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Table of Contents 
Year : 2011  |  Volume : 56  |  Issue : 6  |  Page : 641-646
The possible role of trauma in skin tags through the release of mast cell mediators

1 Dermatology Department, Faculty of Medicine, Cairo University, Egypt
2 Histology Department, Faculty of Medicine, Cairo University, Egypt
3 Clinical Biochemistry Department, Faculty of Medicine, Cairo University, Egypt

Date of Web Publication14-Jan-2012

Correspondence Address:
Rania M Abdel Hay
13th Abrag Othman, Kornish El Maadi, Cairo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-5154.91819

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Background: Skin tags (ST) are common benign tumors of the skin but their etiopathogenesis is not well understood. STs arise in sites subjected to trauma. It was proved that mast cells are recruited to sites of skin trauma and increase their tumor necrosis factor-α (TNF-α) content. Aim: STs are linked to obesity and frictional sites, but this has not been studied at the molecular level. We hypothesized that mast cells, TNF-α and its family member, TNF-related apoptosis-inducing ligand (TRAIL) might play a role in the pathogenesis of STs as a response to trauma. Materials and Methods: A study was done on 15 patients with STs. Two STs and a snip of normal skin were obtained in each subject. We counted the mast cells after Toluidine blue staining. Enzyme-linked immunosorbant assay was used to measure TNF-α level while reverse transcriptase polymerase chain reaction was used to evaluate the level of TRAIL mRNA expression. Results: Mast cell count in all STs was significantly higher than that in control (P=0.0355). There was a highly significant increase in the level of TNF-α in all STs as compared to its level in controls (P<0.0001). Expression of TRAIL mRNA was significantly higher in STs as compared to its expression in controls (P<0.0001). Conclusion: Our study suggests that mast cells, TNF-α and TRAIL may play a role in the pathogenesis of STs.

Keywords: Acrochordon, TNF-α, TRAIL

How to cite this article:
El Safoury OS, Fawzy MM, Abdel Hay RM, Hassan AS, El Maadawi ZM, Rashed LA. The possible role of trauma in skin tags through the release of mast cell mediators. Indian J Dermatol 2011;56:641-6

How to cite this URL:
El Safoury OS, Fawzy MM, Abdel Hay RM, Hassan AS, El Maadawi ZM, Rashed LA. The possible role of trauma in skin tags through the release of mast cell mediators. Indian J Dermatol [serial online] 2011 [cited 2021 Apr 16];56:641-6. Available from: https://www.e-ijd.org/text.asp?2011/56/6/641/91819

   Introduction Top

Skin tags (STs), or acrochordons, are benign connective tissue tumors of the dermis that present as small, soft, usually pedunculated, less commonly sessile skin protrusions. They are skin colored or hyperpigmented. They often develop in areas of skin friction and are particularly found in obese persons. The most frequent localizations are the neck and axillae, but any skin fold, including the groin, may be affected. [1] Histologically, STs are polypoid lesions with overlying mildly acanthotic epidermis. There is a loose, edematous fibrovascular core with mild chronic inflammation. [2]

Mast cells are increased in number in many skin diseases. [3] In addition to being able to mediate immediate hypersensitivity, mast cells are known to have effects on T and B cells, keratinocytes, fibroblasts, Langerhans cells and endothelial cells, through an array of cytokines, chemokines, and growth factors they produce. [4] The presence of mast cells in STs could play a role in fibroblast proliferation and collagen deposition, as well as acanthosis of the epidermis. STs are known to develop in sites subjected to repeated friction and irritation. [1] It has been proved that mast cells are progressively recruited to site of injury as an early response to trauma, and upregulated their tumor necrosis factor-α (TNF-α) content in order to direct tissue response to injury.[5]

Tumor necrosis factor is the prototypic member of the TNF superfamily. This family of structurally related proteins plays important roles in cell death regulation, inflammation and immune response. Members belonging to the TNF family exert their functions through interaction with their transmembrane receptors: the TNF receptor family. [6] TNF-α is a multifunctional pro-inflammatory pro-apoptotic cytokine involved in the regulation of tissue homeostasis as well as immune, inflammatory and stress responses. [7] It is mainly produced by macrophages, as well as other immunologically active cells including mast cells. [6] It has been suggested that TNF-α levels increase in traumatized tissues.[8] TNF-related apoptosis-inducing ligand (TRAIL), another member of the TNF-superfamily, is a type II membrane protein that exerts is functions through interactions with cell surface TRAIL receptors. [9],[10] TRAIL is involved in apoptosis, [9] inflammation, immune regulation and homeostatic control of endothelial biology. [11]

The clinical suspicion of being related to friction is high as ST is linked to obesity and frictional sites, [1] but this has not been studied at the molecular level, our target is to find the relation of trauma to STs formation through the estimation of the release of mast cell mediators. Because of these interrelationships between TNF-α, TRAIL, mast cells and trauma, we wanted to evaluate mast cell numbers and to detect TNF-α and TRAIL content within STs in order to elucidate the possible role of mast cells and their mediators, in response to skin injury and trauma, in the etiopathogenesis of STs.

