The mRNA expression profile of cytokines connected to the regulation of melanocyte functioning in vitiligo skin biopsy samples and peripheral blood mononuclear cells
Introduction
Vitiligo is an idiopathic disorder characterized by depigmented patches in skin due to loss of melanocytes. Death of the pigment cells may be caused by the factors from inside and/or outside the cell and there are many potential systems, which could be involved. However, the exact cause of destruction of epidermal melanocytes is complex and not yet fully understood. There are several theories, involving autoimmune, neural, and biochemical mechanisms [1], [2]. An autoimmune theory has a wide range of supportive evidence; abnormalities in both humoral and cell-mediated immunity have been documented in patients with vitiligo [2], [3]. In addition, vitiligo is associated with increased local and systemic cytokine production [4], [5], [6], [7], [8], [9].
In this study, we observed seven genes associated with interleukin (IL)–10 family cytokines. IL-20 receptor B (IL20RB) forms together with IL20RA or IL22RA1 receptor complexes for IL-19, IL-20 and IL-24, or IL-20 and IL-24, respectively [10], [11]. IL22RA2 (IL22BP) is a soluble monomeric protein that antagonizes IL-22 receptor complex (IL22RA1 and IL10RB) and inhibits IL-22 activity. It is produced primarily by monocytes and lymphocytes [12], [13]. IL-26 is mainly produced by T cells, monocytes, and natural killer cells [13], and it is involved in activation of STAT1 and STAT3 pathways, which are important to stimulate IL-10, IL-8, and ICAM1 production [11]. IL-28A (interferon lambda 2 (IFNL2)), IL28B (IFNL3), and IL29 (IFNL1) are recently recognized members of the IL-10 cytokine family (also categorized under the interferon [IFN] family); they form a cytokine gene cluster in region 19q13 and bind to a receptor complex combined of IL28RA and IL10RB. They are believed to have antiviral, antiproliferative, and antitumor activity [14]. Several members of interleukin-10 family cytokines (IL-10, IL-22, IL-24) and their receptors (IL10RA, IL10RB) have previously been demonstrated to be associated with vitiligo pathogenesis [15], [16].
In addition to genes associated with IL-10 family cytokines, we observed several others. Nuclear protein homolog (mouse) gene (MDM1) is located together with IL22 and IL26 in the locus 12q15; however, the biologic function of MDM1 is unknown [17], [18]. Interferon-α and -β bind to the same cell surface receptor (IFNAR). IFN-α is produced by leukocytes and keratinocytes, whereas IFN-β is synthesized by a variety of cells (fibroblasts, epithelial cells, and macrophages) [19], [20]. Both IFN-α and IFNB mRNAs have been detected in normal human melanocytes [21]. IFN-α is suggested to be important in enhancing biologic defense activities against oxidative stress [22] and may cause induction of antimelanocyte autoantibodies or activation of cytotoxic T cells [23], [24]. IFNB is thought to induce apoptosis and to have antiproliferative effects on malignant cells [25]. IFN-α, IFNB, and also IFNG enhance human B cell proliferation [26]. Both IFN-α and IFNB therapies may cause vitiligo [23], [27], [28]. IFNG is predominantly produced by natural killer cells, CD4+ and CD8+ T cells. Its mRNA expression has increased in vitiligo involved and uninvolved skin compared with control skin [15], [29]. IFNG stimulates the expression of intercellular adhesion molecule 1 (ICAM1), which is important for activating T cells and recruiting leukocytes [30], [31]. ICAM1 protein expression is upregulated in vitiligo skin and in melanocytes from perilesional vitiligo skin [32].
In the present work, we observed different cytokines, their receptors, and a few other genes potentially related to the development, proliferation, and survival of melanocytes and regulation of melanogenesis. The aim of this study was to examine the mRNA expression pattern of these genes in skin biopsy samples and peripheral blood mononuclear cells (PBMCs) derived from vitiligo patients and controls by using quantitative real-time polymerase chain reaction (QRT-PCR).
Section snippets
Subjects and methods
The protocols and informed consent forms used in this study were approved by the Ethical Review Committee on Human Research of the University of Tartu. All the participants signed a written informed consent. All patients and control subjects in the study were individuals of white ethnicity living in Estonia. Unrelated patients with vitiligo from Department of Dermatology, University of Tartu, were included in the study. The diagnosis of vitiligo was based on the following clinical signs: loss
Results
In this study, 12 genes (IL20RB, IL22RA2, IL26, IL-28A, IL28B, IL29, IL28RA, MDM1, IFNA1, IFNB1, IFNG, and ICAM1) connected to immunomodulation, melanogenesis and development and growth of melanocytes were investigated.
This study showed that the mRNA expression of IL20RB has increased in vitiligo uninvolved skin 1.4 times (p = 0.0094) when compared with controls (Fig. 1a). The expression also increased in involved vitiligo skin; however, it was statistically significant only in the case of
Discussion
Several cytokines have been suggested to participate in vitiligo pathogenesis. In the present study, we assessed the importance of cytokines and their receptors and a few other genes possibly involved in the regulation of the development and survival of melanocytes and melanogenesis [4], [5], [6], [7], [8], [9].
Our study revealed changes in the expression of cytokines and receptor genes associated to the IL-10 cytokine family. In skin the IL20RB mRNA level was higher in vitiligo patients'
Acknowledgments
This study was financially supported by the target based funding from the Estonian Ministry of Education grants SF0180043s07 and SF0180148s08, by University of Tartu research grant PARFS 07915, by the Estonian Science Foundation Grants Numbers 6576, 7549, and 7479, by the European Union through the European Regional Development Fund and by the Archimedes Foundation.
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