, 5). Cutaneous expression of the CRH-proopio- endocrine system in the pathogenesis of psoriasis. Using melanocortin (CRH-POMC) system is highly organized, quantitative real-time-PCR, mRNA expression levels of encoding mediators and receptors similar to the HPA 15 genes related to the CRH-POMC system were mea- axis (5, 6) including key enzymes of corticosteroid and sured in punch biopsies from lesional and non-lesional glucocorticoid synthesis (6). CRH stimulates CRH-R1 skin of patients with psoriasis and from skin of healthy and induces the production and secretion of POMC (7). control subjects. Statistically significant up-regulation In melanocytes and fibroblasts CRH-induced CRH-R1 of POMC, CRH receptor type 1, melanin-concentrating stimulation upregulates POMC expression and produc- hormone receptor (MCHR1) and melanocortin receptors tion of adrenocorticotropic hormone (ACTH) through 2, 3 and 4 mRNA expression in lesional and in non-lesi- the activation of cAMP-dependent pathway(s). Melano- onal skin compared with healthy control samples were cytes respond with enhanced production of cortisol and established. Tyrosinase (TYR), T(Y)RP-1 and ASIP genes corticosterone, which is dependent on POMC activity. were statistically significantly down-regulated in lesio- Fibroblasts respond to CRH and ACTH with enhanced nal and non-lesional skin of psoriasis samples compared production of corticosterone, but not cortisol, which is with healthy subjects. The up-regulation of POMC, me- produced constitutively (6). The POMC system consists lanocortin receptors, CRH receptor type 1 and MCHR1 of the melanocortin peptides α-, β-, and γ-melanocyte in the lesional and non-lesional skin of psoriasis patients stimulating hormone (α-, β-, γ-MSH) and ACTH, which supports the importance of the local CRH-POMC sys- derive from post-translational processing of the precur- tem in the pathogenesis of psoriasis. Key words: psoriasis; sor molecule proopiomelanocortin (POMC); a family CRH-POMC system; mRNA expression. of 5 melanocortin receptors (MCRs); 2 endogenous melanocortin receptor antagonists: agouti (ASIP) and Accepted Sep 19, 2012; Epub ahead of print Jan 9, 2013 agouti-related protein (AGRP) (8). The CRH-POMC Acta Derm Venereol 2013; 93: 400–405. system in the skin primarily coordinates pigmentation and the immune response (4, 5). Ulvi Loite, Department of Dermatology, University of The expression of the components of the CRH-POMC Tartu, Raja 31, 50417 Tartu, Estonia. E-mail: Ulvi.loite@ system in the skin has been detected in different cell gmail.com types. In the skin CRH mRNA expression has been de- monstrated in cultured melanocytes and keratinocytes The central nervous system (CNS) regulates inflamma- (5). In humans, CRH-R1 is predominantly expressed tory responses through hormonal and neuronal routes. in all major skin cell populations (9), while CRH-R2 is The neuroendocrine stress response (the hypothalamic- expressed in dermal cells including hair follicle kerati- pituitary-adrenal (HPA) axis) and the sympathetic and nocytes, melanocytes and follicular papilla fibroblasts, parasympathetic nervous systems generally inhibit in- sebaceous and eccrine glands, muscle and dermal blood flammation at the systemic and regional levels, whereas vessels (10). CRH-R1 mediates most phenotypic effects the peripheral nervous system tends to amplify local of CRH, while the main adnexal location of CRH-R2 inflammatory responses (1). A blunted neural regulation indicates a role for this receptor in hair cycling (9). The is seen in a wide range of autoimmune and inflamma- POMC gene is expressed by cutaneous keratinocytes tory diseases in humans, such as rheumatoid arthritis, and melanocytes (8). In the skin the highest expression Sjögren’s syndrome, systemic lupus erythematosus and of MC1R mRNA expression has been detected in mela- irritable bowel syndrome (2, 3). nocytes (11). Human MC1R has the highest, and almost The presence of cutaneous corticotrophin-releasing equal, affinity for α-MSH and ACTH, less affinity for hormone (CRH) peptide and corticotrophin-releasing β-MSH, and least affinity for γ-MSH (12). MC2R is hormone receptor (CRH receptor type 1 and 2 (CRH- the classical adrenocortical ACTH receptor (8) and its Acta Derm Venereol 93 © 2013 The Authors. doi: 10.2340/00015555-1524 Journal Compilation © 2013 Acta Dermato-Venereologica. ISSN 0001-5555 CRH-POMC system gene expression in psoriasis 401 