   Materials and Methods Top

Fifteen nondiabetic patients presenting to the Dermatology outpatient clinic, from January to April 2009, seeking advice for their STs were recruited. This study was approved by the Dermatology Research Ethics Committee Office, Faculty of Medicine, Cairo University. All participants were asked to sign a written informed consent, and then were subjected to proper history and clinical examination, measurement of the body mass index (BMI), fasting blood sugar measurement. From each participant, two STs and a normal skin snip (as a control) were obtained from the same area.

Each skin biopsy was divided into two parts:

  1. The first part was fixed in 10% formol saline and kept for 24 hours then dehydrated in ascending grades of alcohol (70%, 95%, 100%) and cleared in xylene then embedded into paraffin wax. Sections of 5-μm thickness were subjected to staining with hematoxylin and eosin and Toluidine blue metachromatic method for mast cells. [12] Mast cells stained with Toluidine blue were counted manually in five sections of each specimen in the upper layer of dermis just below the epidermis in 10 different fields using an Olympus microscope with magnification x1000. All mast cell profiles were counted by the same person.
  2. Detection of TNF-α by enzyme-linked immunosorbent assay (ELISA) and TRAIL by reverse transcriptase polymerase chain reaction (RT-PCR).

Measurement of TNF-α

About 50 mg of skin tissue was homogenized in 1-ml lysis buffer for protein extraction which contained 0.0625 mol/l tris buffer (pH 6.8), 2% sodium dodecyl sulfate (SDS), 3% β-mercaptoethanol, 10% glycerol, 100 mmol/l sodium fluoride, 10 μg/ml aprotinin and 1 mmol/l phenylmethylsulfonyl fluoride (Sigma). Skin tissues were homogenized using a tissue homogenizer after cell lysis the homogenate was centrifuged at 10000x g for 20 minutes at 4΀C and the supernatant was examined for TNF-α using quantitative sandwich enzyme linked immunoassay the kit was supplied by R and D Systems (Europe, Ltd., United Kingdom) according to manufacturer's instruction.

Detection of TRAIL gene expression by RT-PCR

Total RNA was extracted from skin tissue by the acid guanidinum thiocyanate-phenol-chloroform method. [13]

RNA content and purity were measured by a UV spectrophotometer. The A260/A280 ratio should be 1.8 to 2.0. The RNA was of high integrality, being detected by agarose gel electrophoresis. RT-PCR was done using the extracted RNA for detection of TRAIL gene. For amplification of the targets gene, reverse transcription and PCR were run in two separate steps. Briefly, equal amounts of total RNA (6 μg) were heat denatured and reverse transcribed by incubation at 42΀C for 90 min with 12.5 U avian myeloblastosis virus reverse transcriptase (AMV) (Promega Corp., Madison, WI), 20 U ribonuclease inhibitor RNasin (Promega Corp.), 200 nM deoxy-nucleoside 5'-triphosphate mixture, and 1 nM oligo-dT primer in a final volume of 30 μl of 1x avian myeloblastosis virus reverse transcriptase buffer. The reactions were terminated by heating at 97΀C for 5 min and cooling on ice. The cDNA samples were amplified in 50 μl of 1x PCR buffer in the presence of 2.5 U Taq DNA polymerase (Promega Corp.), 200 nM deoxy-nucleoside 5'-triphosphate mixture, and the appropriate primer pairs (1 nM of each primer) for TRAIL and β-actin, respectively Forward primer: 5-GGTATAAAGCAAAACCTAAA-3 Reverse primer: 5-CATCTAGACTACCAGCCTTA-3 and forward 5-TGTTGTCCCTGTATGCCTCT-3. reverse 5-TAATGTCACGCACGATTTCC-3.

Samples were denatured at 94΀C for 3 min followed by 35 cycles of amplification, each consisting of 1 min at 94΀C, 1 min at 55΀C and at 72΀C for 1 min with a final elongation of 10 min at 72΀C. RT-PCR for β-actin, a housekeeping gene, was performed in the same PCR run to confirm integrity of RNA and for relative quantitation of PCR products. All PCR products were electrophoresed on 2% agarose stained with ethidium bromide and visualized by UV transilluminator.

