Plasma level of α-melanocyte-stimulating hormone in atopic dermatitis patients

Nashwa N El Far; Amany M Abdel-Latif; Mohammed A Swelam; Reham A El-Barbary

doi:10.4103/1110-6530.150257

ORIGINAL ARTICLE

Year : 2014 | Volume : 34 | Issue : 2 | Page : 93-97

Plasma level of α-melanocyte-stimulating hormone in atopic dermatitis patients

Nashwa N El Far¹, Amany M Abdel-Latif¹, Mohammed A Swelam², Reham A El-Barbary¹
¹ Department of Dermatology and Venereology, Faculty of Medicine, Tanta University, Tanta, Egypt
² Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission	16-Jun-2014
Date of Acceptance	09-Dec-2014
Date of Web Publication	29-Jan-2015

Correspondence Address:
Nashwa N El Far
MD, Department of Dermatology and Venereology, Faculty of Medicine, Tanta University, Tanta
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/1110-6530.150257

Abstract

Background
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense pruritus with marked exacerbation and remission. α-Melanocyte-stimulating hormone (α-MSH) is a neuropeptide produced at different sites including the skin. It has immunomodulatory and anti-inflammatory properties. However, its role in the etiopathogenesis of AD still remains largely unclear.
Objective
The aim of this work was to evaluate the plasma level of α-MSH in patients with AD to assess its role in the severity of the disease.
Patients and methods
This study included 30 patients with AD whose severity of disease was assessed by means of the scoring atopic dermatitis (SCORAD) score, in addition to 18 healthy individuals who served as controls. Blood samples were taken from all patients and controls for detection of plasma α-MSH level by means of the enzyme-linked immunosorbent assay.
Results
A highly significant increase was found in the mean plasma α-MSH level of AD patients compared with controls. Further, the plasma α-MSH level was significantly positively correlated with the severity of AD.
Conclusion
T he mean plasma α-MSH level in AD patients was significantly higher than that in normal healthy controls. Moreover, the plasma α-MSH level showed a significant positive correlation with disease severity.

Keywords: α-melanocyte-stimulating hormone, atopic dermatitis, enzyme-linked immunosorbent assay

How to cite this article:
El Far NN, Abdel-Latif AM, Swelam MA, El-Barbary RA. Plasma level of α-melanocyte-stimulating hormone in atopic dermatitis patients. Egypt J Dermatol Venerol 2014;34:93-7

How to cite this URL:
El Far NN, Abdel-Latif AM, Swelam MA, El-Barbary RA. Plasma level of α-melanocyte-stimulating hormone in atopic dermatitis patients. Egypt J Dermatol Venerol [serial online] 2014 [cited 2022 Jul 6];34:93-7. Available from: http://www.ejdv.eg.net/text.asp?2014/34/2/93/150257

Introduction

Atopic dermatitis (AD) is an eczematous highly pruritic chronic inflammatory relapsing skin disease. Its presentation varies from an acute eczematous relapsing eruption in early life to a characteristic lichenified dermatitis in older patients. AD often occurs in people with a personal or family history of other atopic disease [1]. Psychological stress triggers the symptoms of AD; this phenomenon has been explained by the finding that activation of the hypothalamic-pituitary-adrenal axis by stress aggravates the symptoms, mainly by inducing a shift toward the Th2 cell phenotype [2]. The exact pathogenesis of AD is unclear. However, several constitutional abnormalities such as genetic, immunologic, cellular, and environmental factors, as well as defects in skin barrier function, may contribute to the disease [3].

The α-melanocyte-stimulating hormone (α-MSH) is a 13-amino-acid neuroimmunomodulatory peptide [4]. The neuropeptide α-MSH is derived from the precursor protein pro-opiomelanocortin (POMC) by proteolytic cleavage in several cell types like melanocytes, keratinocytes, epithelial cells, B cells, natural killer cells, and subsets of T cells [5]. The biosynthesis of α-MSH by proteolytic cleavage of POMC is catalyzed by prohormone convertases (PCs), including PC1 and PC2, which are currently considered the major processing enzymes of POMC, although other members of the PC family, in particular paired basic amino-acid-cleaving enzyme 4 (PACE4) and furin convertase, may also process POMC [6]. Proinflammatory cytokines as well as corticotropin b-releasing hormone have been identified as the prototypical stimuli that regulate POMC expression and processing in both central and peripheral tissues [7].

