Disparities of Cutaneous Malignancies in the US Military.

Occupational sun exposure is a well-known risk factor for the development of melanoma and nonmelanoma skin cancer (NMSC), especially among US military personnel who may have inadequate access to sun protection, are located in geographic regions with increased sun exposure, and work with potential carcinogens. Herein, we describe a case of a military service member who developed skin cancer at an early age potentially due to occupational sun exposure. We also provide a review of the literature to examine the risk factors and incidence of melanoma and NMSC in US military personnel and veterans, as well as provide recommendations for skin cancer prevention, screening, and intervention in the military population.

Diacerein Alone and in Combination with Infliximab Suppresses the Combined Proinflammatory Effects of IL-17A, IL-22, Oncostatin M, IL-1A, and TNF-alpha in Keratinocytes: A Potential Therapeutic Option in Psoriasis.

Psoriasis is a chronic disorder characterized by a complex interplay between keratinocytes and inflammatory mediators. In a previous study, we evaluated diacerein's ability to diminish interleukin (IL)-1's proinflammatory effects on cultured primary human keratinocytes. In this study, we evaluated diacerein's ability to diminish the inflammatory effects of a cytokine mixture (CM) consisting of IL-17A, IL-22, oncostatin M, IL-1A, and tumor necrosis factor (TNF)-alpha on cultured primary human keratinocytes. These five cytokines have been previously shown to induce an in vivo-equivalent cell culture psoriasis model. We also evaluated diacerein's anti-inflammatory effects in comparison to and in combination with infliximab, a TNF-alpha inhibitor currently used in the treatment of psoriasis. We found 81 genes that were significantly (P < 0.05) dysregulated by CM compared to medium control. All three treatment groups (diacerein alone, infliximab alone, and diacerein plus infliximab) diminished the effects of CM on these genes, with the greatest effect seen with diacerein plus infliximab. Using enzyme-linked immunosorbent assay method on cell culture supernatant, we determined the protein concentration for five genes (IL-19, IL-6, CSF3, S100A8, and NAP-2) significantly (P < 0.05) upregulated by CM at the gene level. Diacerein alone diminished the effect of CM on the protein concentration of two genes, whereas diacerein plus infliximab diminished the effect of CM on the protein concentration of all the five genes. Based on these results, we conclude that diacerein alone or in combination with infliximab may have a therapeutic role in psoriasis by downregulating key inflammatory mediators.

IL-4 dysregulates microRNAs involved in inflammation, angiogenesis and apoptosis in epidermal keratinocytes.

IL-4 plays an important role in the pathogenesis of atopic dermatitis (AD) by dysregulating many key factors at the transcriptional level. In this study, a microRNA array technique and IL-4 transgenic mice were used to demonstrate that IL-4 dysregulates microRNAs involved in inflammation, angiogenesis, lymphangiogenesis and apoptosis. Of the 372 common microRNAs examined, 26 and one microRNAs were found to be up- and down-regulated, respectively. MicroRNA-101-5p, -122-5p, -142-3p, -204-5p, -335-3p, -376a-3p, -378a-5p, -639 and -9-5p are among the most significantly up-regulated microRNAs. MicroRNA-147a, the only one that was down- regulated in the present study, attenuates TLR-induced inflammatory responses. These dysregulated microRNAs may provide post-transcriptional regulation of key genes in AD.

Unusually extensive scalp ulcerations manifested in pemphigus erythematosus.

Senear-Usher Syndrome, or pemphigus erythematosus, is an autoimmune skin blistering disorder with an overlapping clinical presentation of pemphigus foliaceus and lupus erythematosus. Lesions typically involve the scalp, face, and upper chest or back. This case study focuses on a patient who presentedwith progressive scalp ulcers, hyperpigmentation, and eroded plaques with overlying hemorrhagic crust. Pemphigus erythematosus was diagnosedwith direct immunofluorescence, demonstrating immunoglobulin G and complement deposition both intercellularly and at the dermoepidermal junction. The patient is continuing treatment with systemicsteroids and steroid-sparing immunosuppressants.

A molecular mechanism for IL-4 suppression of loricrin transcription in epidermal keratinocytes: implication for atopic dermatitis pathogenesis.