Semiquantitation was performed using the gel documentation system (BioDO, Analyser) supplied by Biometra. According to the following amplification procedure, relative expression of studied gene (R) was calculated following the formula: R= Densitometrical Units of each studied gene/ Densitometrical Units of b-actin.

Data were statistically described in terms of range, mean±standard deviation (±SD), median, frequencies (number of cases) and relative frequencies (percentages) when appropriate. Comparison of quantitative variables between the study groups was done using Mann-Whitney U test for independent samples. Correlation between various variables was done using Spearman rank correlation equation for non-normal variables. A probability value (P value) less than 0.05 was considered statistically significant. All statistical calculations were done using computer programs Microsoft Excel version 7 (Microsoft Corporation, NY, USA) and SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) version 15 for Microsoft Windows.

   Results Top

This study included 15 patients, 5 males (33.3%) and 10 females (66.7%), age range 20-50 years (mean±SD 38.47±9.75), BMI range 21.2-39.7 (mean±SD 31.52±5.33). The duration of STs ranged from 1 month to 240 months (mean±SD 53.33±58.31).

Mast cells stained with Toluidine blue were counted and were commonly close to blood vessels [Figure 1] and [Figure 2]. Mast cell count in all STs was significantly higher than in controls (P=0.0355) [Table 1], [Figure 3]. No correlation was found between mast cell count and each of the patient's sex or BMI. There was a significant increase in the level of TNF-α in STs as compared to the control skin (P <0.0001) [Table 1], [Figure 4]. No correlation was found between TNF-α and each of the patient's sex or BMI. Upregulation of TRAIL RNA was detected in STs as compared to controls [Table 1], this upregulation is significant statistically (P<0.0001) [Figure 5]. There was no correlation between the level of TRAIL and each of the patient's sex or BMI.
Figure 1: Mast cell (arrow) in the dermis of normal skin just below the epidermis & close to blood vessel (*) (Toluidine blue, ×1,000)

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Figure 2: Mast cell (arrow) in the dermis of skin tag (Toluidine blue, ×1,000)

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Figure 3: Mean mast cell count in all skin tags and normal skin

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Figure 4: Mean TNF in all skin tags and normal skin

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Figure 5: Mean TRAIL in all skin tags and normal skin

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Table 1: Mast cell count, level of TNF-α and TRAIL mRNA in skin tags and control skin

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The correlations between each of mast cell count and TNF-α level, mast cell count and TRAIL level, and TNF-α and TRAIL levels were statistically insignificant (P= 0.353, P=0.303, P=0.881, respectively).

   Discussion Top

In our study we found that mast cells were increased in STs as compared to normal skin. Friction is a form of trauma that is a documented association of STs. [1] Although another study was performed on surgically induced wounds, [5] and the form of trauma in our study was different, the finding of increased mast cells in the two studies is consistent. Another study found a statistically significant increase in mast cell count in STs in both diabetic and nondiabetic subjects when compared to normal skin. [14] Our study was restricted to non diabetic subjects but showed similar results.

To our knowledge, this is the first study that examines the role of cytokines in the pathogenesis of STs. The only other report of such a role was in a patient with cutaneous melanoma and associated paraneoplastic acanthosis nigricans (AN), Leser-Trelat sign and multiple STs. Their results showed intense staining for epidermal growth factor receptor (EGFR) in all layers of the epidermis and increased urinary transforming growth factor-α (TGF-α). They suggested that TGF-α binds EGFR in the epidermis, and played a role in the development of all three cutaneous signs.[15]

We found a significant increase in the level of TNF-α in STs as compared to normal skin. Although the main source of TNF-α is macrophages, mast cells are a well-recognized source of both preformed and immunologically induced TNF-α. All potentially noxious stimuli can rapidly induce TNF-α production and release.[16] It was proved that TNF-α level was significantly higher in wounded skin as compared to control skin. Similar to our study the authors used a quantitative measurement of the cytokine level using ELISA. [8] In another study, quantitative assessment of TNF-α was not performed, rather immunohistochemical positivity of mast cells for TNF-α was done. Their study showed that the number of TNF-α-positive mast cells progressively increased in traumatized skin as compared to control skin. This was evident within 15 minutes after trauma. The number of TNF-α negative mast cells followed an opposite course. This study proved that mast cells were a main source of TNF-α in skin subjected to trauma.[5]

The results of our study point that the etiopathogenesis of STs may be initiated in a similar manner as other forms of skin trauma. Friction of the skin may stimulate an increase in the number of mast cells in the dermis. Mast cells then release preformed or newly synthesized TNF-α as well as other mediators. The presence of mast cells and TNF-α could, at least can partially induce several of the histopathological changes found in STs.