Thus, the aim of this study was to evaluate the plasma level of α-MSH in patients with AD to assess its role in the severity of the disease.

Patients and methods

The present study included 30 patients with AD, 16 (53.33%) female and 14 (46.67%) male patients. Their ages ranged from 2 to 30 years with a mean ± SD of 10.060 ± 7.295 years. In addition, the study included 18 healthy individuals as controls: eight (44.44%) female and 10 (55.56%) male. Their ages ranged from 2.5 to 30 years, with a mean ± SD of 13.472 ± 7.403 years. They were selected from the Outpatient Clinic of the Dermatology and Venereology Department, Tanta University Hospital, during the period from March 2012 to December 2012. The study was approved by the Research Ethics Committee. All participants signed an informed consent form before participating in the study.

Patients who had received systemic or topical treatment at least 6 weeks before the study, had other dermatological or systemic disease, had taken systemic steroids or immunosuppressive drugs in the 6 months preceding the study, or were pregnant or lactating were excluded from the study. All patients were subjected to the following:

Full history taking : This included personal history, history of the disease (age at onset, course, duration, exacerbating and relieving factors), past history (other skin or systemic diseases or atopy, previous treatment and the date of termination of the last treatment modality, history of drug intake), and family history of atopy.
Clinical assessment : A complete dermatological examination was carried out to determine the clinical distribution and activity of the lesions in all patients. The diagnosis was made in each case according to the criteria of Hanifin and Rajka et al. [8]. The severity of disease was assessed by scoring atopic dermatitis (SCORAD) score [9].
Laboratory investigations : Venous blood samples (3-5 ml) were collected from each patient and control. The blood was centrifuged at 1600g for 15 min at 4°C and plasma was collected and kept at -70°C until the time for performing the assay. α-MSH level in the plasma samples was determined by using an α-MSH enzyme-linked immunosorbent assay kit (EIA-2951; DRG International Inc., USA).

Statistical analysis

Data were statistically analyzed. Continuous variables are presented as means ± SD and discrete variables as percentages. Both w2 and Fischer's w2 testing were used for intergroup comparisons, and P values less than 0.05 were considered significant. Statistical package for social sciences (SPSS, version 16.0; SPSS Inc., Chicago, Illinois, USA) for Microsoft Windows was used throughout.

Results

For the severity of AD, patients were classified according to their SCORAD score as follows: 10 patients with mild AD, comprising two (6.67%) male and eight (26.67%) female patients, their ages ranging from 2 to 20 years with a mean ± SD of 8.750 ± 6.601 years; 10 patients with moderate AD, comprising six (20.00%) male and four (13.33%) female patients, their ages ranging from 3 to 16 years with a mean ± SD of 6.980 ± 4.174 years; and 10 patients with severe AD, comprising six (20.00%) male and four (13.33%) female patients, their ages ranging from 2.5 to 30 years with a mean ± SD of 14.450 ± 8.754 years. There was no statistically significant difference between the groups (P = 0.055) [Table 1].

Table 1: Severity of disease in the studied atopic dermatitis patients in relation to age

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The plasma α-MSH level in AD patients ranged from 38.100 to 48.900 pg/ml, with a mean of 42.520 ± 3.480 pg/ml, whereas in the control group the plasma α-MSH level ranged from 24.000 to 34.500 pg/ml, with a mean of 28.944 ± 3.120 pg/ml. There was significant increase in the mean plasma α-MSH level in AD patients compared with controls [Table 2].

Table 2: Plasma level of α -melanocyte-stimulating hormone in the studied atopic dermatitis patients and control groups

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When the relation between plasma α-MSH level and severity of AD according to SCORAD score was studied [Table 3], the plasma α-MSH level in the mild form was found to range from 38.1 to 40 pg/ml, with a mean of 38.950 ± 0.564 pg/ml; in the moderate AD group, the plasma α-MSH level ranged from 39.900 to 44.000 pg/ml, with a mean of 41.900 ± 1.459 pg/ml; and in the severe AD group the plasma α-MSH level ranged from 44.500 to 48.900 pg/ml, with a mean of 46.710 ± 1.578 pg/ml. The plasma α-MSH level in severe AD was markedly higher compared with each of the mild and moderate AD groups. It was also significantly higher in moderate compared with mild AD groups. A significant positive correlation was found between the plasma α-MSH level and the SCORAD score of the studied patients [Figure 1].