Skin barrier defects play an important role in atopic dermatitis (AD) pathogenesis. Loricrin, an important barrier protein suppressed in human AD, is down-regulated by IL-4 in keratinocytes. However, the molecular mechanism is unknown. Since loricrin transcription requires p300/CBP, and Stat6 also recruits this common coactivator for its stimulated factors, we hypothesize that IL-4-activated Stat6 competes for the available endogenous p300/CBP, leading to loricrin transcription inhibition. First, we showed that loricrin is suppressed in the skin of IL-4 transgenic mice, an AD mouse model. In human keratinocytes, IL-4 down-regulation of loricrin is abrogated by a pan-Jak inhibitor, suggesting that the Jak-Stat pathway is involved. To further investigate the downstream molecular mechanism, we transfected HaCat cells with a loricrin promoter and then treated them with either IL-4 or vehicle. Not surprisingly, IL-4 greatly suppressed the promoter activity. Interestingly, this suppression was prevented when we knocked down Stat6, indicating that Stat6 participates in IL-4 regulation of loricrin. A Stat6-specific inhibitor confirmed the knockdown study. Finally, IL-4 suppression of loricrin was reversed with transfection of a CBP expression vector in a dose-dependent manner. Taken together, for the first time, we delineate a molecular mechanism for IL-4 down-regulation of loricin expression in human keratinocytes, which may play an important role in AD pathogenesis.

Diacerein inhibits the pro-atherogenic & pro-inflammatory effects of IL-1 on human keratinocytes & endothelial cells.

We investigated IL-1-induced regulation of genes related to inflammation and atherogenesis in human keratinocytes and endothelial cells, and if 'diacerein', an oral IL-1 inhibiting drug currently approved for use in osteoarthritis, would reverse IL-1's effects on these cells. Primary human keratinocytes and coronary artery endothelial cells were treated with either IL-1α or IL-1ß, with and without diacerein. Using PCR-array, we assessed differential gene-expression regulated by IL-1 and diacerein. We identified 34 pro-atherogenic genes in endothelial cells and 68 pro-inflammatory genes in keratinocytes significantly (p<0.05) regulated at least 2-fold by IL-1, in comparison to control. Diacerein completely or partially reversed this regulation on almost all genes. Using ELISA, we confirmed diacerein's ability to reverse IL-1-driven gene-regulation of 11 selected factors, at the protein level. The results support a novel idea that diacerein acts as an inhibitor of the pro-atherogenic and pro-inflammatory effects of IL-1. Diacerein may have therapeutic applications to diminish IL-1-induced skin inflammation in psoriasis and attenuate IL-1-induced development of atherosclerosis. Further investigation into diacerein's effect on skin inflammation, atherogenesis and cardiovascular risk in animal models or humans is warranted.

Paraneoplastic Pemphigus and Autoimmune Blistering Diseases Associated with Neoplasm: Characteristics, Diagnosis, Associated Neoplasms, Proposed Pathogenesis, Treatment.

Autoimmune paraneoplastic and neoplasm-associated skin syndromes are characterized by autoimmune-mediated cutaneous lesions in the presence of a neoplasm. The identification of these syndromes provides information about the underlying tumor, systemic symptoms, and debilitating complications. The recognition of these syndromes is particularly helpful in cases of skin lesions presenting as the first sign of the malignancy, and the underlying malignancy can be treated in a timely manner. Autoimmune paraneoplastic and neoplasm-associated bullous skin syndromes are characterized by blister formation due to an autoimmune response to components of the epidermis or basement membrane in the context of a neoplasm. The clinical manifestations, histopathology and immunopathology findings, target antigens, associated neoplasm, current diagnostic criteria, current understanding of pathogenesis, and treatment options for a selection of four diseases are reviewed. Paraneoplastic pemphigus manifests with clinically distinct painful mucosal erosions and polymorphic cutaneous lesions, and is often associated with lymphoproliferative neoplasm. In contrast, bullous pemphigoid associated with neoplasm presents with large tense subepidermal bullae of the skin, and mild mucosal involvement, but without unique clinical features. Mucous membrane pemphigoid associated with neoplasm is a disorder of chronic subepithelial blisters that evolve into erosions and ulcerations that heal with scarring, and involves stratified squamous mucosal surfaces. Linear IgA dermatosis associated with neoplasm is characterized by annularly grouped pruritic papules, vesicles, and bullae along the extensor surfaces of elbows, knees, and buttocks. Physicians should be aware that these autoimmune paraneoplastic and neoplasm-associated syndromes can manifest distinct or similar clinical features as compared with the non-neoplastic counterparts.