The role of mast cells and their products has been proved as an important role in nonallergic diseases. [17] Various studies have supported the notion that mast cells are pro-fibrotic. Mast cells accumulate in fibrotic conditions including wound healing, liver cirrhosis, pulmonary fibrosis and scleroderma. [4] When cocultured with fibroblasts in vitro, activated mast cells induced proliferation and type I collagen production by dermal fibroblasts [18] through the action of several mediators, cytokines and growth factors. [14] Human mast cells are also a source of basic fibroblast growth factor (FGF), a potent mitogenic factor for fibroblasts. [19]

Mast cells may also stimulate fibroblasts through the release of TNF-α. TNF-α has been recognized as having a powerful growth promoting effect on fibroblasts through increasing the latter's proliferation and mitogenicity. [16],[20] TNF-α is essential in developing cardiac fibrosis,[21] intestinal fibrosis [22] and idiopathic pulmonary fibrosis. Some articles reported that TNF-α promoted collagen synthesis, [23] while others suggested that TNF-α inhibited collagen synthesis and induced matrix metalloproteinases.[20] This discrepancy in results may be explained by differences between primary versus secondary responses to TNF-α, differences in overall TNF-α levels, or differences between the direct effects of TNF-α on fibroblasts versus indirect effects on fibroblasts exerted by other cell types within the skin that are influenced by TNF-α.[24]

It has been suggested that mast cell mediators may play a part in induction of epidermal hyperplasia in some diseases [25],[26],[27] due to the increased number of mast cells found in lesional skin in these conditions. Since we found an increase in mast cell numbers in STs, we speculated that mast cell mediators could play a role in induction of acanthosis in STs. Human dermal mast cells have been shown to express other growth factors for keratinocytes in wound healing. [28],[29],[30],[31],[32]

Although TNF-α is well known as an apoptotic protein, it was found to induce both pro-apoptotic and anti-apoptotic proteins, as well as proteins that can block keratinocytes in the G1 phase. TNF-α sensitizes keratinocytes to additional extracellular stimuli that will direct the cells toward or away from these outcomes. TNF-α primes the keratinocytes to react quickly and effectively to such stimuli.[7] The same could apply to TNF-α released from mast cells in STs leading to epidermal proliferation rather than the apoptosis that would have been expected.

Although TRAIL was first identified as an apoptosis-inducing protein, [33] findings imply that it also plays a role in inflammation, immunomodulation, regulation of blood vessel wall [11] and chemokine release. [34] TRAIL and its receptors are constitutively expressed in a wide variety of cells and tissues including normal skin. [35] TRAIL was found to induce release of several chemokines. [34] The increased level of TRAIL we found in STs probably plays a role in recruiting mast cells to the dermis through induction of CXCL8. The mechanism by which TRAIL is increased in this instance needs further studies and evaluation but could be related to trauma of the skin through friction. TRAIL could also play a role in ST pathogenesis through stimulating collagen production by fibroblasts. It was found that TRAIL increased total soluble collagen secretion by human lung fibroblasts through upregulation of TGF-β.[36] Hypothetically, a similar effect by TRAIL could be expected on dermal fibroblasts.

In conclusion this study suggests that TRAIL, mast cells and TNF-α may play a role in the pathogenesis of STs. Following trauma to the skin, in the form of friction, TRAIL is upregulated and can induce mast cell migration into the skin through the release of chemokines. Mast cells in turn release TNF-α. The latter, through direct or indirect interactions with fibroblasts and keratinocytes could initiate some of the changes that lead to the formation of STs. Further studies need to be performed to determine whether the levels of other cytokines are increased to further clarify their role in the pathogenesis of STs.

It is suggested that areas with high mast cells count can only initiate ST formation. Mast cells stimulated by friction can localize and start ST formation through its interaction with fibroblasts and keratinocytes. Further, the finding that STs are not a common association in mastocytosis indicates that mast cells without precipitating factor cannot initiate STs.

Mast cells are heterogeneous in terms of cytokine-regulation, expression of antigens and response to ligands. Growth, differentiation and function of mast cells are regulated by a complex network of cytokines, surface receptors, signaling molecules, the microenvironment and the genetic background. In systemic mastocytosis, the stem cell factor receptor KIT (CD117) is often expressed in mast cell in a mutated and constitutively activated form and other surface molecules are overexpressed. [37] STs generally are uncommon in children and it has been proven that there is an association between the high level of estrogen-α and β as well as the androgen receptors and STs, which in turn explains the absence of STs before puberty and the arrest of their development following menopause.[38] These two factors could explain why children with mastocytosis do not develop ST on friction.

   Acknowledgment Top

We are indebted to Prof. Magdy Ibrahim, MD, Professor of Statistical Unit, Faculty of Medicine, Cairo University, for his statistical analysis of this work.

   References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

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