Current knowledge on psoriasis and autoimmune diseases

PubMed Central

Ayala-Fontánez, Nilmarie; Soler, David C; McCormick, Thomas S

2016-01-01

Psoriasis is a prevalent, chronic inflammatory disease of the skin, mediated by crosstalk between epidermal keratinocytes, dermal vascular cells, and immunocytes such as antigen presenting cells (APCs) and T cells. Exclusive cellular “responsibility” for the induction and maintenance of psoriatic plaques has not been clearly defined. Increased proliferation of keratinocytes and endothelial cells in conjunction with APC/T cell/monocyte/macrophage inflammation leads to the distinct epidermal and vascular hyperplasia that is characteristic of lesional psoriatic skin. Despite the identification of numerous susceptibility loci, no single genetic determinant has been identified as responsible for the induction of psoriasis. Thus, numerous other triggers of disease, such as environmental, microbial and complex cellular interactions must also be considered as participants in the development of this multifactorial disease. Recent advances in therapeutics, especially systemic so-called “biologics” have provided new hope for identifying the critical cellular targets that drive psoriasis pathogenesis. Recent recognition of the numerous co-morbidities and other autoimmune disorders associated with psoriasis, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus suggest common signaling elements and cellular mediators may direct disease pathogenesis. In this review, we discuss common cellular pathways and participants that mediate psoriasis and other autoimmune disorders that share these cellular signaling pathways. PMID:29387591

HLA-C expression pattern is spatially different between psoriasis and eczema skin lesions.

PubMed

Carlén, Lina; Sakuraba, Kazuko; Ståhle, Mona; Sánchez, Fabio

2007-02-01

Interactions between genetic and environmental factors underlie the immune dysregulation and keratinocyte abnormalities that characterize psoriasis. Among known psoriasis susceptibility loci (PSORS), PSORS1 on chromosome 6 has the strongest association to disease. Altered expression of some PSORS1 candidate genes has been reported but little is known about HLA-C expression in psoriasis. This study compared expression of major histocompatibility complex class Ia and HLA-C in psoriasis, allergic contact eczema, and normal skin. Although HLA-C was abundant in protein extracts from both eczema and psoriasis, a consistent and intriguing difference in the expression pattern was observed; strong immunoreactivity in the basal cell layer, polarized towards the basement membrane in psoriasis, whereas in eczema lesions HLA-C immunostaining was present mostly in suprabasal cells. Inflammatory cells in the dermis were strongly stained in both diseases. Normal skin epithelium showed less intense but similar HLA-C staining as eczema lesions. HLA class Ia expression overall resembled that of HLA-C in all samples. The distinct HLA-C expression patterns in psoriasis and eczema suggest a functional role in the specific psoriasis immune response and not only a general feature of inflammation.

Molecular and Cellular Profiling of Scalp Psoriasis Reveals Differences and Similarities Compared to Skin Psoriasis

PubMed Central

Ruano, Juan; Suárez-Fariñas, Mayte; Shemer, Avner; Oliva, Margeaux

2016-01-01

Scalp psoriasis shows a variable clinical spectrum and in many cases poses a great therapeutic challenge. However, it remains unknown whether the immune response of scalp psoriasis differs from understood pathomechanisms of psoriasis in other skin areas. We sought to determine the cellular and molecular phenotype of scalp psoriasis by performing a comparative analysis of scalp and skin using lesional and nonlesional samples from 20 Caucasian subjects with untreated moderate to severe psoriasis and significant scalp involvement and 10 control subjects without psoriasis. Our results suggest that even in the scalp, psoriasis is a disease of the inter-follicular skin. The immune mechanisms that mediate scalp psoriasis were found to be similar to those involved in skin psoriasis. However, the magnitude of dysregulation, number of differentially expressed genes, and enrichment of the psoriatic genomic fingerprint were more prominent in skin lesions. Furthermore, the scalp transcriptome showed increased modulation of several gene-sets, particularly those induced by interferon-gamma, compared with that of skin psoriasis, which was mainly associated with activation of TNFα/L-17/IL-22-induced keratinocyte response genes. We also detected differences in expression of gene-sets involving negative regulation, epigenetic regulation, epidermal differentiation, and dendritic cell or Th1/Th17/Th22-related T-cell processes. PMID:26849645

Nrf2 Regulates the Sensitivity of Mouse Keratinocytes to Nitrogen Mustard via Multidrug Resistance-Associated Protein 1 (Mrp1)

PubMed Central

Udasin, Ronald G.; Wen, Xia; Bircsak, Kristin M.; Aleksunes, Lauren M.; Shakarjian, Michael P.; Kong, Ah-Ng Tony; Heck, Diane E.; Laskin, Debra L.; Laskin, Jeffrey D.

2016-01-01

Sulfur mustard and nitrogen mustard (mechlorethamine, HN2) are potent vesicants developed as chemical warfare agents. These electrophilic, bifunctional alkylating agents cause skin injury, including inflammation, edema, and blistering. HN2 covalently modifies macromolecules such as DNA, RNA, and proteins or is scavenged by glutathione, forming adducts that can contribute to toxicity. Multidrug resistance-associated protein 1 (Mrp1/MRP1) is a transmembrane ATPase known to efflux glutathione-conjugated electrophiles. In the present studies, we examined the effects of modulating Mrp1-mediated transport activity on the sensitivity of primary and PAM212 mouse keratinocytes to HN2. Primary keratinocytes, and to a lesser extent, PAM212 cells, express Mrp1 mRNA and protein and possess Mrp1 functional activity, as measured by calcein efflux. Sulforaphane, an activator of Nrf2, increased Mrp1 mRNA, protein, and functional activity in primary keratinocytes and PAM212 cells and decreased their sensitivity to HN2-induced growth inhibition (IC50 = 1.4 and 4.8 µM in primary keratinocytes and 1 and 13 µM in PAM212 cells, in the absence and presence of sulforaphane, respectively). The Mrp1 inhibitor, MK-571, reversed the effects of sulforaphane on HN2-induced growth inhibition in both primary keratinocytes and PAM212 cells. In primary keratinocytes from Nrf2−/− mice, sulforaphane had no impact on Mrp1 expression or activity, or on sensitivity to HN2, demonstrating that its effects depend on Nrf2. These data suggest that Mrp1-mediated efflux is important in regulating HN2-induced keratinocyte growth inhibition. Enhancing HN2 efflux from keratinocytes may represent a novel strategy for mitigating vesicant-induced cytotoxicity. PMID:26454883

Decreased A-to-I RNA editing as a source of keratinocytes' dsRNA in psoriasis.

PubMed

Shallev, Lea; Kopel, Eli; Feiglin, Ariel; Leichner, Gil S; Avni, Dror; Sidi, Yechezkel; Eisenberg, Eli; Barzilai, Aviv; Levanon, Erez Y; Greenberger, Shoshana

2018-06-01

Recognition of dsRNA molecules activates the MDA5-MAVS pathway and plays a critical role in stimulating type-I interferon responses in psoriasis. However, the source of the dsRNA accumulation in psoriatic keratinocytes remains largely unknown. A-to-I RNA editing is a common co- or post-transcriptional modification that diversifies adenosine in dsRNA, and leads to unwinding of dsRNA structures. Thus, impaired RNA editing activity can result in an increased load of endogenous dsRNAs. Here we provide a transcriptome-wide analysis of RNA editing across dozens of psoriasis patients, and we demonstrate a global editing reduction in psoriatic lesions. In addition to the global alteration, we also detect editing changes in functional recoding sites located in the IGFBP7 , COPA , and FLNA genes. Accretion of dsRNA activates autoimmune responses, and therefore the results presented here, linking for the first time an autoimmune disease to reduction in global editing level, are relevant to a wide range of autoimmune diseases. © 2018 Shallev et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

TRB3 is elevated in psoriasis vulgaris lesions and mediates HaCaT cells proliferation in vitro.

PubMed

Yu, Xiao-Jing; Song, Tie-Jun; Zhang, Lu-Wei; Su, Ying; Wang, Ke-Yu; Sun, Qing

2017-10-01

Psoriasis is a chronic skin disease characterized by abnormal keratinocyte proliferation and differentiation, inflammation, and angiogenesis. Overexpression of tribbles homolog3 (TRB3), which belongs to the tribbles family of pseudokinases, has been found in several human tumors and metabolic diseases, but its role in psoriasis has not been fully clarified. The aim of this study is to investigate the expression of TRB3 in psoriasis and explore its roles in the proliferation of keratinocytes. Twenty-four patients with psoriasis vulgaris were recruited for the study. Diagnosis of psoriasis was based on clinical and histologic examinations. Immunohistochemistry and real-time reverse transcription PCR (RT-PCR) were performed to determine protein and messenger RNA (mRNA) expression of TRB3 in psoriasis lesions. 5-Bromo-2-deoxyUridine (BrdU) incorporation assay were performed for cell proliferation. Cell cycle distribution was assessed by flow cytometry analysis. The levels of TRB3 is elevated in psoriatic lesions compared with psoriatic non-lesions. The HaCat cells expressed the TRB3 gene. We found TRB3 silencing to significantly inhibit HaCat cell proliferation. Furthermore, the specific knockdown of TRB3 slowed down the cell cycle at the gap 0/first gap phase. In conclusion, our data suggest that TRB3 is overexpressed in lesions of patients with psoriasis and may be involved in the abnormal proliferation of keratinocytes. Therefore, TRB3 may be a potential therapeutic target for psoriasis. © American Federation for Medical Research (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Steroid synthesis by primary human keratinocytes; implications for skin disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hannen, Rosalind F., E-mail: r.f.hannen@qmul.ac.uk; Michael, Anthony E.; Jaulim, Adil

2011-01-07

Research highlights: {yields} Primary keratinocytes express the steroid enzymes required for cortisol synthesis. {yields} Normal primary human keratinocytes can synthesise cortisol. {yields} Steroidogenic regulators, StAR and MLN64, are expressed in normal epidermis. {yields} StAR expression is down regulated in eczema and psoriatic epidermis. -- Abstract: Cortisol-based therapy is one of the most potent anti-inflammatory treatments available for skin conditions including psoriasis and atopic dermatitis. Previous studies have investigated the steroidogenic capabilities of keratinocytes, though none have demonstrated that these skin cells, which form up to 90% of the epidermis are able to synthesise cortisol. Here we demonstrate that primary humanmore » keratinocytes (PHK) express all the elements required for cortisol steroidogenesis and metabolise pregnenolone through each intermediate steroid to cortisol. We show that normal epidermis and cultured PHK express each of the enzymes (CYP11A1, CYP17A1, 3{beta}HSD1, CYP21 and CYP11B1) that are required for cortisol synthesis. These enzymes were shown to be metabolically active for cortisol synthesis since radiometric conversion assays traced the metabolism of [7-{sup 3}H]-pregnenolone through each steroid intermediate to [7-{sup 3}H]-cortisol in cultured PHK. Trilostane (a 3{beta}HSD1 inhibitor) and ketoconazole (a CYP17A1 inhibitor) blocked the metabolism of both pregnenolone and progesterone. Finally, we show that normal skin expresses two cholesterol transporters, steroidogenic acute regulatory protein (StAR), regarded as the rate-determining protein for steroid synthesis, and metastatic lymph node 64 (MLN64) whose function has been linked to cholesterol transport in steroidogenesis. The expression of StAR and MLN64 was aberrant in two skin disorders, psoriasis and atopic dermatitis, that are commonly treated with cortisol, suggesting dysregulation of epidermal steroid synthesis in these patients. Collectively

Investigating the potential of Oxymatrine as a psoriasis therapy.

PubMed

Chen, Qian; Zhou, Hui; Yang, Yinxue; Chi, Mingwei; Xie, Nan; Zhang, Hong; Deng, Xingwang; Leavesley, David; Shi, Huijuan; Xie, Yan

2017-06-01

Psoriasis vulgaris is a chronic inflammatory skin disease, stubbornly intractable, with substantial consequences for patient physical and mental welfare. Approaches currently available to treat psoriasis are not satisfactory due to undesirable side-effects or expense. Psoriasis is characterized by hyperproliferation and inflammation. Oxymatrine, an active component extracted from Sophora flavescens, has been demonstrated to possess anti-proliferation, anti-inflammatory, anti-tumorigenic, immune regulation and pro-apoptotic properties. This investigation presents a detailed retrospective review examining the effect of Oxymatrine on psoriasis and investigates the mechanisms underlying patient responses to Oxymatrine. We confirm that Oxymatrine administration significantly reduced the Psoriasis Area Severity Index score, with high efficacy compared to the control group. In addition, we have found that Oxymatrine significantly inhibits the viability, proliferation and differentiation of human keratinocyte in vitro. Immunohistochemical analysis indicates Oxymatrine significantly suppresses the expression of Pan-Cytokeratin, p63 and keratin 10. The results indicate that the suppression of p63 expression may lead to the anti-proliferation effect of Oxymatrine on human skin keratinocytes. Oxymatrine does not affect the formation of basement membrane, which is very important to maintain the normal function of human skin keratinocytes. In summary, Oxymatrine offers an effective, economical, and safe treatment for patients presenting with intractable psoriasis vulgaris. Copyright © 2017 Elsevier B.V. All rights reserved.

Brief Report: Interleukin-17A-Dependent Asymmetric Stem Cell Divisions Are Increased in Human Psoriasis: A Mechanism Underlying Benign Hyperproliferation.