expression has been detected in keratinocytes (13) and mediators of the CRH-POMC system and melanogene- adipocytes (14). MC3R expression in the skin has been sis enzymes in lesional and non-lesional psoriasis skin shown in our previous studies, although its expression and in the skin of healthy controls. has not been localized to distinct cell types (15). All of the melanocortins are roughly equipotent with MC3R (8). MC4R is expressed in dermal papilla cells (16) and MATERIALS AND METHODS melanocytes (17), and is activated by α-MSH and ACTH The protocols and informed consent forms for this study were (8). The expression of MC5R has been detected in skin approved by the ethics Review Committee on Human Research of the University of Tartu. All of the participants signed a writ- mast cells, adipocytes and sebocytes (5, 18). Its affinity ten informed consent. for POMC peptides is similar to that of MC1R (8). Tyrosinase (TYR) is regarded as the key enzyme in me- Patients and healthy controls lanogenesis; it is found in melanosomes (19). Tyrosinase- The patients and control subjects in the study were Caucasi- related protein 1 (TYRP1) and dopachrome tautomerase ans living in Estonia. Twenty (2 females; 18 males) unrelated (DCT) are additional melanogenesis enzymes. The signal patients with plaque-psoriasis, mean age 40.85 years (range from the CRH-POMC system in human melanocytes 18–64 years) were recruited from the outpatient as well as reaches the melanogenesis enzymes TYR, TYRP1 from the inpatient clinic at the Department of Dermatology, and DCT over MC1R through cyclic adenosine mono- Tartu University Hospital. The mean age of psoriasis onset of the patients was 28.4 years. The Psoriasis Area Severity Index phosphate/protein kinase A (cAMP/PKA) pathway and (PASI) score was recorded by the same physician in all cases. it is modulated by Wnt and MAPK (mitogen-activated The mean PASI score was 25.05 (range 7–69). One patient had protein kinase) pathways (17, 20). ASIP is an antagonist PASI less than 7 (mild disease) and all others had PASI over 7 of human MC1R. It acts as a competitive inhibitor of (moderate and severe disease). Ten of the patients had psoriatic α-MSH and inhibits the expression of the melanogenic nail involvement, 3 had psoriatic arthropathy, and 7 patients had a positive family history of psoriasis. The biopsies were enzymes tyrosinase, TYRP-1, and DCT (21). taken from non-sun-exposed areas. Prior to taking the biopsies In cultured human melanocytes the melanogenic the patients’ group had not received any treatment, including actions of α-MSH were inhibited by melanin-concen- ultraviolet B (UVB)-therapy, local corticosteroids and syste- trating hormone (MCH), resulting in reduced melanin mic medication for at least a month. Healthy volunteers free production in pigment cells. Such evidence suggests that from other dermatoses and from the positive family history of psoriasis, were recruited as a control group (n = 56; (18 male, one of the roles of MCH/MCH-R1 in the skin could be 38 female); Mean age 36.1 years (range 21–70 years). As the in regulating pigmentation by opposing the actions of female/male ratio differs between study groups it should be the melanocortin system (22). MCH is produced from clarified that, based on current literature, sex and age do not pro-melanin-concentrating hormone (PMCH). In the influence the mRNA expression of studied genes. human skin the expression of PMCH has been detected in cultured endothelial cells, whereas no signal has been Skin samples and TaqMan-quantitative real-time-PCR found in keratinocytes, melanocytes and fibroblasts. Two 4-mm punch biopsies from both involved and non-involved MCHR1 expression has been demonstrated in melano- skin were obtained from each patient with psoriasis. One skin cytes and melanoma cells (23). biopsy (diameter 4 mm) was obtained from healthy control subjects. All probands had skin phototype II or III, Fitzpatrick The abnormal expression of CRH-POMC system pep- classification. Biopsies were instantly snap-frozen and stored tides has been described in a number of skin conditions, at –80ºC until RNA extraction. such as neoplastic melanocytic naevi, melanoma, basal For total RNA extraction from skin biopsies the RNeasy cell carcinoma, squamous cell carcinoma, inflammatory Fibrous Tissue Mini Kit (QIAGEN Sciences, Maryland, USA) keloids, and scarring
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