Figure 1: Significant positive correlation between α-melanocyte-stimulating hormone (α-MSH) plasma level and severity of disease in the studied atopic dermatitis (AD) patients.

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Table 3: Plasma level of α -melanocyte-stimulating hormone as regards severity of the different studied atopic dermatitis groups

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A significant positive correlation was found between the plasma α-MSH level and age of the studied patients [Figure 2].

Figure 2: Significant positive correlation between α-melanocyte-stimulating hormone (α-MSH) plasma level and age in the studied atopic dermatitis (AD) patients.

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Discussion

A complex interaction between susceptibility genes encoding skin barrier molecules and markers of the inflammatory response, host environments, infectious agents, and specific immunologic responses is involved in the pathophysiology of AD [10]. The discovery of the physiological influence of α-MSH on the immune system indicates that the α-MSH peptide and its receptors could be used for bidirectional communication between the immune and endocrine systems to modulate the cutaneous inflammatory process [11].

The current study revealed that the mean plasma α-MSH level in AD patients was significantly higher than that in normal healthy controls. Moreover, the plasma α-MSH level showed a significant positive correlation with disease severity. These results were in accordance with those of Hiramoto et al. [12], who observed an association of increased α-MSH, adrenocorticotropic hormone (ACTH) levels, and melanocortin receptor (MCR) expression with pigmentation in an NC/Nga mouse model of AD. Furthermore, the expression of MC1R was increased in the skin, and MC3R expression was increased in the intestine. These results indicate that the pigmentation of AD is related to increased levels of α-MSH, MC1R (in the skin), and MC3R (in the intestine) [12].

Paus et al. [13] suggested the skin as an ultimate model of neuroimmunological stress, in which upregulation of corticotropin-releasing hormone (CRH) and POMC peptides have been detected. Lee et al. [14] found that interleukin (IL)-18 is a potent inducer of Th1 responses. CRH significantly decreased the expression of IL-18 in dendritic cells of AD patients. Stress-induced CRH may enhance Th2 immune responses by acting directly on dendritic cells through CRH-R and aggravate the clinical manifestations in AD. CRH has anti-inflammatory property. The peptide diminishes nuclear factor-κβ activation in epidermal melanocytes [15] and inhibits IL-18 expression through the MAPK signaling pathway in human HaCaT keratinocytes [16]. IL-18 is a key mediator of peripheral inflammation and host defense responses. ACTH stimulates human keratinocytes to secrete IL-18 through MC1R, MC2R, p38, and MAPK pathways. As CRH inhibits IL-18 expression in HaCaT cells, IL-18 may play an important role in the negative feedback loop of CRH regulation [17]. This provides insights into the pathophysiology of stress-related skin diseases.

The role of α-MSH in the pathogenesis of AD is unclear, but the proinflammatory effect of α-MSH on keratinocytes or activation of mast cells is highly suspected. CRH has been shown to stimulate the production of IL-6 and IL-11 in human keratinocytes during cutaneous stress [18].

AD is also exacerbated by stress through mast cell activation [19]. Mast cells have a higher CRH-R and CRH expression level [20]. CRH may activate mast cells through a CRH-R-dependent mechanism, leading to release of histamine and hence vasodilatation with increased vascular permeability [18]. Mast cells secrete numerous proinflammatory cytokines such as IL-6, IL-8, and tumor necrosis factor α (TNF-α), which are released in response to stressful stimuli. They are recognized as potent stimulators of CRH and POMC production in human skin. CRH modulates the expression of intercellular adhesion molecules (ICAM-1), which promotes the proliferation of lymphocytes and enhances the vascular permeability through increased vascular endothelial growth factor [21].