PubMed

Charruyer, Alexandra; Fong, Stephen; Vitcov, Giselle G; Sklar, Samuel; Tabernik, Leah; Taneja, Monica; Caputo, Melinda; Soeung, Catherine; Yue, Lili; Uchida, Yoshi; Arron, Sarah T; Horton, Karen M; Foster, Robert D; Sano, Shigetoshi; North, Jeffrey P; Ghadially, Ruby

2017-08-01

The balance between asymmetric and symmetric stem cell (SC) divisions is key to tissue homeostasis, and dysregulation of this balance has been shown in cancers. We hypothesized that the balance between asymmetric cell divisions (ACDs) and symmetric cell divisions (SCDs) would be dysregulated in the benign hyperproliferation of psoriasis. We found that, while SCDs were increased in squamous cell carcinoma (SCC) (human and murine), ACDs were increased in the benign hyperproliferation of psoriasis (human and murine). Furthermore, while sonic hedgehog (linked to human cancer) and pifithrinα (p53 inhibitor) promoted SCDs, interleukin (IL)-1α and amphiregulin (associated with benign epidermal hyperproliferation) promoted ACDs. While there was dysregulation of the ACD:SCD ratio, no change in SC frequency was detected in epidermis from psoriasis patients, or in human keratinocytes treated with IL-1α or amphiregulin. We investigated the mechanism whereby immune alterations of psoriasis result in ACDs. IL17 inhibitors are effective new therapies for psoriasis. We found that IL17A increased ACDs in human keratinocytes. Additionally, studies in the imiquimod-induced psoriasis-like mouse model revealed that ACDs in psoriasis are IL17A-dependent. In summary, our studies suggest an association between benign hyperproliferation and increased ACDs. This work begins to elucidate the mechanisms by which immune alteration can induce keratinocyte hyperproliferation. Altogether, this work affirms that a finely tuned balance of ACDs and SCDs is important and that manipulating this balance may constitute an effective treatment strategy for hyperproliferative diseases. Stem Cells 2017;35:2001-2007. © 2017 AlphaMed Press.

Trichohyalin-like 1 protein, a member of fused S100 proteins, is expressed in normal and pathologic human skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamakoshi, Takako; Makino, Teruhiko, E-mail: tmakino@med.u-toyama.ac.jp; Ur Rehman, Mati

2013-03-01

Highlights: ► Trichohyalin-like 1 protein is a member of the fused-type S100 protein gene family. ► Specific antibodies against the C-terminus of the TCHHL1 protein were generated. ► TCHHL1 proteins were expressed in the basal layer of the normal epidermis. ► TCHHL1 proteins were strongly expressed in tumor nests of BCC and SCC. ► The expression of TCHHL1 proteins increased in epidermis of psoriasis vulgaris. - Abstract: Trichohyalin-like 1 (TCHHL1) protein is a novel member of the fused-type S100 protein gene family. The deduced amino acid sequence of TCHHL1 contains an EF-hand domain in the N-terminus, one trans-membrane domain andmore » a nuclear localization signal. We generated specific antibodies against the C-terminus of the TCHHL1 protein and examined the expression of TCHHL1 proteins in normal and pathological human skin. An immunohistochemical study showed that TCHHL1 proteins were expressed in the basal layer of the normal epidermis. In addition, signals of TCHHL1 proteins were observed around the nuclei of cultured growing keratinocytes. Accordingly, TCHHL1 mRNA has been detected in normal skin and cultured growing keratinocytes. Furthermore, TCHHL1 proteins were strongly expressed in the peripheral areas of tumor nests in basal cell carcinomas and squamous cell carcinomas. A dramatic increase in the number of Ki67 positive cells was observed in TCHHL1-expressing areas. The expression of TCHHL1 proteins also increased in non-cancerous hyperproliferative epidermal tissues such as those of psoriasis vulgaris and lichen planus. These findings highlight the possibility that TCHHL1 proteins are expressed in growing keratinocytes of the epidermis and might be associated with the proliferation of keratinocytes.« less

GATA3 Expression Is Decreased in Psoriasis and during Epidermal Regeneration; Induction by Narrow-Band UVB and IL-4

PubMed Central

Kant, Marius; Baerveldt, Ewout M.; Florencia, Edwin; Mourits, Sabine; de Ridder, Dick; Laman, Jon D.; van der Fits, Leslie; Prens, Errol P.

2011-01-01

Psoriasis is characterized by hyperproliferation of keratinocytes and by infiltration of activated Th1 and Th17 cells in the (epi)dermis. By expression microarray, we previously found the GATA3 transcription factor significantly downregulated in lesional psoriatic skin. Since GATA3 serves as a key switch in both epidermal and T helper cell differentiation, we investigated its function in psoriasis. Because psoriatic skin inflammation shares many characteristics of epidermal regeneration during wound healing, we also studied GATA3 expression under such conditions. Psoriatic lesional skin showed decreased GATA3 mRNA and protein expression compared to non-lesional skin. GATA3 expression was also markedly decreased in inflamed skin of mice with a psoriasiform dermatitis induced with imiquimod. Tape-stripping of non-lesional skin of patients with psoriasis, a standardized psoriasis-triggering and skin regeneration-inducing technique, reduced the expression of GATA3. In wounded skin of mice, low GATA3 mRNA and protein expression was detected. Taken together, GATA3 expression is downregulated under regenerative and inflammatory hyperproliferative skin conditions. GATA3 expression could be re-induced by successful narrow-band UVB treatment of both human psoriasis and imiquimod-induced psoriasiform dermatitis in mice. The prototypic Th2 cytokine IL-4 was the only cytokine capable of inducing GATA3 in skin explants from healthy donors. Based on these findings we argue that GATA3 serves as a key regulator in psoriatic inflammation, keratinocyte hyperproliferation and skin barrier dysfunction. PMID:21611195

IL-17 in psoriasis: Implications for therapy and cardiovascular co-morbidities

PubMed Central

Golden, Jackelyn B.; McCormick, Thomas S.; Ward, Nicole L.

2013-01-01

Psoriasis is a prevalent, chronic inflammatory disease of the skin mediated by cross-talk occurring between epidermal keratinocytes, dermal vascular cells and immunocytes, including activated antigen presenting cells (APCs), monocytes/macrophages, and Th1 and Th17 cells. Increased proliferation of keratinocytes and endothelial cells in conjunction with immune cell infiltration leads to the distinct epidermal and vascular hyperplasia that is characteristic of lesional psoriatic skin. Interaction of activated T cells with monocytes/macrophages occurs via the Th17/IL-23 axis and is crucial for maintaining the chronic inflammation. Recent epidemiological evidence has demonstrated that psoriasis patients have an increased risk of developing and dying of cardiovascular disease. Similar pathology between psoriasis and cardiovascular disease, including involvement of key immunologic cell populations together with release of common inflammatory mediators such as IL-17A suggest a mechanistic link between the two diseases. This review will focus on concepts critical to psoriasis pathogenesis, systemic manifestations of psoriasis, the role of IL-17 in psoriasis and cardiovascular disease and the potential role for IL-17 in mediating cardiovascular co-morbidities in psoriasis patients. PMID:23562549

AP1S3 Mutations Are Associated with Pustular Psoriasis and Impaired Toll-like Receptor 3 Trafficking

PubMed Central

Setta-Kaffetzi, Niovi; Simpson, Michael A.; Navarini, Alexander A.; Patel, Varsha M.; Lu, Hui-Chun; Allen, Michael H.; Duckworth, Michael; Bachelez, Hervé; Burden, A. David; Choon, Siew-Eng; Griffiths, Christopher E.M.; Kirby, Brian; Kolios, Antonios; Seyger, Marieke M.B.; Prins, Christa; Smahi, Asma; Trembath, Richard C.; Fraternali, Franca; Smith, Catherine H.; Barker, Jonathan N.; Capon, Francesca

2014-01-01

Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis. PMID:24791904

Psoriasis lesions are associated with specific types of emotions. Emotional profile in psoriasis.

PubMed

Martín-Brufau, Ramón; Romero-Brufau, Santiago; Martín-Gorgojo, Alejandro; Brufau Redondo, Carmen; Corbalan, Javier; Ulnik, Jorge

2015-01-01

At present there is still controversy about the relationship between emotional stress and psoriasis lesions. Most of the published literature does not include the broad spectrum of emotional response. The aim of this study was to evaluate the association between skin lesions and emotional state in a large sample of patients with psoriasis. 823 psoriasis patients were recruited (mean age 45.9 years, 55.7% female) and answered two online questionnaires: lesion severity and current extension were evaluated using a self-administered psoriasis severity index (SAPASI); emotional state was assessed using the positive and negative affect schedule (PANAS). Second order factors were calculated and correlated with the SAPASI. We found positive associations between the extent and severity of skin lesions and the negative and submissive emotions, a negative correlation with dominance emotions and no association with positive emotions. Our data supports the relationship between emotions and skin lesions. It also allows for discrimination of the associations between psoriasis lesions and the specific type of emotions.

Psoriasis and Cardiovascular Risk: Strength in Numbers Part II

PubMed Central

Gelfand, Joel M.; Mehta, Nehal N.; Langan, Sinéad M.

2012-01-01

Summary The Psoralen plus Ultraviolet-A (PUVA) cohort study has been a tremendous success in determining how a novel treatment (i.e. PUVA) impacts the long-term risk of keratinocyte carcinoma. The ability to follow patients from the initial multi-center clinical trial for over three decades has been a remarkable achievement in dermatoepidemiology. In this issue, Stern and Huibregste report results from the PUVA follow-up study and conclude that only patients with exceptionally severe psoriasis have an increased overall mortality risk and that there is no significant risk of cardiovascular mortality associated with psoriasis. The results are in contrast to a large and growing body of literature that suggests patients with more severe psoriasis have a clinically significant increased risk of mortality in general, and cardiovascular disease in particular. In addition, the authors found no association between severe psoriasis and obesity or between obesity and cardiovascular mortality, despite extensive literature establishing these associations. Basic principles of epidemiological study design may explain these discrepancies. Ultimately, however, , randomized clinical trials will be necessary to determine whether severe psoriasis is in fact a “visible killer”, as four decades ago (after many years of controversy), hypertension was recognized to be a “silent killer”. PMID:21494241

Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study.

PubMed

Krueger, James; Clark, James D; Suárez-Fariñas, Mayte; Fuentes-Duculan, Judilyn; Cueto, Inna; Wang, Claire Q; Tan, Huaming; Wolk, Robert; Rottinghaus, Scott T; Whitley, Maryann Z; Valdez, Hernan; von Schack, David; O'Neil, Shawn P; Reddy, Padmalatha S; Tatulych, Svitlana

2016-04-01

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. We sought to elucidate the molecular mechanisms underlying the clinical efficacy of tofacitinib in patients with psoriasis. Twelve patients with plaque psoriasis were randomized (3:1) to receive 10 mg of tofacitinib or placebo twice daily for 12 weeks. Biopsy specimens were taken from nonlesional (baseline) and lesional (baseline, days 1 and 3, and weeks 1, 2, 4, and 12) skin. Biopsy specimens were examined for psoriatic epidermal features (thickness, Ki67(+) keratinocytes and keratin 16 [KRT16] mRNA expression, and phosphorylated signal transducer and activator of transcription [pSTAT](+) nuclei) and T-cell and dendritic cell (DC) subsets by using immunohistochemistry, and mRNA transcripts were quantified by using a microarray. In lesional skin keratinocyte pSTAT1 and pSTAT3 staining was increased at baseline but reduced after 1 day of tofacitinib (baseline, median of 1290 pSTAT1(+) cells/μm(2); day 1, median of 332 pSTAT1(+) cells/μm(2); and nonlesional, median of 155 pSTAT1(+) cells/μm(2)). Epidermal thickness and KRT16 mRNA expression were significantly and progressively reduced after days 1 and 3 of tofacitinib administration, respectively (eg, KRT16 decreased 2.74-fold, day 3 vs baseline, P = .016). Decreases in DC and T-cell numbers were observed after weeks 1 and 2, respectively. At week 4, significant decreases in IL-23/TH17 pathways were observed that persisted through week 12. Improvements in clinical and histologic features were strongly associated with changes in expression of psoriasis-related genes and reduction in IL-17 gene expression. Tofacitinib has a multitiered response in patients with psoriasis: (1) rapid attenuation of keratinocyte Janus kinase/STAT signaling; (2) removal of keratinocyte-induced cytokine signaling, leading to reductions in pathologic DC and T-cell numbers to nonlesional levels; and (3) inhibition of the IL-23/TH17 pathway. Copyright © 2016

Current and potential immune therapies and vaccines in the management of psoriasis

PubMed Central

Kaffenberger, Benjamin H; Lee, Grace L; Tyler, Kelly; Chan, Derek V; Jarjour, Wael; Ariza, Maria E; Williams, Marshall V; Wong, Henry K

2014-01-01

Psoriasis is a chronic, immune skin disease associated with significant morbidity. Development of psoriasis is influenced by numerous genes, one allele is HLA-CW*0602. Other genes and single nucleotide polymorphisms affect immunologic pathways and antimicrobial peptide synthesis. Dendritic cells initiate psoriasis by activating T-cells toward a Th1 and Th17 response, with increased cytokines including TNF-α, IL-6, -12, -17, -22, and -23. IL-22 appears to promote keratinocyte dedifferentiation and increased antimicrobial peptide synthesis while TNF-α and IL-17 induce leukocyte localization within the psoriatic plaque. These recent insights identifying key cytokine pathways have led to the development of inhibitors with significant efficacy in the treatment of psoriasis. While a strategy for vaccine modulation of the immune response in psoriasis is in progress, with new technology they may provide a cost-effective long-term treatment that may induce tolerance or targeted self-inhibition for patients with autoimmune disorders, such as psoriasis. PMID:24492530

IFI27, a novel epidermal growth factor-stabilized protein, is functionally involved in proliferation and cell cycling of human epidermal keratinocytes.