Interleukin-4 Downregulation of Involucrin Expression in Human Epidermal Keratinocytes Involves Stat6 Sequestration of the Coactivator CREB-Binding Protein.

Skin barrier defects play an important role in atopic dermatitis (AD). Involucrin, an important barrier protein suppressed in human AD, is downregulated by interleukin-4 (IL-4). However, the molecular mechanism for IL-4 downregulation of involucrin has not been delineated, and especially how Stat6, a transcriptional activator, represses involucrin expression is unknown. Since Stats usually recruit p300/CBP in the general transcription machinery of their target genes and involucrin expression also involves p300/CBP, we hypothesize that Stat6 activated by IL-4 may sequestrate p300/CBP from the involucrin transcription complex, thus suppressing involucrin expression in keratinocytes. Using IL-4 transgenic mice, an AD mouse model, we find that involucrin expression is similarly downregulated as in human AD. In HaCat cells, the Jak inhibitor and dominant negative studies indicate that the Jaks-Stat6 pathway is involved in IL-4 downregulation of involucrin. Next, we transfected HaCat cells with an involucrin promoter-luciferase construct and then treated them with IL-4. IL-4 greatly suppresses the promoter activity, which is totally abolished by cotransfecting the CREB-binding protein (CBP) expression vector, indicating that IL-4 cannot downregulate involucrin in the presence of excess CBP. Finally, chromatin immunoprecipitation assay demonstrates that IL-4 decreases CBP binding to the involucrin transcription complex. For the first time, we defined a molecular mechanism for IL-4 downregulation of involucrin in keratinocytes, which may play an important role in the pathogenesis of AD.

Aberrant Wound Healing in an Epidermal Interleukin-4 Transgenic Mouse Model of Atopic Dermatitis.

Wound healing in a pre-existing Th2-dominated skin milieu was assessed by using an epidermal specific interleukin-4 (IL-4) transgenic (Tg) mouse model, which develops a pruritic inflammatory skin condition resembling human atopic dermatitis. Our results demonstrated that IL-4 Tg mice had delayed wound closure and re-epithelialization even though these mice exhibited higher degrees of epithelial cell proliferation. Wounds in IL-4 Tg mice also showed a marked enhancement in expression of inflammatory cytokines/chemokines, elevated infiltration of inflammatory cells including neutrophils, macrophages, CD3+ lymphocytes, and epidermal dendritic T lymphocytes. In addition, these mice exhibited a significantly higher level of angiogenesis as compared to wild type mice. Furthermore, wounds in IL-4 Tg mice presented with larger amounts of granulation tissue, but had less expression and deposition of collagen. Taken together, an inflamed skin condition induced by IL-4 has a pronounced negative influence on the healing process. Understanding more about the pathogenesis of wound healing in a Th2- dominated environment may help investigators explore new potential therapeutic strategies.

Differential expression of inflammation-related genes in IL-4 transgenic mice before and after the onset of atopic dermatitis skin lesions.

IL-4 plays an important role in the pathogenesis of atopic dermatitis (AD), a common chronic inflammatory skin disease. We have generated IL-4 transgenic (Tg) mice by over-expressing IL-4 in the epidermis. These mice spontaneously develop chronic pruritic inflammatory skin lesions, which meet the clinical and histological diagnostic criteria for human AD. Systemic survey of immune-related genes in this mouse model, however, has not been performed. In this study, we utilize PCR array technique to examine hundreds of inflammation-related genes in the IL-4 Tg mice before and after the onset of skin lesions as well as in their wild type (WT) littermates. Only those genes with at least 2-fold up-regulation or down-regulation and with a P-value of less than 0.05 in comparison to WT controls were identified and analyzed. In the skin lesions, many chemokines, pro-inflammatory cytokines, and other AD-related factors are dysregulated compared to the wild type mice. Particularly, CXCL5, IL-1ß, IL-24, IL-6, oncostatin M, PTGS2, FPR1 and REG3γ are up-regulated several hundred-fold. In the pre-lesional group that shows no obvious skin abnormality on clinical observation, 30 dysregulated genes are nevertheless identified though the fold changes are much less than that of the lesional group, including CCL6, CCL8, CCL11, CCL17, CXCL13, CXCL14, CXCR3 and IL-12Rß2. Finally using ELISA, we demonstrate that 4 most dramatically up-regulated factors in the skin are also elevated in the peripheral blood of the IL-4 Tg mice. Taken together, our data have identified hundreds of dysregulated factors in the IL-4 Tg mice before and after the onset of skin lesions. Future detailed examination of these factors will shed light on our understanding of the development and progression of AD and help to discover important biomarkers for clinical AD diagnosis and treatment.