The neuroendocrine regulation of the inflammatory response is highly significant from the point of view of immune homeostasis. Malfunction of this circuit leads to disease and is often life-threatening [2]. The immune system emits signals toward the neuroendocrine system through cytokine mediators that reach significant levels in the blood (cytokine hormones) during systemic immune/inflammatory reactions in AD. IL-6 and TNF-α are the major cytokines mediating the acute phase response [22]. These cytokines induce profound neuroendocrine and metabolic changes by interacting with the central nervous system and tissues in the body. CRH functions under these conditions as a major coordinator of the response and is responsible for activating the ACTH-adrenal axis, leading to a sympathetic outflow. Increased ACTH secretion leads to α-MSH functions [2].

The previous explanation is supported by Orita et al. [23], who found that under the standard experimental conditions plasma concentrations of α-MSH in conventional mice increase markedly with concomitant exacerbation of the symptoms of AD. The plasma concentrations of this hormone were elevated after strong exercise but decreased after mild exercise. In addition, Hiramoto et al. [24] observed that the level of α-MSH in conventional mice was decreased with mild stress, in comparison with a nonstress control group, and increased in strong stress. Although the plasma levels of ACTH were elevated markedly in the conventional group, they were unaffected by strong or mild exercise, despite the marked effects of these different degrees of exercise on the symptoms of dermatitis. Therefore, the stress elicited by symptoms of dermatitis, such as pruritus, might be strong enough to increase ACTH levels maximally in the plasma. This observation suggested that α-MSH-induced signaling might participate in the exacerbation of the symptoms of AD. In fact, α-MSH interacts with MCRs (especially MC1R) on a variety of leukocytes, thereby modulating inflammatory reactions induced by endotoxin and related cytokines, including IL-1, TNF-α, and interferon b [25]. α-MSH enhances the production of transforming growth factor β1 (TGF-β1). Therefore, the TGF-b/TGF-b-R signaling pathway might activate the POMC system to increase plasma levels of α-MSH, thereby exacerbating the symptoms of AD. Their results confirmed the hormonal regulation supporting the phenomenon that mild exercise is effective for AD. This knowledge could lead to the development of new drugs for the prevention of AD [24].

Another role of α-MSH in the pathogenesis of AD was suggested from the antimicrobial activity of the hormone against the major human pathogen Staphylococcus aureus. S. aureus can exacerbate AD by secreting exotoxins. Some of them function as superantigens, which stimulate the activation of T cells and major histocompitability complex (MHC), antigen presenting cells (APCs), macrophages, and KCs [26].

It can be concluded that α-MSH plasma level increases in AD, indicating its possible involvement in the pathogenesis of the disease. The level of α-MSH is correlated positively with the severity of the disease. This may open the way for another therapeutic approach targeting α-MSH in the treatment of AD.

Acknowledgements

Conflicts of interest

None declared.