PubMed

Hsieh, W-L; Huang, Y-H; Wang, T-M; Ming, Y-C; Tsai, C-N; Pang, J-H S

2015-04-01

IFI27 is highly expressed in psoriatic lesions but its function has not been known. The present study aimed to explore its role in proliferation of epidermal keratinocytes. IFI27 knockdown and over-expression in keratinocytes were used to compare their proliferation, by MTT assay, apoptosis (by annexin V binding) and cell cycle progression by flow cytometry. Formation of cyclin A/CDK1 complex was examined by a co-immunoprecipitaion method. Anti-proliferation effects of IFI27 were also examined in vivo by topical application of IFI27 siRNA on imiquimod-induced psoriatic lesions, in a mouse model. Epidermal growth factor was demonstrated to increase IFI27 expression by prolonging half-life of IFI27 protein. The IFI27 knockdown in keratinocytes reduced the proliferation rate, but had no effect on apoptosis nor on apoptosis-related genes. Interestingly, IFI27 knockdown resulted in S-phase arrest that was found to be associated with increased Tyr15 phosphorylation of CDK1, reduced CDC25B and reduced formation of cyclin A/CDK1 complex. In addition, IFI27 knockdown was also shown to activate p53 by Ser15 phosphorylation and increase p21 expression. Topical application of IFI27 siRNA on imiquimod-induced psoriatic lesion in a mouse model reduced epidermal thickness, formation of rete ridges and PCNA expression. Our study demonstrates for the first time, that cell function of IFI27 is involved in proliferation of skin keratinocytes both in vitro and in vivo. It suggests that IFI27 might be a suitable target for development of a novel anti-psoriasis therapy. © 2015 John Wiley & Sons Ltd.

Inhibitory effect of Paeonia lactiflora Pallas extract (PE) on poly (I:C)-induced immune response of epidermal keratinocytes.

PubMed

Choi, Mi-Ra; Choi, Dae-Kyoung; Sohn, Kyung-Cheol; Lim, Seul Ki; Kim, Dong-Il; Lee, Young Ho; Im, Myung; Lee, Young; Seo, Young-Joon; Kim, Chang Deok; Lee, Jeung-Hoon

2015-01-01

Epidermal keratinocytes provide protective role against external stimuli by barrier formation. In addition, kertinocytes exerts their role as the defense cells via activation of innate immunity. Disturbance of keratinocyte functions is related with skin disorders. Psoriasis is a common skin disease related with inflammatory reaction in epidermal cells. We attempted to find therapeutics for psoriasis, and found that Paeonia lactiflora Pallas extract (PE) has an inhibitory potential on poly (I:C)-induced inflammation of keratinocytes. PE significantly inhibited poly (I:C)-induced expression of crucial psoriatic cytokines, such as IL-6, IL-8, CCL20 and TNF-α, via down-regulation of NF-κB signaling pathway in human keratinocytes. In addition, PE significantly inhibited poly (I:C)-induced inflammasome activation, in terms of IL-1β and caspase-1 secretion. Finally, PE markedly inhibited poly (I:C)-increased NLRP3, an important component of inflammasome. These results indicate that PE has an inhibitory effect on poly (I:C)-induced inflammatory reaction of keratinocytes, suggesting that PE can be developed for the treatment of psoriasis.

Galectin-7 overexpression is associated with the apoptotic process in UVB-induced sunburn keratinocytes

PubMed Central

Bernerd, Francoise; Sarasin, Alain; Magnaldo, Thierry

1999-01-01

Galectin-7 is a β-galactoside binding protein specifically expressed in stratified epithelia and notably in epidermis, but barely detectable in epidermal tumors and absent from squamous carcinoma cell lines. Galectin-7 gene is an early transcriptional target of the tumor suppressor protein P53 [Polyak, K., Xia, Y., Zweier, J., Kinzler, K. & Vogelstein, B. (1997) Nature (London) 389, 300–305]. Because p53 transcriptional activity is increased by genotoxic stresses we have examined the possible effects of ultraviolet radiations (UVB) on galectin-7 expression in epidermal keratinocytes. The amounts of galectin-7 mRNA and protein are increased rapidly after UVB irradiation of epidermal keratinocytes. The increase of galectin-7 is parallel to P53 stabilization. UVB irradiation of skin reconstructed in vitro and of human skin ex vivo demonstrates that galectin-7 overexpression is associated with sunburn/apoptotic keratinocytes. Transfection of a galectin-7 expression vector results in a significant increase in terminal deoxynucleotidyltransferase-mediated UTP end labeling-positive keratinocytes. The present findings demonstrate a keratinocyte-specific protein involved in the UV-induced apoptosis, an essential process in the maintenance of epidermal homeostasis. PMID:10500176

Tumor Necrosis Factor-alpha Induced Protein 3 Interacting Protein 1 Gene Polymorphisms and Pustular Psoriasis in Chinese Han Population

PubMed Central

Han, Jian-Wen; Wang, Yong; Alateng, Chulu; Li, Hong-Bin; Bai, Yun-Hua; Lyu, Xin-Xiang; Wu, Rina

2016-01-01

Background: Psoriasis is a common immune-mediated inflammatory dermatosis. Generalized pustular psoriasis (GPP) is the severe and rare type of psoriasis. The association between tumor necrosis factor-alpha induced protein 3 interacting protein 1 (TNIP1) gene and psoriasis was confirmed in people with multiple ethnicities. This study was to investigate the association between TNIP1 gene polymorphisms and pustular psoriasis in Chinese Han population. Methods: Seventy-three patients with GPP, 67 patients with palmoplantar pustulosis (PPP), and 476 healthy controls were collected from Chinese Han population. Six single nucleotide polymorphisms (SNPs) of the TNIP1 gene, namely rs3805435, rs3792798, rs3792797, rs869976, rs17728338, and rs999011 were genotyped by using polymerase chain reaction-ligase detection reaction. Statistical analyses were performed using the PLINK 1.07 package. Allele frequencies and genotyping frequencies for six SNPs were compared by using Chi-square test, odd ratio (OR) (including 95% confidence interval) were calculated. The haplotype analysis was conducted by Haploview software. Results: The frequencies of alleles of five SNPs were significantly different between the GPP group and the control group (P ≤ 7.22 × 10−3), especially in the GPP patients without psoriasis vulgaris (PsV). In the haplotype analysis, the most significantly different haplotype was H4: ACGAAC, with 13.1% frequency in the GPP group but only 3.4% in the control group (OR = 4.16, P = 4.459 × 10−7). However, no significant difference in the allele frequencies was found between the PPP group and control group for each of the six SNPs (P > 0.05). Conclusions: Polymorphisms in TNIP1 are associated with GPP in Chinese Han population. However, no association with PPP was found. These findings suggest that TNIP1 might be a susceptibility gene for GPP. PMID:27364786

AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking.

PubMed

Setta-Kaffetzi, Niovi; Simpson, Michael A; Navarini, Alexander A; Patel, Varsha M; Lu, Hui-Chun; Allen, Michael H; Duckworth, Michael; Bachelez, Hervé; Burden, A David; Choon, Siew-Eng; Griffiths, Christopher E M; Kirby, Brian; Kolios, Antonios; Seyger, Marieke M B; Prins, Christa; Smahi, Asma; Trembath, Richard C; Fraternali, Franca; Smith, Catherine H; Barker, Jonathan N; Capon, Francesca

2014-05-01

Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

A Dynamic Model for Prediction of Psoriasis Management by Blue Light Irradiation

PubMed Central

Félix Garza, Zandra C.; Liebmann, Joerg; Born, Matthias; Hilbers, Peter A. J.; van Riel, Natal A. W.

2017-01-01

Clinical investigations prove that blue light irradiation reduces the severity of psoriasis vulgaris. Nevertheless, the mechanisms involved in the management of this condition remain poorly defined. Despite the encouraging results of the clinical studies, no clear guidelines are specified in the literature for the irradiation scheme regime of blue light-based therapy for psoriasis. We investigated the underlying mechanism of blue light irradiation of psoriatic skin, and tested the hypothesis that regulation of proliferation is a key process. We implemented a mechanistic model of cellular epidermal dynamics to analyze whether a temporary decrease of keratinocytes hyper-proliferation can explain the outcome of phototherapy with blue light. Our results suggest that the main effect of blue light on keratinocytes impacts the proliferative cells. They show that the decrease in the keratinocytes proliferative capacity is sufficient to induce a transient decrease in the severity of psoriasis. To study the impact of the therapeutic regime on the efficacy of psoriasis treatment, we performed simulations for different combinations of the treatment parameters, i.e., length of treatment, fluence (also referred to as dose), and intensity. These simulations indicate that high efficacy is achieved by regimes with long duration and high fluence levels, regardless of the chosen intensity. Our modeling approach constitutes a framework for testing diverse hypotheses on the underlying mechanism of blue light-based phototherapy, and for designing effective strategies for the treatment of psoriasis. PMID:28184200

Psoriasis-associated vascular disease: the role of HDL.

PubMed

Paiva-Lopes, Maria Joao; Delgado Alves, José

2017-09-14

Psoriasis is a chronic inflammatory systemic disease with a prevalence of 2-3%. Overwhelming evidence show an epidemiological association between psoriasis, cardiovascular disease and atherosclerosis. Cardiovascular disease is the most frequent cause of death in patients with severe psoriasis. Several cardiovascular disease classical risk factors are also increased in psoriasis but the psoriasis-associated risk persists after adjusting for other risk factors.Investigation has focused on finding explanations for these epidemiological data. Several studies have demonstrated significant lipid metabolism and HDL composition and function alterations in psoriatic patients. Altered HDL function is clearly one of the mechanisms involved, as these particles are of the utmost importance in atherosclerosis defense. Recent data indicate that biologic therapy can reverse both structural and functional HDL alterations in psoriasis, reinforcing their therapeutic potential.

Generalized pustular psoriasis triggered by Zika virus infection.

PubMed

Paniz Mondolfi, A E; Hernandez Perez, M; Blohm, G; Marquez, M; Mogollon Mendoza, A; Hernandez-Pereira, C E; Escalona, M A; Lodeiro Colatosti, A; Rothe DeArocha, J; Rodriguez Morales, A J

2018-03-01

Zika virus is an emerging arbovirus, which is expanding in epidemic proportions through tropical and subtropical areas of the world. Although Zika is linked to a number of congenital and neurological complications, there is scarce knowledge on the impact of ZIKV infection in human skin. We report the case of a 68-year old woman who presented with generalized pustular psoriasis after a preceding and otherwise uneventful episode of ZIKV infection. Based on recent experimental data on the biology of ZIKV infection in the cutaneous environment, we speculate that ZIKV may have directly triggered the development of generalized pustular psoriasis by stimulation of keratinocyte-derived mediators of inflammation and a polyfunctional T-cell driven immune reaction in the cutaneous milieu. © 2017 British Association of Dermatologists.

Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.

PubMed

Nair, Rajan P; Duffin, Kristina Callis; Helms, Cynthia; Ding, Jun; Stuart, Philip E; Goldgar, David; Gudjonsson, Johann E; Li, Yun; Tejasvi, Trilokraj; Feng, Bing-Jian; Ruether, Andreas; Schreiber, Stefan; Weichenthal, Michael; Gladman, Dafna; Rahman, Proton; Schrodi, Steven J; Prahalad, Sampath; Guthery, Stephen L; Fischer, Judith; Liao, Wilson; Kwok, Pui-Yan; Menter, Alan; Lathrop, G Mark; Wise, Carol A; Begovich, Ann B; Voorhees, John J; Elder, James T; Krueger, Gerald G; Bowcock, Anne M; Abecasis, Gonçalo R

2009-02-01

Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation.

PubMed

Li, Hui; Yao, Qi; Mariscal, Alberto Garcia; Wu, Xudong; Hülse, Justus; Pedersen, Esben; Helin, Kristian; Waisman, Ari; Vinkel, Caroline; Thomsen, Simon Francis; Avgustinova, Alexandra; Benitah, Salvador Aznar; Lovato, Paola; Norsgaard, Hanne; Mortensen, Mette Sidsel; Veng, Lone; Rozell, Björn; Brakebusch, Cord

2018-04-12

The chronic skin inflammation psoriasis is crucially dependent on the IL-23/IL-17 cytokine axis. Although IL-23 is expressed by psoriatic keratinocytes and immune cells, only the immune cell-derived IL-23 is believed to be disease relevant. Here we use a genetic mouse model to show that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation with an IL-17 profile. Furthermore, we reveal a cell-autonomous nuclear function for the actin polymerizing molecule N-WASP, which controls IL-23 expression in keratinocytes by regulating the degradation of the histone methyltransferases G9a and GLP, and H3K9 dimethylation of the IL-23 promoter. This mechanism mediates the induction of IL-23 by TNF, a known inducer of IL-23 in psoriasis. Finally, in keratinocytes of psoriatic lesions a decrease in H3K9 dimethylation correlates with increased IL-23 expression, suggesting relevance for disease. Taken together, our data describe a molecular pathway where epigenetic regulation of keratinocytes can contribute to chronic skin inflammation.

The caspase-1 inhibitor CARD18 is specifically expressed during late differentiation of keratinocytes and its expression is lost in lichen planus.