Eruptive Syringocystadenoma Papilliferum, Keratoacanthoma, and Verruca Vulgaris in a Keratinocytic Epidermal Nevus on the Leg.

An otherwise healthy 43-year-old man presented with seven papules that had all erupted within the previous 6 months from an epidermal nevus on his left lower extremity. He reported that one of the new growths was painful and bled with minor trauma. Physical examination revealed a linear blaschkoid cobblestoned dark brown plaque that extended from the disto-lateral left thigh 30 cm to the mid-calf. Within the plaque inferior to the lateral popliteal fossa were six verrucous papules and a 4-mm round, pink, crusted, exophytic papule (Figure 1). A punch biopsy was taken from the plaque and saucerization shave biopsies of all the discrete papules.

Interleukin-4 up-regulation of epidermal interleukin-19 expression in keratinocytes involves the binding of signal transducer and activator of transcription 6 (Stat6) to the imperfect Stat6 sites.

Interleukin-19 (IL-19) plays an important role in asthma by stimulating T helper type 2 (Th2) cytokine production. Interestingly, IL-4, a key Th2 cytokine, in turn up-regulates IL-19 expression in bronchial epithelial cells, so forming a positive feedback loop. In atopic dermatitis (AD), another Th2 disease closely related to asthma, IL-19 is up-regulated in the skin. We propose to use IL-4 transgenic (Tg) mice and human keratinocyte culture to delineate the molecular mechanisms involved in the up-regulation of IL-19 in AD. IL-19 is similarly up-regulated in the skin of IL-4 Tg mice as in human AD. Next we show that IL-4 up-regulates IL-19 expression in keratinocytes. Interestingly, the up-regulation was suppressed by a pan-Janus kinase (Jak) inhibitor, suggesting that the Jak-signal transducer and activator of transcription (Jak-STAT) pathway may be involved. Dominant negative studies further indicate that STAT6, but not other STATs, mediates the up-regulation. Serial 5' deletion of the IL-19 promoter and mutagenesis studies demonstrate that IL-4 up-regulation of IL-19 in keratinocytes involves two imperfect STAT6 response elements. Finally, chromatin immunoprecipitation assay studies indicate that IL-4 increases the binding of STAT6 to its response elements in the IL-19 promoter. Taken together, we delineate the detailed molecular pathway for IL-4 up-regulation of IL-19 in keratinocytes, which may play an important role in AD pathogenesis.

The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis.

Atopic dermatitis (AD), a common chronic inflammatory skin disease, is characterized by inflammatory cell skin infiltration. The JAK-STAT pathway has been shown to play an essential role in the dysregulation of immune responses in AD, including the exaggeration of Th2 cell response, the activation of eosinophils, the maturation of B cells, and the suppression of regulatory T cells (Tregs). In addition, the JAK-STAT pathway, activated by IL-4, also plays a critical role in the pathogenesis of AD by upregulating epidermal chemokines, pro-inflammatroy cytokines, and pro-angiogenic factors as well as by downregulating antimicrobial peptides (AMPs) and factors responsible for skin barrier function. In this review, we will highlight the recent advances in our understanding of the JAK-STAT pathway in the pathogenesis of AD.