References

1.	Simpson EL, Hanifin JM. Atopic dermatitis. J Am Acad Dermatol 2005; 53 :115-128.
2.	Kim JE, Cho BK, Cho DH, Park HJ. Expression of hypothalamic-pituitary-adrenal axis in common skin diseases: evidence of its association with stress-related disease activity. Acta Derm Venereol 2013; 93 :387-393.
3.	Comeau MR, Ziegler SF. The influence of TSLP on the allergic response. Mucosal Immunol 2010; 3 :138-147.
4.	Xu PB, Mao YF, Meng HB, Tian YP, Deng XM. STY39, a novel alpha-melanocyte-stimulating hormone analogue, attenuates bleomycin-induced pulmonary inflammation and fibrosis in mice. Shock 2011; 35 :308-314.
5.	Loser K, Brzoska T, Oji V, Auriemma M, Voskort M, Kupas V, et al. The neuropeptide alpha-melanocyte-stimulating hormone is critically involved in the development of cytotoxic CD8+ T cells in mice and humans. PLoS One 2010; 5 :e8958.
6.	Böhm M, Luger TA, Tobin DJ, García-Borrón JC. Melanocortin receptor ligands: new horizons for skin biology and clinical dermatology. J Invest Dermatol 2006; 126 :1966-1975.
7.	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.
8.	Rudzki E, Samochocki Z, Rebandel P, Saciuk E, Galecki W, Raczka A, et al. Frequency and significance of the major and minor features of Hanifin and Rajka among patients with atopic dermatitis. Dermatol 1994; 189 :41-46.
9.	Oranje AP, Glazenburg EJ, Wolkerstorfer A, de Waard-van der Spek FB. Practical issues on interpretation of scoring atopic dermatitis: the SCORAD index, objective SCORAD and the three-item severity score. Br J Dermatol 2007; 157 :645-648.
10.	Bieber T. Mechanisms of disease atopic dermatitis. N Engl J Med 2008; 358 :1483-1494.
11.	Lotti T, Bianchi B, Ghersetich I, Brazzini B, Hercogova J. Can the brain inhibit inflammation generated in the skin? The lesson of gamma-melanocyte-stimulating hormone. Int J Dermatol 2002; 41 :311-318.
12.	Hiramoto K, Kobayashi H, Ishii M, Sato E, Inoue M. Increased alpha-melanocyte-stimulating hormone (alpha-MSH) levels and melanocortin receptors expression associated with pigmentation in an NC/Nga mouse model of atopic dermatitis. Exp Dermatol 2010; 19 :132-136.
13.	Paus R, Theoharides TC, Arck PC. Neuroimmuno-endocrine circuitry of the ′brain-skin connection′. Trends Immunol 2006; 27 :32-39.
14.	Lee HJ, Kwon YS, Park CO, Oh SH, Lee JH, Wu WH, et al. Corticotropin-releasing factor decreases IL-18 in the monocyte-derived dendritic cell. Exp Dermatol 2009; 18 :199-204.
15.	Zbytek B, Pfeffer LM, Slominski AT. CRH inhibits NF-kappa B signaling in human melanocytes. Peptides 2006; 27 :3276-3283.
16.	Park HJ, Kim HJ, Lee, JH, Lee JY, Cho BK, Kang JS, et al. 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.
17.	Park HJ, Kim HJ, Lee JY, Cho BK, Gallo RL, Cho DH. Adrenocorticotropin hormone stimulates interleukin-18 expression in human HaCaT keratinocytes. J Invest Dermatol 2007; 127 :1210-1216.
18.	O′Kane M, Murphy EP, Kirby B. The role of corticotropin-releasing hormone in immune-mediated cutaneous inflammatory disease. Exp Dermatol 2006; 15 :143-153.
19.	Katsarou-Katsari A, Filippou A, Theoharides TC. Effect of stress and other psychological factors on the pathophysiology and treatment of dermatoses. Int J Immunopathol Pharmacol 1999; 12 :7-11.
20.	Theoharides TC, Singh LK, Boucher W, Pang X, Letourneau R, Webster E, et al. Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. Endocrinology 1998; 139 :403-413
21.	Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, et al. Mast cells and inflammation. Biochim Biophys Acta 2012; 1822 :21-33.
22.	Di Cesare A, Di Meglio P, Nestle FO. A role for Th17 cells in the immunopathogenesis of atopic dermatitis?. J Invest Dermatol 2008; 128 :2569-2571.
23.	Orita K, Hiramoto K, Inoue R, Sato EF, Kobayashi H, Ishii M, Inoue M Strong exercise stress exacerbates dermatitis in atopic model mice, NC/Nga mice, while proper exercise reduces it. Exp Dermatol 2010; 19 :1067-1072.
24.	Hiramoto K, Kobayashi H, Sekiyama A, Sato EF, Tsuruta D, Ishii1 M. Mild exercise suppresses exacerbation of dermatitis by increasing cleavage of the b-endorphin from proopiomelanocortin in NC/Nga mice. J Clin Biochem Nutr 2013; 52 :58-63.
25.	Ichiyama T, Sakai T, Catania A, Barsh GS, Furukawa S, Lipton JM. Systemically administered alpha-melanocyte-stimulating peptides inhibit NF-kappaB activation in experimental brain inflammation. Brain Res 1999; 836 :31-37.
26.	Madhuri S, Shireen T, Venugopal SK, Ghosh D, Gadepalli R, Dhawan B, Mukhopadhyay K. In vitro antimicrobial activity of alpha-melanocyte stimulating hormone against major human pathogen Staphylococcus aureus. Peptides 2009; 3:1627-1635.