PubMed

Qin, Haihong; Jin, Jiang; Fischer, Heinz; Mildner, Michael; Gschwandtner, Maria; Mlitz, Veronika; Eckhart, Leopold; Tschachler, Erwin

2017-08-01

CARD18 contains a caspase recruitment domain (CARD) via which it binds to caspase-1 and thereby inhibits caspase-1-mediated activation of the pro-inflammatory cytokine interleukin (IL)-1β. To determine the expression profile and the role of CARD18 during differentiation of keratinocytes and to compare the expression of CARD18 in normal skin and in inflammatory skin diseases. Human keratinocytes were induced to differentiate in monolayer and in 3D skin equivalent cultures. In some experiments, CARD18-specific siRNAs were used to knock down expression of CARD18. CARD18 mRNA levels were determined by quantitative real-time PCR, and CARD18 protein was detected by Western blot and immunofluorescence analyses. In situ expression was analyzed in skin biopsies obtained from healthy donors and patients with psoriasis and lichen planus. CARD18 mRNA was expressed in the epidermis at more than 100-fold higher levels than in any other human tissue. Within the epidermis, CARD18 was specifically expressed in the granular layer. In vitro CARD18 was strongly upregulated at both mRNA and protein levels in keratinocytes undergoing terminal differentiation. In skin equivalent cultures the expression of CARD18 was efficiently suppressed by siRNAs without impairing stratum corneum formation. Epidermal expression of CARD18 was increased after ultraviolet (UV)B irradiation of skin explants. In skin biopsies of patients with psoriasis no consistent regulation of CARD18 expression was observed, however, in lesional epidermis of patients with lichen planus, CARD18 expression was either greatly diminished or entirely absent whereas in non-lesional areas expression was comparable to normal skin. Our results identify CARD18 as a differentiation-associated keratinocyte protein that is altered in abundance by UV stress. Its downregulation in lichen planus indicates a potential role in inflammatory reactions of the epidermis in this disease. Copyright © 2017 Japanese Society for Investigative

Aberrant production of interleukin-8 and thrombospondin-1 by psoriatic keratinocytes mediates angiogenesis.

PubMed Central

Nickoloff, B. J.; Mitra, R. S.; Varani, J.; Dixit, V. M.; Polverini, P. J.

1994-01-01

Psoriasis is a common inherited skin disease that is characterized by hyperproliferation of epidermal keratinocytes and excessive dermal angiogenesis. A growing body of evidence supports a key pathogenetic role for activated keratinocytes in the angiogenic response that accompanies psoriasis. We investigated the role of psoriatic epidermis in the aberrant expression of angiogenesis by examining the ability of pure populations of multipassaged keratinocytes obtained from the skin of normal individuals and psoriatic patients to induce angiogenesis in vivo in the rat corneal bioassay and endothelial cell chemotaxis in vitro. Media conditioned by keratinocytes from psoriatic patients, including both symptomless skin and psoriatic plaques, induced vigorous angiogenic responses in over 90% of corneas tested and potently stimulated directional migration of capillary endothelial cells in vitro. In contrast, conditioned medium from normal keratinocyte cultures was weakly positive in less than 10% of corneas assayed and failed to stimulate endothelial cell chemotaxis. Furthermore, keratinocytes from psoriatic skin exhibited a 10- to 20-fold increase in interleukin-8 production and a seven-fold reduction in thrombospondin-1 production. The angiogenic activity present in keratinocyte-conditioned media from psoriatic patients was suppressed by adding either highly purified thrombospondin-1 (125 ng) or following the addition of either normal keratinocyte-conditioned media or neutralizing interleukin-8 antibody. We conclude that psoriatic keratinocytes are phenotypically different from normal keratinocytes with respect to their angiogenic capacity and that this aberrant phenotype is attributable to a defect in the overproduction of interleukin-8 and a deficiency in the production of the angiogenesis inhibitor thrombospondin-1. Images Figure 1 PMID:7512793

Indigo naturalis upregulates claudin-1 expression in human keratinocytes and psoriatic lesions.

PubMed

Lin, Yin-Ku; Chen, Hsiao-Wen; Leu, Yann-Lii; Yang, Yueh-Lung; Fang, Yu; Su Pang, Jong-Hwei; Hwang, Tsong-Long

2013-01-30

Indigo naturalis is used in traditional Chinese medicine to treat various dermatoses. Our previous clinical studies showed that indigo naturalis is an effective treatment for psoriasis. Herein, the capabilities of indigo naturalis extract and its derivatives to increase claudin-1 expression and tight junction (TJ) function in human keratinocytes and psoriatic lesions were further studied. Claudin-1 expression in psoriatic plaques with or without indigo naturalis treatment was analyzed by immunohistochemical methods. In primary human keratinocytes, the expression of claudin-1 was analyzed by fluorescent immunostaining, a real-time RT-PCR, and Western blot analysis. The effect of indigo naturalis on TJs was evaluated by measuring the transepithelial electrical resistance (TEER) and paracellular tracer flux. The indigo naturalis extract upregulated mRNA and protein expressions of claudin-1 and function of TJs in primary human keratinocytes in concentration-dependent manners. Its main components, indirubin, indigo, and tryptanthrin, exerted synergistic effects on upregulating TJ functions in primary human keratinocytes. In addition, indigo naturalis increased the activity of protein kinase C (PKC), and a known potent PKC inhibitor, Ro318220, attenuated the indigo naturalis-induced claudin-1 expression. Significantly, restoration of claudin-1 was observed in healed psoriatic lesions after indigo naturalis treatment. Indigo naturalis upregulates claudin-1 expression and restores TJ function in keratinocytes. Our data also suggest that indirubin, indigo, and tryptanthrin have a synergistic effect on TJ function. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses.

PubMed

Lambert, Sylviane; Swindell, William R; Tsoi, Lam C; Stoll, Stefan W; Elder, James T

2017-07-01

TRAF3IP2 is a candidate psoriasis susceptibility gene encoding Act1, an adaptor protein with ubiquitin ligase activity that couples the IL-17 receptor to downstream signaling pathways. We investigated the role of Act1 in keratinocyte responses to IL-17 using a tetracycline inducible short hairpin RNA targeting TRAF3IP2. Tetracycline exposure for 7 days effectively silenced TRAF3IP2 mRNA and Act1 protein, resulting in 761 genes with significant changes in expression (495 down, 266 up; >1.5-fold, P < 0.05). Gene ontology analysis showed that genes affected by TRAF3IP2 silencing are involved in epidermal differentiation, with early differentiation genes (KRT1, KRT10, DSC1, DSG1) being down-regulated and late differentiation genes (SPRR2, SPRR3, LCE3) being up-regulated. AP1 binding sites were enriched upstream of genes up-regulated by TRAF3IP2 silencing. Correspondingly, nuclear expression of FosB and Fra1 was increased in TRAF3IP2-silenced cells. Many genes involved in host defense were induced by IL-17 in a TRAF3IP2-dependent fashion. Inflammatory differentiation conditions (serum addition for 4 days postconfluence) markedly amplified these IL-17 responses and increased basal levels and TRAF3IP2 silencing-dependent up-regulation of multiple late differentiation genes. These findings suggest that TRAF3IP2 may alter both epidermal homeostasis and keratinocyte defense responses to influence psoriasis risk. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Tofacitinib Represses the Janus Kinase-Signal Transducer and Activators of Transcription Signalling Pathway in Keratinocytes.

PubMed

Srivastava, Ankit; Ståhle, Mona; Pivarcsi, Andor; Sonkoly, Enikö

2018-05-08

Tofacitinib is a Janus kinase (JAK) inhibitor, which has shown efficacy in treating psoriasis. The mode of action of tofacitinib is not completely understood but it has been thought to be mediated by the inhibition of CD4+ T-cell activation. Here, we investigated whether the molecular targets of tofacitinib are expressed in keratinocytes, and whether tofacitinib can modulate the activity of the JAK/Signal Transducer and Activators of Transcription (STAT)-pathway in keratinocytes. Transcriptomic profiling of human keratinocytes treated with IL-22 in combination with tofacitinib revealed that tofacitinib could prevent the majority of IL-22-mediated gene expression changes. Pathway analysis of tofacitinib-regulated genes in keratinocytes revealed enrichment of genes involved in the JAK/STAT signalling pathway. Quantitative real-time-PCR confirmed the upregulation of S100A7 and downregulation of EGR1 expression by IL-22, which was prevented by tofacitinib pre-treatment. These results indicate a direct effect of tofacinitib on keratinocytes, which can have relevance for systemic as well as for topical treatment of psoriasis with tofacitinib.

Acute guttate psoriasis patients have positive streptococcus hemolyticus throat cultures and elevated antistreptococcal M6 protein titers.

PubMed

Zhao, Guang; Feng, Xiaoling; Na, Aihua; Yongqiang, Jiang; Cai, Qing; Kong, Jian; Ma, Huijun

2005-02-01

To further study the role of Streptococci hemolyticus infection and streptococcal M6 protein in the pathogenesis of acute guttate psoriasis, streptococcal cultures were taken from the throats of 68 patients with acute guttate psoriasis. PCR technique was applied to detect M6 protein encoding DNA from those cultured streptococci. Pure M6 protein was obtained by Sephacry/S-200HR and Mono-Q chromatography from proliferated Streptococcus hemolyticus. Antistreptococcal M6 protein titers were measured in the serum of patients with acute guttate psoriasis, plaque psoriasis and healthy controls by ELISA. A high incidence of Streptococcus hemolyticus culture was observed in the guttate psoriatic group compared with the plaque psoriasis and control groups. Fourteen strains of Streptococcus hemolyticus were cultured from the throats of 68 acute guttate psoriasis patients. Of these, 5 strains contain DNA encoding the M6 protein gene as confirmed by PCR technique. More than 85% purification of M6 protein was obtained from Streptococcus pyogenes. Applying our pure M6 protein with the ELISA methods, we found that the titer of antistreptococcal M6 protein was significantly higher in the serum of guttate psoriasis patients than in the control or plaque psoriasis groups (P < 0.01). We verified that patients of acute guttate psoriasis have a high incidence of Streptococcus hemolyticus in their throats and raised titers of antistreptococcal M6 protein in their sera.

Immortalized N/TERT keratinocytes as an alternative cell source in 3D human epidermal models.

PubMed

Smits, Jos P H; Niehues, Hanna; Rikken, Gijs; van Vlijmen-Willems, Ivonne M J J; van de Zande, Guillaume W H J F; Zeeuwen, Patrick L J M; Schalkwijk, Joost; van den Bogaard, Ellen H

2017-09-19

The strong societal urge to reduce the use of experimental animals, and the biological differences between rodent and human skin, have led to the development of alternative models for healthy and diseased human skin. However, the limited availability of primary keratinocytes to generate such models hampers large-scale implementation of skin models in biomedical, toxicological, and pharmaceutical research. Immortalized cell lines may overcome these issues, however, few immortalized human keratinocyte cell lines are available and most do not form a fully stratified epithelium. In this study we compared two immortalized keratinocyte cell lines (N/TERT1, N/TERT2G) to human primary keratinocytes based on epidermal differentiation, response to inflammatory mediators, and the development of normal and inflammatory human epidermal equivalents (HEEs). Stratum corneum permeability, epidermal morphology, and expression of epidermal differentiation and host defence genes and proteins in N/TERT-HEE cultures was similar to that of primary human keratinocytes. We successfully generated N/TERT-HEEs with psoriasis or atopic dermatitis features and validated these models for drug-screening purposes. We conclude that the N/TERT keratinocyte cell lines are useful substitutes for primary human keratinocytes thereby providing a biologically relevant, unlimited cell source for in vitro studies on epidermal biology, inflammatory skin disease pathogenesis and therapeutics.

Association of Serum Uric Acid Levels in Psoriasis

PubMed Central

Li, Xin; Miao, Xiao; Wang, Hongshen; Wang, Yifei; Li, Fulun; Yang, Qiong; Cui, Rutao; Li, Bin

2016-01-01

Abstract High levels of serum uric acid (SUAC) are frequently detected in patients with psoriasis. However, the relationship between psoriasis and hyperuricemia remains unknown. Here we conducted a meta-analysis to identify the SUAC levels in subjects with psoriasis and to determine whether there is an associated risk between psoriasis and hyperuricemia. A comprehensive search of the literature from January 1980 to November 2014 across 7 databases (MEDLINE, Embase, Cochrane Central Register, and 4 Chinese databases) was conducted to determine whether there is an associated risk between psoriasis and hyperuricemia. Among the 170 identified reports, 14 observational studies were included in this meta-analysis. We found a significant higher SUAC level (MD 0.68, 95% CI 0.26–1.09; P = 0.002) in patients with psoriasis in Western Europe, but no significant differences were found between the East Asia and India subgroup (MD 1.22, 95% CI –0.13–2.56; P = 0.08) or the Middle East subgroup (MD 0.48, 95% CI –0.49–1.44; P = 0.33). Similar results were obtained from the meta-analysis of SUAC levels in subjects with severe psoriasis. Our meta-analysis showed that the correlation between psoriasis and hyperuricemia was either ethnicity- or region-dependent and that patients with psoriasis in Western Europe were more likely to have hyperuricemia. PMID:27175702

A novel DLX3-PKC integrated signaling network drives keratinocyte differentiation.

PubMed

Palazzo, Elisabetta; Kellett, Meghan D; Cataisson, Christophe; Bible, Paul W; Bhattacharya, Shreya; Sun, Hong-Wei; Gormley, Anna C; Yuspa, Stuart H; Morasso, Maria I

2017-04-01

Epidermal homeostasis relies on a well-defined transcriptional control of keratinocyte proliferation and differentiation, which is critical to prevent skin diseases such as atopic dermatitis, psoriasis or cancer. We have recently shown that the homeobox transcription factor DLX3 and the tumor suppressor p53 co-regulate cell cycle-related signaling and that this mechanism is functionally involved in cutaneous squamous cell carcinoma development. Here we show that DLX3 expression and its downstream signaling depend on protein kinase C α (PKCα) activity in skin. We found that following 12-O-tetradecanoyl-phorbol-13-acetate (TPA) topical treatment, DLX3 expression is significantly upregulated in the epidermis and keratinocytes from mice overexpressing PKCα by transgenic targeting (K5-PKCα), resulting in cell cycle block and terminal differentiation. Epidermis lacking DLX3 (DLX3cKO), which is linked to the development of a DLX3-dependent epidermal hyperplasia with hyperkeratosis and dermal leukocyte recruitment, displays enhanced PKCα activation, suggesting a feedback regulation of DLX3 and PKCα. Of particular significance, transcriptional activation of epidermal barrier, antimicrobial peptide and cytokine genes is significantly increased in DLX3cKO skin and further increased by TPA-dependent PKC activation. Furthermore, when inhibiting PKC activity, we show that epidermal thickness, keratinocyte proliferation and inflammatory cell infiltration are reduced and the PKC-DLX3-dependent gene expression signature is normalized. Independently of PKC, DLX3 expression specifically modulates regulatory networks such as Wnt signaling, phosphatase activity and cell adhesion. Chromatin immunoprecipitation sequencing analysis of primary suprabasal keratinocytes showed binding of DLX3 to the proximal promoter regions of genes associated with cell cycle regulation, and of structural proteins and transcription factors involved in epidermal differentiation. These results indicate

Imiquimod-induced psoriasis-like inflammation in differentiated Human keratinocytes: Its evaluation using curcumin.