IL-4 up-regulates epidermal chemotactic, angiogenic, and pro-inflammatory genes and down-regulates antimicrobial genes in vivo and in vitro: relevant in the pathogenesis of atopic dermatitis.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Although the pathogenesis of AD is not fully understood, we and others have shown that IL-4 plays a key role. In this study we aimed to identify keratinocyte genes regulated by IL-4 that may play important roles in the pathophysiology of AD. HaCat cells were treated with IL-4 at various concentrations for 24h, and PCR gene array on inflammation/autoimmunity was performed three times for analysis of differential gene expression. Of all the 370 genes examined, 32 and 53 genes are up- and down-regulated, respectively. Specifically related to AD, chemokines CCL3L1, CCL8, CCL24, CCL25, CCL26, CXCL6 and CXCL16 are up-regulated by IL-4. Pro-inflammatory factors, such as IL-19, IL-20, IL-1α, IL-12Rß2, IL-25, IL-31RA, OSMR and nitric oxide synthase 2, are also up-regulated. In addition, IL-4 up-regulates VEGFA, a pro-angiogenic factor. In contrast, antimicrobial peptides (AMPs) or factors involved in APM production, such as IFN-κ, S100s, Toll-like receptors, and several chemokines are down-regulated. Similarly IL-4 also down-regulates TNF-α, lymphotoxin-ß, an IgE suppressor, TNFSF18, a T-cells function regulator, and the glucocorticoid receptor. On the in vivo level, real-time RT-PCR on the selected genes confirmed that IL-4 up-regulates chemokines, proinflammatory cytokines while it suppresses AMP production related genes in the skin obtained from IL-4 Tg mice. Detailed examination of these genes will delineate their specific roles in chemotaxis, inflammation, angiogenesis and AMP production, all of which may contribute to the development and progression of AD.

Inflammation-driven dermal lymphangiogenesis in atopic dermatitis is associated with CD11b+ macrophage recruitment and VEGF-C up-regulation in the IL-4-transgenic mouse model.

OBJECTIVE: To investigate the presence and extent of inflammatory lymphangiogenesis in AD and determine the role of IL-4 in lymphatic proliferation in both K14-IL-4 Tg mouse model of AD and cultured human epidermal cells. METHODS: Skin tissues from Tg mice were collected for immunostaining against PDPN, LYVE-1, CD11b and VEGF-C. The regulation of specific lymphatic biomarkers and growth factors were determined using qPCR and Western Blot analyses. Dermal lymphatic uptake and drainage were assessed using intradermal EB dye micro-injections. Total RNA from IL-4-stimulated HaCaT cells was analyzed in a PCR array to evaluate the regulation of lymphangiogenic-related genes. RESULTS: Prominent dermal microvascular lymphangiogenesis occurs in the Tg mice, characterized by a significant increase in number and caliber of the vasculature. The extent of both lymphatic proliferation and drainage parallels the progression of lesion severity, as does the up-regulation of pro-lymphangiogenic factors VEGF-C, VEGFR-3, ANG-1, and ANG-2. IL-4-stimulated HaCaT cells express high levels of MCP-1, a strong macrophage chemo-attractant. Additionally, Tg mice show significantly increased number of dermal CD11b+ macrophages expressing VEGF-C in the skin. CONCLUSIONS: Our results provide the first demonstration of inflammation-mediated lymphangiogenesis in AD and that IL-4 triggered macrophage recruitment may be closely linked to this phenomenon.

IL-4 regulates chemokine CCL26 in keratinocytes through the Jak1, 2/Stat6 signal transduction pathway: Implication for atopic dermatitis.

Atopic dermatitis (AD), a chronic, pruritic, inflammatory skin disease, is histopathologically characterized by epidermal hyperplasia and infiltration of T cells, mast cells, and eosinophils. Clinical study and basic research have established that IL-4 plays an important role in the pathogenesis of AD. In this report, using HaCat cells, we show that CCL26, a chemokine for eosinophils, is up-regulated by IL-4 at both the mRNA and protein levels. IL-4 also enhances CCL26 promoter activity. Serial 5' deletion of the promoter and mutagenesis study reveal that the proximal Stat site is the key response element for IL-4 regulation of CCL26. Although IL-4 increases phosphorylation of both Stat3 and Stat6, it only activates Stat6 as shown by dominant negative studies. In addition, we found that IL-4 induces Stat6 nuclear translocation and stimulates phosphorylation of Jak1 and Jak2 but not Tyk2. IL-4 up-regulation of CCL26 can be suppressed by Jak inhibitors in a dose-dependent manner. Taken together, results of this investigation reveal that IL-4 signals through the Jak1, 2/Stat6 pathway in keratinocytes to stimulate CCL26 expression and this may provide an explanation for the pathogenesis of AD.