PubMed

Varma, Sandeep R; Sivaprakasam, Thiyagarajan O; Mishra, Abheepsa; Prabhu, Sunil; M, Rafiq; P, Rangesh

2017-10-15

Psoriasis is considered to be a systemic disease of immune dysfunction. It is still unclear what triggers the inflammatory cascade associated with psoriasis but recent evidences suggest the vital role of IL-23/IL-17A cytokine axis in etiology of psoriasis. Several studies have been conducted in psoriatic-like animal models but ethical issues and complexity surrounding it halts the screening of new anti-psoriatic drug candidates. Hence, in this study, we developed a new in-vitro model for psoriasis using imiquimod (IMQ) induced differentiated HaCaT cells which could be used for screening of new anti-psoriatic drug candidates. The differentiated HaCaT cells were treated with IMQ (100μM) to induce psoriatic like inflammation and its effect was investigated using a natural anti-psoriatic compound, curcumin. The proliferation of psoriatic-like cells was inhibited by curcumin at 25 and 50µM concentrations. The psoriatic-like cells decreased in number with increase in apoptotic and dead cells upon curcumin treatment. Curcumin inhibited the proliferation of IMQ-induced differentiated HaCaT cells (Psoriatic-like cells) by down-regulation of pro-inflammatory cytokines, interleukin-17, tumor necrosis factor-α, interferon-γ, and interleukin-6. Apart from this, curcumin significantly enhanced the skin-barrier function by up-regulation of involucrin (iNV) and filaggrin (FLG), the regulators of epidermal skin barrier. The IMQ-induced differentiated HaCaT in vitro model recapitulated some aspects of the psoriasis pathogenesis similar to murine model. Henceforth, we conclude that this model may be used for rapid screening of anti-psoriatic drug candidates and warrant further mechanistic studies. Copyright © 2017 Elsevier B.V. All rights reserved.

New insights of T cells in the pathogenesis of psoriasis

PubMed Central

Cai, Yihua; Fleming, Chris; Yan, Jun

2012-01-01

Psoriasis is one of the most common immune-mediated chronic, inflammatory skin diseases characterized by hyperproliferative keratinocytes and infiltration of T cells, dendritic cells, macrophages and neutrophils. Although the pathogenesis of psoriasis is not fully understood, there is ample evidence suggesting that the dysregulation of immune cells in the skin, particularly T cells, plays a critical role in psoriasis development. In this review, we mainly focus on the pathogenic T cells and discuss how these T cells are activated and involved in the disease pathogenesis. Newly identified ‘professional' IL-17-producing dermal γδ T cells and their potential role in psoriasis will also be included. Finally, we will briefly summarize the recent progress on the T cell and its related cytokine-targeted therapy for psoriasis treatment. PMID:22705915

Cross-disease transcriptomics: Unique IL-17A signaling in psoriasis lesions and an autoimmune PBMC signature

PubMed Central

Sarkar, Mrinal K.; Liang, Yun; Xing, Xianying; Gudjonsson, Johann E.

2016-01-01

Transcriptome studies of psoriasis have identified robust changes in mRNA expression through large-scale analysis of patient cohorts. These studies, however, have analyzed all mRNA changes in aggregate, without distinguishing between disease-specific and non-specific differentially expressed genes (DEGs). In this study, RNA-seq meta-analysis was used to identify (1) psoriasis-specific DEGs altered in few diseases besides psoriasis and (2) non-specific DEGs similarly altered in many other skin conditions. We show that few cutaneous DEGs are psoriasis-specific and that the two DEG classes differ in their cell type and cytokine associations. Psoriasis-specific DEGs are expressed by keratinocytes and induced by IL-17A, whereas non-specific DEGs are expressed by inflammatory cells and induced by IFN-gamma and TNF. PBMC-derived DEGs were more psoriasis-specific than cutaneous DEGs. Nonetheless, PBMC DEGs associated with MHC class I and NK cells were commonly downregulated in psoriasis and other autoimmune diseases (e.g., multiple sclerosis, sarcoidosis and juvenile rheumatoid arthritis). These findings demonstrate “cross-disease” transcriptomics as an approach to gain insights into the cutaneous and non-cutaneous psoriasis transcriptomes. This highlighted unique contributions of IL-17A to the cytokine network and uncovered a blood-based gene signature that links psoriasis to other diseases of autoimmunity. PMID:27206706

A novel DLX3–PKC integrated signaling network drives keratinocyte differentiation

PubMed Central

Palazzo, Elisabetta; Kellett, Meghan D; Cataisson, Christophe; Bible, Paul W; Bhattacharya, Shreya; Sun, Hong-wei; Gormley, Anna C; Yuspa, Stuart H; Morasso, Maria I

2017-01-01

Epidermal homeostasis relies on a well-defined transcriptional control of keratinocyte proliferation and differentiation, which is critical to prevent skin diseases such as atopic dermatitis, psoriasis or cancer. We have recently shown that the homeobox transcription factor DLX3 and the tumor suppressor p53 co-regulate cell cycle-related signaling and that this mechanism is functionally involved in cutaneous squamous cell carcinoma development. Here we show that DLX3 expression and its downstream signaling depend on protein kinase C α (PKCα) activity in skin. We found that following 12-O-tetradecanoyl-phorbol-13-acetate (TPA) topical treatment, DLX3 expression is significantly upregulated in the epidermis and keratinocytes from mice overexpressing PKCα by transgenic targeting (K5-PKCα), resulting in cell cycle block and terminal differentiation. Epidermis lacking DLX3 (DLX3cKO), which is linked to the development of a DLX3-dependent epidermal hyperplasia with hyperkeratosis and dermal leukocyte recruitment, displays enhanced PKCα activation, suggesting a feedback regulation of DLX3 and PKCα. Of particular significance, transcriptional activation of epidermal barrier, antimicrobial peptide and cytokine genes is significantly increased in DLX3cKO skin and further increased by TPA-dependent PKC activation. Furthermore, when inhibiting PKC activity, we show that epidermal thickness, keratinocyte proliferation and inflammatory cell infiltration are reduced and the PKC-DLX3-dependent gene expression signature is normalized. Independently of PKC, DLX3 expression specifically modulates regulatory networks such as Wnt signaling, phosphatase activity and cell adhesion. Chromatin immunoprecipitation sequencing analysis of primary suprabasal keratinocytes showed binding of DLX3 to the proximal promoter regions of genes associated with cell cycle regulation, and of structural proteins and transcription factors involved in epidermal differentiation. These results indicate

Metabolic syndrome, C-reactive protein and cardiovascular risk in psoriasis patients: a cross-sectional study*

PubMed Central

Paschoal, Renato Soriani; Silva, Daniela Antoniali; Cardili, Renata Nahas; Souza, Cacilda da Silva

2018-01-01

Background Psoriasis has been associated with co-morbidities and elevated cardiovascular risk. Objectives To analyze the relationships among metabolic syndrome, cardiovascular risk, C-reactive protein, gender, and Psoriasis severity. Methods In this cross-sectional study, plaque Psoriasis patients (n=90), distributed equally in gender, were analyzed according to: Psoriasis Area and Severity Index, cardiovascular risk determined by the Framingham risk score and global risk assessment, C-reactive protein and metabolic syndrome criteria (NCEPT-ATP III). Results Metabolic syndrome frequency was 43.3% overall, without significance between genders (P=0.14); but women had higher risk for obesity (OR 2.56, 95%CI 1.02-6.41; P=0.04) and systemic arterial hypertension (OR 3.29, 95%CI 1.39-7.81; P=0.006). The increase in the Psoriasis Area and Severity Index also increased the risk for metabolic syndrome (OR 1.060, 95%CI 1.006-1.117; P=0.03). Absolute 10-year cardiovascular risk was higher in males (P=0.002), but after global risk assessment, 51.1% patients, 52.2% women, were re-classified as high-intermediate cardiovascular risk; without significance between genders (P=0.83). C-reactive protein level was elevated nearly six-fold overall, higher in metabolic syndrome (P=0.05), systemic arterial hypertension (P=0.004), and high-intermediate 10-year cardiovascular risk patients (P<0.001); positively correlated to: Framingham risk score (P<0.001; r=0.60), absolute 10-year cardiovascular risk (P<0.001; r=0.58), and age (P=0.001; r=0.35); but not to Psoriasis Area and Severity Index (P=0.14; r=0.16); increased the 10-year cardiovascular risk (R2=33.6; P<0.001), MetS risk (OR 1.17, 95%CI 0.99-1.37; P=0.05) and with age (P=0.001). HDL-cholesterol level was higher in normal C-reactive protein patients (t=1.98; P=0.05). Study limitations Restricted sample, hospital-based and representative of a single center and no specification of psoriatic arthritis. Conclusions Psoriasis, metabolic

Psoriasis or not? Review of 51 clinically confirmed cases reveals an expanded histopathologic spectrum of psoriasis.

PubMed

Chau, Thinh; Parsi, Kory K; Ogawa, Toru; Kiuru, Maija; Konia, Thomas; Li, Chin-Shang; Fung, Maxwell A

2017-12-01

Psoriasis is usually diagnosed clinically, so only non-classic or refractory cases tend to be biopsied. Diagnostic uncertainty persists when dermatopathologists encounter features regarded as non-classic for psoriasis. Define and document classic and non-classic histologic features in skin biopsies from patients with clinically confirmed psoriasis. Minimal clinical diagnostic criteria were informally validated and applied to a consecutive series of biopsies histologically consistent with psoriasis. Clinical confirmation required 2 of the following criteria: (1) classic morphology, (2) classic distribution, (3) nail pitting, and (4) family history, with #1 and/or #2 as 1 criterion in every case RESULTS: Fifty-one biopsies from 46 patients were examined. Classic features of psoriasis included hypogranulosis (96%), club-shaped rete ridges (96%), dermal papilla capillary ectasia (90%), Munro microabscess (78%), suprapapillary plate thinning (63%), spongiform pustules (53%), and regular acanthosis (14%). Non-classic features included irregular acanthosis (84%), junctional vacuolar alteration (76%), spongiosis (76%), dermal neutrophils (69%), necrotic keratinocytes (67%), hypergranulosis (65%), neutrophilic spongiosis (61%), dermal eosinophils (49%), compact orthokeratosis (37%), papillary dermal fibrosis (35%), lichenoid infiltrate (25%), plasma cells (16%), and eosinophilic spongiosis (8%). Psoriasis exhibits a broader histopathologic spectrum. The presence of some non-classic features does not necessarily exclude the possibility of psoriasis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Protein kinase C negatively regulates Akt activity and modifies UVC-induced apoptosis in mouse keratinocytes.

PubMed

Li, Luowei; Sampat, Keeran; Hu, Nancy; Zakari, Julia; Yuspa, Stuart H

2006-02-10

Skin keratinocytes are subject to frequent chemical and physical injury and have developed elaborate cell survival mechanisms to compensate. Among these, the Akt/protein kinase B (PKB) pathway protects keratinocytes from the toxic effects of ultraviolet light (UV). In contrast, the protein kinase C (PKC) family is involved in several keratinocyte death pathways. During an examination of potential interactions among these two pathways, we found that the insulin-like growth factor (IGF-1) activates both the PKC and the Akt signaling pathways in cultured primary mouse keratinocytes as indicated by increased phospho-PKC and phospho-Ser-473-Akt. IGF-1 also selectively induced translocation of PKCdelta and PKCepsilon from soluble to particulate fractions in mouse keratinocytes. Furthermore, the PKC-specific inhibitor, GF109203X, increased IGF-1-induced phospho-Ser-473-Akt and Akt kinase activity and enhanced IGF-1 protection from UVC-induced apoptosis. Selective activation of PKC by 12-O-tetradecanoylphorbol-13-acetate (TPA) reduced phospho-Ser-473-Akt, suggesting that activation of PKC inhibits Akt activity. TPA also attenuated IGF-1 and epidermal growth factor-induced phospho-Ser-473-Akt, reduced Akt kinase activity, and blocked IGF-1 protection from UVC-induced apoptosis. The inhibition of Akt activity by TPA was reduced by inhibitors of protein phosphatase 2A, and TPA stimulated the association of phosphatase 2A with Akt. Individual PKC isoforms were overexpressed in cultured keratinocytes by transduction with adenoviral vectors or inhibited with PKC-selective inhibitors. These studies indicated that PKCdelta and PKCepsilon were selectively potent at causing dephosphorylation of Akt and modifying cell survival, whereas PKCalpha enhanced phosphorylation of Akt on Ser-473. Our results suggested that activation of PKCdelta and PKCepsilon provide a negative regulation for Akt phosphorylation and kinase activity in mouse keratinocytes and serve as modulators of cell

Th17 cell-mediated immune responses promote mast cell proliferation by triggering stem cell factor in keratinocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cho, Kyung-Ah; Park, Minhwa; Kim, Yu-Hee

Although mast cells are traditionally thought to function as effector cells in allergic responses, they have increasingly been recognized as important regulators of various immune responses. Mast cells mature locally; thus, tissue-specific influences are important for promoting mast cell accumulation and survival in the skin and the gastrointestinal tract. In this study, we determined the effects of keratinocytes on mast cell accumulation during Th17-mediated skin inflammation. We observed increases in dermal mast cells in imiquimod-induced psoriatic dermatitis in mice accompanied by the expression of epidermal stem cell factor (SCF), a critical mast cell growth factor. Similar to mouse epidermal keratinocytes,more » SCF was highly expressed in the human HaCaT keratinocyte cell line following stimulation with IL−17. Further, keratinocytes promoted mast cell proliferation following stimulation with IL−17 in vitro. However, the effects of keratinocytes on mast cells were significantly diminished in the presence of anti−CD117 (stem cell factor receptor) blocking antibodies. Taken together, our results revealed that the Th17-mediated inflammatory environment promotes mast cell accumulation through keratinocyte-derived SCF. - Highlights: • Psoriasis-like skin inflammation increase dermal mast cells. • Keratinocyte produce stem cell factor in psoriasis-like skin inflammation. • Keratinocyte promote mast cell proliferation by stem cell factor dependent manner.« less

Deciphering psoriasis. A bioinformatic approach.

PubMed

Melero, Juan L; Andrades, Sergi; Arola, Lluís; Romeu, Antoni

2018-02-01

Psoriasis is an immune-mediated, inflammatory and hyperproliferative disease of the skin and joints. The cause of psoriasis is still unknown. The fundamental feature of the disease is the hyperproliferation of keratinocytes and the recruitment of cells from the immune system in the region of the affected skin, which leads to deregulation of many well-known gene expressions. Based on data mining and bioinformatic scripting, here we show a new dimension of the effect of psoriasis at the genomic level. Using our own pipeline of scripts in Perl and MySql and based on the freely available NCBI Gene Expression Omnibus (GEO) database: DataSet Record GDS4602 (Series GSE13355), we explore the extent of the effect of psoriasis on gene expression in the affected tissue. We give greater insight into the effects of psoriasis on the up-regulation of some genes in the cell cycle (CCNB1, CCNA2, CCNE2, CDK1) or the dynamin system (GBPs, MXs, MFN1), as well as the down-regulation of typical antioxidant genes (catalase, CAT; superoxide dismutases, SOD1-3; and glutathione reductase, GSR). We also provide a complete list of the human genes and how they respond in a state of psoriasis. Our results show that psoriasis affects all chromosomes and many biological functions. If we further consider the stable and mitotically inheritable character of the psoriasis phenotype, and the influence of environmental factors, then it seems that psoriasis has an epigenetic origin. This fit well with the strong hereditary character of the disease as well as its complex genetic background. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

The 3'UTR 1188A/C polymorphism of IL-12p40 is not associated with susceptibility for developing plaque psoriasis in Mestizo population from western Mexico.

PubMed

Sandoval-Talamantes, Ana Karen; Brito-Luna, Myrian Johanna; Fafutis-Morris, Mary; Villanueva-Quintero, Delfina Guadalupe; Graciano-Machuca, Omar; Ramírez-Dueñas, María Guadalupe; Alvarado-Navarro, Anabell

2015-02-01

Psoriasis is a chronic autoimmune inflammatory disease that affects the skin and the joints. Psoriasis is characterized by the keratinocyte proliferation, which is induced by cytokines Th1 and Th17. Patients with plaque psoriasis present a chronic inflammatory response with high levels of interleukin (IL)-12 and IL-23. Various single-nucleotide polymorphisms (SNP) have been identified in the IL12B gene, such as SNP 3' UTR 1188 A/C (SNP rs3212227), which has been associated with susceptibility to developing plaque psoriasis and with the production of IL-12 and IL-23 in individuals of different ethnic groups. In this study, we determined whether there is an association of SNP rs3212227 with the susceptibility of developing plaque psoriasis and with serum levels of IL-12 and IL-23 in Mestizo population in western Mexico. We included 112 patients with psoriasis and 112 clinical healthy individuals in the study. The frequencies of genotypes A/A, A/C, and C/C in patients with plaque psoriasis were 41, 53, and 6%, respectively, while in the control group, these were 37, 53, and 10%, respectively, without finding statistically significant differences between both groups (p>0.05). Although IL-12 and IL-23 serum levels were higher in patients than in controls, we found no significant differences. The group of patients with genotype CC presented the highest levels of IL-23 (p<0.05). These data suggest that the SNP rs3212227 phenotype is not associated with the risk of developing plaque psoriasis or with IL-12 and IL-23 levels in Mestizo population in western Mexico. Copyright © 2014 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

All-trans-retinoic acid and 13-cis-retinoic acid: pharmacokinetics and biological activity in different cell culture models of human keratinocytes.

PubMed

Schroeder, M; Zouboulis, C C

2007-02-01

Despite its known biological effect on epithelial cells, 13- CIS-retinoic acid shows low binding affinity to either cellular retinoic acid-binding proteins or nuclear retinoid receptors compared to its isomer all- TRANS-retinoic acid. We have postulated a prodrug-drug relation with 13- CIS-retinoic acid which isomerizes to all- TRANS-retinoic acid. On the other hand, the biological effects of these two compounds can differ in the widely used cell culture models of HaCaT and normal primary keratinocytes. In this study, we seeded HaCaT and normal keratinocytes at high densities leading to early confluence in order to imitate high keratinocyte proliferation, such as in acne and psoriasis, while to model decreased keratinocyte proliferation, as in aged and steroid-damaged skin, cells were seeded at a low density. High performance liquid chromatography was administered to examine retinoid uptake and metabolism in monolayer HaCaT and normal keratinocyte cultures and the 4-methylumbelliferyl heptanoate assay to estimate cell growth at different cell densities. Major qualitative and quantitative differences were detected in the two cell types regarding intracellular 13- CIS-retinoic acid isomerization to all- TRANS-retinoic acid. On the other hand, the two retinoic acid isomers showed similar effects on cell growth of both cell types tested with increasing proliferation at low cell densities, but being rather inactive at high ones in normal keratinocytes and exhibiting an antiproliferative effect in HaCaT keratinocytes. The missing effect of retinoids on cell proliferation in high seeding densities of normal keratinocytes may indicate that the normalizing activity of retinoids on hyperkeratotic diseases, such as acne or psoriasis, is likely to be carried out by modulation of cell differentiation than cell growth. On the other hand, induced keratinocyte proliferation in low seeding densities may provide an explanation for the acanthosis induced by topical retinoids in aged

Cyclooxygenases in human and mouse skin and cultured human keratinocytes: association of COX-2 expression with human keratinocyte differentiation

NASA Technical Reports Server (NTRS)

Leong, J.; Hughes-Fulford, M.; Rakhlin, N.; Habib, A.; Maclouf, J.; Goldyne, M. E.

1996-01-01

Epidermal expression of the two isoforms of the prostaglandin H-generating cyclooxygenase (COX-1 and COX-2) was evaluated both by immunohistochemistry performed on human and mouse skin biopsy sections and by Western blotting of protein extracts from cultured human neonatal foreskin keratinocytes. In normal human skin, COX-1 immunostaining is observed throughout the epidermis whereas COX-2 immunostaining increases in the more differentiated, suprabasilar keratinocytes. Basal cell carcinomas express little if any COX-1 or COX-2 immunostaining whereas both isozymes are strongly expressed in squamous cell carcinomas deriving from a more differentiated layer of the epidermis. In human keratinocyte cultures, raising the extracellular calcium concentration, a recognized stimulus for keratinocyte differentiation, leads to an increased expression of both COX-2 protein and mRNA; expression of COX-1 protein, however, shows no significant alteration in response to calcium. Because of a recent report that failed to show COX-2 in normal mouse epidermis, we also looked for COX-1 and COX-2 immunostaining in sections of normal and acetone-treated mouse skin. In agreement with a previous report, some COX-1, but no COX-2, immunostaining is seen in normal murine epidermis. However, following acetone treatment, there is a marked increase in COX-1 expression as well as the appearance of significant COX-2 immunostaining in the basal layer. These data suggest that in human epidermis as well as in human keratinocyte cultures, the expression of COX-2 occurs as a part of normal keratinocyte differentiation whereas in murine epidermis, its constitutive expression is absent, but inducible as previously published.

Atypical Diabetic Foot Ulcer Keratinocyte Protein Signaling Correlates with Impaired Wound Healing.

PubMed

Hoke, Glenn D; Ramos, Corrine; Hoke, Nicholas N; Crossland, Mary C; Shawler, Lisa G; Boykin, Joseph V

2016-01-01

Diabetes mellitus is associated with chronic diabetic foot ulcers (DFUs) and wound infections often resulting in lower extremity amputations. The protein signaling architecture of the mechanisms responsible for impaired DFU healing has not been characterized. In this preliminary clinical study, the intracellular levels of proteins involved in signal transduction networks relevant to wound healing were non-biasedly measured using reverse-phase protein arrays (RPPA) in keratinocytes isolated from DFU wound biopsies. RPPA allows for the simultaneous documentation and assessment of the signaling pathways active in each DFU. Thus, RPPA provides for the accurate mapping of wound healing pathways associated with apoptosis, proliferation, senescence, survival, and angiogenesis. From the study data, we have identified potential diagnostic, or predictive, biomarkers for DFU wound healing derived from the ratios of quantified signaling protein expressions within interconnected pathways. These biomarkers may allow physicians to personalize therapeutic strategies for DFU management on an individual basis based upon the signaling architecture present in each wound. Additionally, we have identified altered, interconnected signaling pathways within DFU keratinocytes that may help guide the development of therapeutics to modulate these dysregulated pathways, many of which parallel the therapeutic targets which are the hallmarks of molecular therapies for treating cancer.

Atypical Diabetic Foot Ulcer Keratinocyte Protein Signaling Correlates with Impaired Wound Healing

PubMed Central

Hoke, Glenn D.; Ramos, Corrine; Hoke, Nicholas N.; Crossland, Mary C.; Shawler, Lisa G.

2016-01-01

Diabetes mellitus is associated with chronic diabetic foot ulcers (DFUs) and wound infections often resulting in lower extremity amputations. The protein signaling architecture of the mechanisms responsible for impaired DFU healing has not been characterized. In this preliminary clinical study, the intracellular levels of proteins involved in signal transduction networks relevant to wound healing were non-biasedly measured using reverse-phase protein arrays (RPPA) in keratinocytes isolated from DFU wound biopsies. RPPA allows for the simultaneous documentation and assessment of the signaling pathways active in each DFU. Thus, RPPA provides for the accurate mapping of wound healing pathways associated with apoptosis, proliferation, senescence, survival, and angiogenesis. From the study data, we have identified potential diagnostic, or predictive, biomarkers for DFU wound healing derived from the ratios of quantified signaling protein expressions within interconnected pathways. These biomarkers may allow physicians to personalize therapeutic strategies for DFU management on an individual basis based upon the signaling architecture present in each wound. Additionally, we have identified altered, interconnected signaling pathways within DFU keratinocytes that may help guide the development of therapeutics to modulate these dysregulated pathways, many of which parallel the therapeutic targets which are the hallmarks of molecular therapies for treating cancer. PMID:27840833

Serum peptides as putative modulators of inflammation in psoriasis.

PubMed

Matsuura, Tetsuhiko; Sato, Masaaki; Nagai, Kouhei; Sato, Toshiyuki; Arito, Mitsumi; Omoteyama, Kazuki; Suematsu, Naoya; Okamoto, Kazuki; Kato, Tomohiro; Soma, Yoshinao; Kurokawa, Manae S

2017-07-01

Psoriasis is a refractory inflammatory disease, however, its pathophysiology is still not fully understood. We tried to identify novel serum peptides associated with the pathophysiology of psoriasis. Serum peptides from 24 patients with psoriasis vulgaris (PV), 10 patients with psoriatic arthritis (PsA), 14 patients with atopic dermatitis (AD), and 23 healthy control (HC) subjects were analyzed by mass spectrometry. The effects of some peptides on the secretion of humoral factors from dermal cells were investigated by cytokine arrays and ELISAs. A total of 93 peptides were detected. 24, 20, 23, and 2 peptides showed at least 1.2-fold difference in ion intensity between the psoriasis (PV+PsA) and HC groups, between the PV+PsA and AD groups, between the PV and PsA groups, and between patients with severe-to-moderate PV (n=6) and those with mild PV (n=18), respectively (p<0.05). 13 out of 27 peptides that showed at least 1.5-fold ion intensity difference in the abovementioned 4 comparisons were identified. The parent proteins of the identified peptides included a coagulation factor, proteins involved in the maintenance of skin, and a protein relating to cytoskeleton. We focused on 2 peptides that were increased in the PV+PsA group: a fibrinogen α chain-derived peptide (1462m/z), the unmodified form of which was fibrinopeptide A-des-alanine (FPAdA), and a filaggrin (FLG)-derived peptide (1977m/z), a modified form of FLG 2099-2118 (Q 2099 pE, Q 2115 E; FLG-pEE). FPAdA stimulation increased the secretion of GROα from dermal microvascular endothelial cells (dMVECs) and decreased the secretion of lipocalin-2 from keratinocytes in comparison to FPAdA-resequenced peptide stimulation (GROα, 280.9±7.3pg/mL vs. 229.6±5.0pg/mL, p<0.001; lipocalin-2, 273±13pg/mL vs. 350±10pg/mL, p<0.01). Interestingly, FLG-pEE stimulation decreased the secretion of GROα, IL-8, and MCP-1 from dMVECs in comparison to FLG-derived control peptide stimulation (GROα, 844.3±47.5pg/mL vs. 1038

Melanosome uptake is associated with the proliferation and differentiation of keratinocytes.

PubMed

Choi, Hye-In; Sohn, Kyung-Cheol; Hong, Dong-Kyun; Lee, Young; Kim, Chang Deok; Yoon, Tae-Jin; Park, Jin Woon; Jung, Sunggyun; Lee, Jeung-Hoon; Lee, Young Ho

2014-01-01

Melanosomes are synthesized in melanocytes and transferred to neighboring keratinocytes. However, the associations of melanosome uptake with the proliferation and differentiation of keratinocytes are not fully understood. We examined the associations of melanosome uptake with keratinocyte differentiation and proliferation. SV40T-transformed human epidermal keratinocytes (SV-HEKs) were treated with isolated melanosomes. The effects of melanosome uptake on the proliferation and differentiation of the keratinocytes were analyzed by Western blotting and flow cytometry. The relationship between melanosome uptake and keratinocyte differentiation status was verified by determining the melanin content in the cells. Melanosomes reduced the proliferation of SV-HEKs in a dose-dependent manner, but did not induce differentiation. Melanosome uptake was higher in differentiating keratinocytes compared to non-differentiating keratinocytes, and inhibited significantly by PAR-2 inhibitor. Melanosomes inhibit keratinocyte proliferation. Moreover, melanosome uptake is influenced by keratinocyte differentiation status, being highest in mid-stage differentiating keratinocytes in a PAR-2 dependent manner.

Inhibition of TYK2 and JAK1 Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis by Inhibiting IL-22 and the IL-23/IL-17 axis

PubMed Central

Works, Melissa G.; Yin, Fangfang; Yin, Catherine C.; Yiu, Ying; Shew, Kenneth; Tran, Thanh-Thuy; Dunlap, Nahoko; Lam, Jennifer; Mitchell, Tim; Reader, John; Stein, Paul L.; D’Andrea, Annalisa

2014-01-01

Psoriasis is a chronic autoimmune disease affecting the skin and characterized by aberrant keratinocyte proliferation and function. Immune cells infiltrate the skin and release proinflammatory cytokines that play important roles in psoriasis. The Th17 network, including IL-23 and IL-22, has recently emerged as a critical component in the pathogenesis of psoriasis. IL-22 and IL-23 signaling is dependent on the JAK family of protein tyrosine kinases, making Janus kinase (JAK) inhibition an appealing strategy for the treatment of psoriasis. Here we report the activity of SAR-20347, a small molecule inhibitor with specificity for JAK1 and Tyrosine Kinase 2 (TYK2) over other JAK family members. In cellular assays, SAR-20347 dose-dependently (1 nM-10 μM) inhibited JAK1 and/or TYK2 dependent signaling from the IL-12/IL-23, IL-22, and IFN-α receptors. In vivo, TYK2 mutant mice or treatment of wild type mice with SAR-20347 significantly reduced IL-12 induced IFN-γ production and IL-22-dependent Serum Amyloid A (SAA) to similar extents, indicating that in these models, SAR-20347 is probably acting through inhibition of TYK2. In an imiquimod-induced psoriasis model, the administration of SAR-20347 led to a striking decrease in disease pathology, including reduced activation of keratinocytes, and proinflammatory cytokine levels compared to both TYK2 mutant mice and wild type controls. Taken together, these data indicate that targeting both JAK1 and TYK2-mediated cytokine signaling is more effective than TYK2 inhibition alone in reducing psoriasis pathogenesis. PMID:25156366

Conditional analysis identifies three novel major histocompatibility complex loci associated with psoriasis.

PubMed

Knight, Jo; Spain, Sarah L; Capon, Francesca; Hayday, Adrian; Nestle, Frank O; Clop, Alex; Barker, Jonathan N; Weale, Michael E; Trembath, Richard C

2012-12-01

Psoriasis is a common, chronic, inflammatory skin disorder. A number of genetic loci have been shown to confer risk for psoriasis. Collectively, these offer an integrated model for the inherited basis for susceptibility to psoriasis that combines altered skin barrier function together with the dysregulation of innate immune pathogen sensing and adap-tive immunity. The major histocompatibility complex (MHC) harbours the psoriasis susceptibility region which exhibits the largest effect size, driven in part by variation contained on the HLA-Cw*0602 allele. However, the resolution of the number and genomic location of potential independent risk loci are hampered by extensive linkage disequilibrium across the region. We leveraged the power of large psoriasis case and control data sets and the statistical approach of conditional analysis to identify potential further association signals distributed across the MHC. In addition to the major loci at HLA-C (P = 2.20 × 10(-236)), we observed and replicated four additional independent signals for disease association, three of which are novel. We detected evidence for association at SNPs rs2507971 (P = 6.73 × 10(-14)), rs9260313 (P = 7.93 × 10(-09)), rs66609536 (P = 3.54 × 10(-07)) and rs380924 (P = 6.24 × 10(-06)), located within the class I region of the MHC, with each observation replicated in an independent sample (P ≤ 0.01). The previously identified locus is close to MICA, the other three lie near MICB, HLA-A and HCG9 (a non-coding RNA gene). The identification of disease associations with both MICA and MICB is particularly intriguing, since each encodes an MHC class I-related protein with potent immunological function.

In vitro psoriasis models with focus on reconstructed skin models as promising tools in psoriasis research

PubMed Central

Desmet, Eline; Ramadhas, Anesh; Lambert, Jo

2017-01-01

Psoriasis is a complex chronic immune-mediated inflammatory cutaneous disease associated with the development of inflammatory plaques on the skin. Studies proved that the disease results from a deregulated interplay between skin keratinocytes, immune cells and the environment leading to a persisting inflammatory process modulated by pro-inflammatory cytokines and activation of T cells. However, a major hindrance to study the pathogenesis of psoriasis more in depth and subsequent development of novel therapies is the lack of suitable pre-clinical models mimicking the complex phenotype of this skin disorder. Recent advances in and optimization of three-dimensional skin equivalent models have made them attractive and promising alternatives to the simplistic monolayer cultures, immunological different in vivo models and scarce ex vivo skin explants. Moreover, human skin equivalents are increasing in complexity level to match human biology as closely as possible. Here, we critically review the different types of three-dimensional skin models of psoriasis with relevance to their application potential and advantages over other models. This will guide researchers in choosing the most suitable psoriasis skin model for therapeutic drug testing (including gene therapy via siRNA molecules), or to examine biological features contributing to the pathology of psoriasis. However, the addition of T cells (as recently applied to a de-epidermized dermis-based psoriatic skin model) or other immune cells would make them even more attractive models and broaden their application potential. Eventually, the ultimate goal would be to substitute animal models by three-dimensional psoriatic skin models in the pre-clinical phases of anti-psoriasis candidate drugs. Impact statement The continuous development of novel in vitro models mimicking the psoriasis phenotype is important in the field of psoriasis research, as currently no model exists that completely matches the in vivo psoriasis

In vitro psoriasis models with focus on reconstructed skin models as promising tools in psoriasis research.

PubMed

Desmet, Eline; Ramadhas, Anesh; Lambert, Jo; Van Gele, Mireille

2017-06-01

Psoriasis is a complex chronic immune-mediated inflammatory cutaneous disease associated with the development of inflammatory plaques on the skin. Studies proved that the disease results from a deregulated interplay between skin keratinocytes, immune cells and the environment leading to a persisting inflammatory process modulated by pro-inflammatory cytokines and activation of T cells. However, a major hindrance to study the pathogenesis of psoriasis more in depth and subsequent development of novel therapies is the lack of suitable pre-clinical models mimicking the complex phenotype of this skin disorder. Recent advances in and optimization of three-dimensional skin equivalent models have made them attractive and promising alternatives to the simplistic monolayer cultures, immunological different in vivo models and scarce ex vivo skin explants. Moreover, human skin equivalents are increasing in complexity level to match human biology as closely as possible. Here, we critically review the different types of three-dimensional skin models of psoriasis with relevance to their application potential and advantages over other models. This will guide researchers in choosing the most suitable psoriasis skin model for therapeutic drug testing (including gene therapy via siRNA molecules), or to examine biological features contributing to the pathology of psoriasis. However, the addition of T cells (as recently applied to a de-epidermized dermis-based psoriatic skin model) or other immune cells would make them even more attractive models and broaden their application potential. Eventually, the ultimate goal would be to substitute animal models by three-dimensional psoriatic skin models in the pre-clinical phases of anti-psoriasis candidate drugs. Impact statement The continuous development of novel in vitro models mimicking the psoriasis phenotype is important in the field of psoriasis research, as currently no model exists that completely matches the in vivo psoriasis

Drug-induced psoriasis: clinical perspectives.

PubMed

Balak, Deepak Mw; Hajdarbegovic, Enes

2017-01-01

Exposure to certain drugs can elicit an induction or exacerbation of psoriasis. Although well-conducted systematic studies on drug-related psoriasis are mostly lacking, traditionally strong associations have been documented for beta-blockers, lithium, antimalarial drugs such as (hydroxy)chloroquine, interferons, imiquimod, and terbinafine. More recently, new associations have been reported for monoclonal antibody- and small-molecule-based targeted therapies used for oncological and immunological indications, such as tumor necrosis factor-alpha antagonists and anti-programmed cell death protein 1 immune checkpoint inhibitors. Recognizing potential drug-related psoriasis is of clinical relevance to allow an optimal management of psoriasis. However, in clinical practice, identifying medication-related exacerbations and induction of psoriasis can be challenging. The clinical and histopathological features of drug-provoked psoriasis may differ little from that of "classical" nondrug-related forms of psoriasis. In addition, the latency period between start of the medication and onset of psoriasis can be significantly long for some drugs. Assessment of the Naranjo adverse drug reaction probability scale could be used as a practical tool to better differentiate drug-related psoriasis. The first step in the management of drug-related psoriasis is cessation and replacement of the offending drug when deemed clinically possible. However, the induced psoriasis skin lesions may persist after treatment withdrawal. Additional skin-directed treatment options for drug-related psoriasis follows the conventional psoriasis treatment guidelines and includes topical steroids and vitamin D analogs, ultraviolet phototherapy, systemic treatments, such as acitretin, methotrexate, and fumaric acid esters, and biological treatments.

The Human Papillomavirus Type 8 E6 Protein Interferes with NOTCH Activation during Keratinocyte Differentiation

PubMed Central

Meyers, Jordan M.; Spangle, Jennifer M.

2013-01-01

Cutaneous β-human papillomavirus (β-HPV) E6 proteins inhibit NOTCH signaling by associating with the transcriptional coactivator MAML1. NOTCH has tumor suppressor activities in epithelial cells and is activated during keratinocyte differentiation. Here we report that HPV type 8 (HPV8) E6 subverts NOTCH activation during keratinocyte differentiation by inhibiting RBPJ/MAML1 transcriptional activator complexes at NOTCH target DNA. NOTCH inhibition impairs epithelial differentiation and may thus contribute to β-HPV replication and viral oncogenesis. PMID:23365452

EphA2 proteomics in human keratinocytes reveals a novel association with afadin and epidermal tight junctions.

PubMed

Perez White, Bethany E; Ventrella, Rosa; Kaplan, Nihal; Cable, Calvin J; Thomas, Paul M; Getsios, Spiro

2017-01-01

EphA2 is a receptor tyrosine kinase that helps to maintain epidermal tissue homeostasis. A proximity-dependent biotin identification (BioID) approach was used to identify proteins in close proximity to EphA2 within primary human keratinocytes and three-dimensional (3D) reconstituted human epidermis (RHE) cultures to map a putative protein interaction network for this membrane receptor that exhibits a polarized distribution in stratified epithelia. Although a subset of known EphA2 interactors were identified in the BioID screen, >97% were uniquely detected in keratinocytes with over 50% of these vicinal proteins only present in 3D human epidermal culture. Afadin (AFDN), a cytoskeletal and junction-associated protein, was present in 2D and 3D keratinocyte cultures, and validated as a so-far-unknown EphA2-interacting protein. Loss of EphA2 protein disrupted the subcellular distribution of afadin and occludin in differentiated keratinocytes, leading to impairment of tight junctions. Collectively, these studies illustrate the use of the BioID approach in order to map receptor interaction networks in 3D human epithelial cultures, and reveal a positive regulatory role for EphA2 in the organization of afadin and epidermal tight junctions. © 2017. Published by The Company of Biologists Ltd.

EphA2 proteomics in human keratinocytes reveals a novel association with afadin and epidermal tight junctions

PubMed Central

Perez White, Bethany E.; Ventrella, Rosa; Kaplan, Nihal; Cable, Calvin J.; Thomas, Paul M.

2017-01-01

ABSTRACT EphA2 is a receptor tyrosine kinase that helps to maintain epidermal tissue homeostasis. A proximity-dependent biotin identification (BioID) approach was used to identify proteins in close proximity to EphA2 within primary human keratinocytes and three-dimensional (3D) reconstituted human epidermis (RHE) cultures to map a putative protein interaction network for this membrane receptor that exhibits a polarized distribution in stratified epithelia. Although a subset of known EphA2 interactors were identified in the BioID screen, >97% were uniquely detected in keratinocytes with over 50% of these vicinal proteins only present in 3D human epidermal culture. Afadin (AFDN), a cytoskeletal and junction-associated protein, was present in 2D and 3D keratinocyte cultures, and validated as a so-far-unknown EphA2-interacting protein. Loss of EphA2 protein disrupted the subcellular distribution of afadin and occludin in differentiated keratinocytes, leading to impairment of tight junctions. Collectively, these studies illustrate the use of the BioID approach in order to map receptor interaction networks in 3D human epithelial cultures, and reveal a positive regulatory role for EphA2 in the organization of afadin and epidermal tight junctions. PMID:27815408

Psoriasis and dilated cardiomyopathy: coincidence or associated diseases?

PubMed

Eliakim-Raz, Noa; Shuvy, Mony; Lotan, Chaim; Planer, David

2008-01-01

Psoriasis is a common immune-mediated disease which affects 1-3% of the population. The etiology of psoriasis is unknown. Idiopathic dilated cardiomyopathy is probably the end result of a variety of toxic, metabolic or infectious agents. During a computerized search for cardiomyopathy among all patients hospitalized with psoriasis in the Hadassah University Hospital since 1980 we found an increased prevalence of cardiomyopathy, and specifically dilated cardiomyopathy. We present 4 patients who suffer from both conditions. In accordance with previous data, an association between preexisting psoriasis and dilated cardiomyopathy is suggested. We suggest that the genetic risk factors of dilated cardiomyopathy are shared by psoriasis, and more specifically psoriatic arthritis. Alternatively, the immune reaction that is triggered in dilated cardiomyopathy leading to the progression of the disease might be enhanced in patients with psoriasis or psoriatic arthritis. Chronic inflammation and persistent secretion of proinflammatory cytokines may be considered a potential pathway, triggering the initiation and progression of dilated cardiomyopathy in psoriatic patients. Further investigation of the genetic and immune risk factors involved in dilated cardiomyopathy and in psoriasis may lead to a better understanding of the pathogenesis and treatment of dilated cardiomyopathy. Copyright 2008 S. Karger AG, Basel.

Psoriasis and cardiometabolic traits: modest association but distinct genetic architectures

PubMed Central

Koch, Manja; Baurecht, Hansjörg; Ried, Janina S.; Rodriguez, Elke; Schlesinger, Sabrina; Volks, Natalie; Gieger, Christian; Rückert, Ina-Maria; Heinrich, Luise; Willenborg, Christina; Smith, Catherine; Peters, Annette; Thorand, Barbara; Koenig, Wolfgang; Lamina, Claudia; Jansen, Henning; Kronenberg, Florian; Seissler, Jochen; Thiery, Joachim; Rathmann, Wolfgang; Schunkert, Heribert; Erdmann, Jeanette; Barker, Jonathan; Nair, Rajan P; Tsoi, Lam C; Elder, James T; Mrowietz, Ulrich; Weichenthal, Michael; Mucha, Sören; Schreiber, Stefan; Franke, Andre; Schmitt, Jochen; Lieb, Wolfgang; Weidinger, Stephan

2015-01-01

Psoriasis has been linked to cardiometabolic diseases, but epidemiological findings are inconsistent. We investigated the association between psoriasis and cardiometabolic outcomes in a German cross-sectional study (n=4.185) and a prospective cohort of German Health Insurance beneficiaries (n=1.811.098). A potential genetic overlap was explored using genome-wide data from >22.000 coronary artery disease (CAD) and >4.000 psoriasis cases, and with a dense genotyping study of cardiometabolic risk loci on 927 psoriasis cases and 3.717 controls. Controlling for major confounders, in the cross-sectional analysis psoriasis was significantly associated with type 2 diabetes (T2D, adjusted odd’s ratio OR=2.36; 95% confidence interval CI=1.26–4.41) and myocardial infarction (MI, OR=2.26, 95% CI=1.03–4.96). In the longitudinal study, psoriasis slightly increased the risk for incident T2D (adjusted relative risk RR=1.11; 95%CI=1.08–1.14) and MI (RR=1.14; 95%CI=1.06–1.22), with highest risk increments in systemically treated psoriasis, which accounted for 11 and 17 excess cases of T2D and MI per 10,000 person-years. Except for weak signals from within the MHC, there was no evidence for genetic risk loci shared between psoriasis and cardiometabolic traits. Our findings suggest that psoriasis, in particular severe psoriasis, increases risk for T2D and MI, and that the genetic architecture of psoriasis and cardiometabolic traits is largely distinct. PMID:25599394

Expression of psoriasis-associated fatty acid-binding protein in senescent human dermal microvascular endothelial cells.

PubMed

Ha, Moon Kyung; Chung, Kee Yang; Lee, Ju Hee; Bang, Dongsik; Park, Yoon Kee; Lee, Kwang Hoon

2004-09-01

Aging is associated with the progressive pathophysiologic modification of endothelial cells. In vitro endothelial cell senescence is accompanied by proliferative activity failure and by perturbations in gene and protein expressions. Moreover, this cellular senescence in culture has been proposed to reflect processes that occur in aging organisms. In order to observe the changing patterns of protein expression in senescent human dermal microvascular endothelial cells (HDMECs), proteins obtained from both early- and late-passaged HDMECs were separated by two-dimensional electrophoresis, visualized by silver staining, and quantified by image processing. Proteins of interest were extracted by in-gel digestion with trypsin and quantified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), by searching the National Center for Biotechnology Information protein-sequence database. More than 2000 spots were detected by 2D electrophoresis within a linear pH range of 3-10. Twenty-two major differentially expressed spots were observed in serially passaged HDMECs and identified with high confidence by MALDI-TOF-MS. One of these spots was found to be a 14-15 kDa psoriasis-associated fatty acid-binding protein (PA-FABP) with high affinity for long-chain fatty acids. The expression of PA-FABP was confirmed to be elevated in senescent HDMECs (passage 20) by fluorescence-activated cell sorting (FACS), confocal laser microscopy, and by immunohistochemistry in aged human skin tissue. Our results suggest that the overexpression of FABP in cultured senescent HDMECs is closely related to skin aging.

Psoriasis is associated with increased beta-defensin genomic copy number

PubMed Central

Hollox, Edward J.; Huffmeier, Ulrike; Zeeuwen, Patrick L.J.M.; Palla, Raquel; Lascorz, Jesús; Rodijk-Olthuis, Diana; van de Kerkhof, Peter C.M.; Traupe, Heiko; de Jongh, Gys; den Heijer, Martin; Reis, André; Armour, John A.L.; Schalkwijk, Joost

2008-01-01

Psoriasis is a common inflammatory skin disease with a strong genetic component. We have analysed the genomic copy number polymorphism of the beta-defensin region on human chromosome 8 in 179 Dutch psoriasis patients and 272 controls, and in 319 German psoriasis patients and 305 controls. Comparisons in both cohorts show a significant association between higher genomic copy number for beta-defensin genes and the risk of psoriasis. PMID:18059266

East Indian Sandalwood Oil (EISO) Alleviates Inflammatory and Proliferative Pathologies of Psoriasis.

PubMed

Sharma, Manju; Levenson, Corey; Clements, Ian; Castella, Paul; Gebauer, Kurt; Cox, Michael E

2017-01-01

Psoriasis, a chronic inflammatory skin disease marked by hyper proliferation and aberrant differentiation of keratinocytes, affects 2-3% of the world's population. Research into the pathogenesis of psoriasis has been hampered by the lack of models that accurately reflect the biology of the psoriatic phenotype. We have previously reported that East Indian Sandalwood oil (EISO) has significant anti-inflammatory properties in skin models and hypothesized that EISO might provide therapeutic benefit to psoriasis patients due to its anti-inflammatory and anti-proliferative properties. Here we present interim results from an on-going proof-of-concept Phase 2 clinical trial in which topically applied EISO is demonstrating to be well tolerated and helpful in alleviating mild to moderate psoriasis symptoms. This led us to evaluate the ability of EISO to affect the psoriatic phenotype using MatTek Corporation reconstituted organotypic psoriatic and normal human skin models. EISO had no impact on the phenotype of the normal skin tissue model, however, EISO treatment of the psoriasis tissue model reverted psoriatic pathology as demonstrated by histologic characterization and expression of keratinocyte proliferation markers, Ki67 and psoriasin. These phenotypic affects correlated with suppressed production of ENA-78, IL-6, IL-8, MCP-1, GM-CSF, and IL-1β. Demonstration of the ability of EISO to abrogate these psoriasis symptoms in well-characterized in vitro psoriatic tissue models, supports the hypothesis that the clinically observed symptom alleviation is due to suppression of intrinsic tissue inflammation reactions in afflicted lesions. This study presents a systematic approach to further study the underlying mechanisms that cause psoriasis, and presents data supporting the potential of EISO as a new ethnobotanical therapeutic concept to help direct and accelerate the development of more effective therapies.

East Indian Sandalwood Oil (EISO) Alleviates Inflammatory and Proliferative Pathologies of Psoriasis

PubMed Central

Sharma, Manju; Levenson, Corey; Clements, Ian; Castella, Paul; Gebauer, Kurt; Cox, Michael E.

2017-01-01

Psoriasis, a chronic inflammatory skin disease marked by hyper proliferation and aberrant differentiation of keratinocytes, affects 2–3% of the world’s population. Research into the pathogenesis of psoriasis has been hampered by the lack of models that accurately reflect the biology of the psoriatic phenotype. We have previously reported that East Indian Sandalwood oil (EISO) has significant anti-inflammatory properties in skin models and hypothesized that EISO might provide therapeutic benefit to psoriasis patients due to its anti-inflammatory and anti-proliferative properties. Here we present interim results from an on-going proof-of-concept Phase 2 clinical trial in which topically applied EISO is demonstrating to be well tolerated and helpful in alleviating mild to moderate psoriasis symptoms. This led us to evaluate the ability of EISO to affect the psoriatic phenotype using MatTek Corporation reconstituted organotypic psoriatic and normal human skin models. EISO had no impact on the phenotype of the normal skin tissue model, however, EISO treatment of the psoriasis tissue model reverted psoriatic pathology as demonstrated by histologic characterization and expression of keratinocyte proliferation markers, Ki67 and psoriasin. These phenotypic affects correlated with suppressed production of ENA-78, IL-6, IL-8, MCP-1, GM-CSF, and IL-1β. Demonstration of the ability of EISO to abrogate these psoriasis symptoms in well-characterized in vitro psoriatic tissue models, supports the hypothesis that the clinically observed symptom alleviation is due to suppression of intrinsic tissue inflammation reactions in afflicted lesions. This study presents a systematic approach to further study the underlying mechanisms that cause psoriasis, and presents data supporting the potential of EISO as a new ethnobotanical therapeutic concept to help direct and accelerate the development of more effective therapies. PMID:28360856

The acitretin and methotrexate combination therapy for psoriasis vulgaris achieves higher effectiveness and less liver fibrosis.

PubMed

An, Jingang; Zhang, Dingwei; Wu, Jiawen; Li, Jiong; Teng, Xiu; Gao, Xiaomin; Li, Ruilian; Wang, Xiuying; Xia, Linlin; Xia, Yumin

2017-07-01

Both acitretin and methotrexate are effective in ameliorating psoriatic lesion. However, their combination has been seldom reported in the treatment of psoriasis because of the warning regarding the potential hepatotoxicity of the drug interactions. This study was designed to investigate the effectiveness of such combination therapy for psoriasis vulgaris, and the potential benefit as well as side effect during the treatment. Thirty-nine patients with psoriasis vulgaris were treated with acitretin, methotrexate or their combination or as control. Similarly, K14-VEGF transgenic psoriasis-like mice were treated with these drugs. Human primary keratinocytes and hepatic stellate cells were used for analyzing their effect in vitro. The results showed that the combination therapy exhibited higher effectiveness in remitting skin lesion, but did not significantly affect the liver function of both patients and mice. Moreover, the combination groups showed less elevation of profibrotic factors in sera when compared with methotrexate alone groups accordingly. Furthermore, primary keratinocytes expressed more involucrin as well as loricrin and proliferated more slowly on the combined stimulation. Interestingly, such combination treatment induced lower expression of profibrotic factors in hepatic stellate cells. In conclusion, the acitretin-methotrexate combination therapy for psoriasis vulgaris can achieve higher effectiveness and result in less liver fibrosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Disruption of Spectrin-Like Cytoskeleton in Differentiating Keratinocytes by PKCδ Activation Is Associated with Phosphorylated Adducin

PubMed Central

Zhao, Kong-Nan; Masci, Paul P.; Lavin, Martin F.

2011-01-01

Spectrin is a central component of the cytoskeletal protein network in a variety of erythroid and non-erythroid cells. In keratinocytes, this protein has been shown to be pericytoplasmic and plasma membrane associated, but its characteristics and function have not been established in these cells. Here we demonstrate that spectrin increases dramatically in amount and is assembled into the cytoskeleton during differentiation in mouse and human keratinocytes. The spectrin-like cytoskeleton was predominantly organized in the granular and cornified layers of the epidermis and disrupted by actin filament inhibitors, but not by anti-mitotic drugs. When the cytoskeleton was disrupted PKCδ was activated by phosphorylation on Thr505. Specific inhibition of PKCδ(Thr505) activation with rottlerin prevented disruption of the spectrin-like cytoskeleton and the associated morphological changes that accompany differentiation. Rottlerin also inhibited specific phosphorylation of the PKCδ substrate adducin, a cytoskeletal protein. Furthermore, knock-down of endogenous adducin affected not only expression of adducin, but also spectrin and PKCδ, and severely disrupted organization of the spectrin-like cytoskeleton and cytoskeletal distribution of both adducin and PKCδ. These results demonstrate that organization of a spectrin-like cytoskeleton is associated with keratinocytes differentiation, and disruption of this cytoskeleton is mediated by either PKCδ(Thr505) phosphorylation associated with phosphorylated adducin or due to reduction of endogenous adducin, which normally connects and stabilizes the spectrin-actin complex. PMID:22163289

A Review of Indigo Naturalis as an Alternative Treatment for Nail Psoriasis.

PubMed

McDermott, Laura; Madan, Raman; Rupani, Reena; Siegel, Daniel

2016-03-01

Nail psoriasis is challenging to treat. The few currently available therapies are limited in efficacy, and often produce unfavorable side effects. A plant extract widely used in Traditional Chinese Medicine, indigo naturalis (Qing Dai), is presented in this review as an alternative topical treatment for skin and nail psoriasis. The purpose of this article is to present information on a viable alternative treatment with a favorable side effect profile for a difficult disease to treat. A PubMed search for the term "indigo naturalis" was performed, and literature from 2006 to the present relevant to indigo naturalis and treatment of psoriasis and nail psoriasis was reviewed. Indigo naturalis shares several therapeutic mechanisms with current psoriasis treatments, such as regulation of keratinocyte proliferation and differentiation, restoration of epidermal barrier function, and reduction of inflammatory processes. Clinically, it is well tolerated. Recent research of indigo naturalis suggests that it is a safe, inexpensive, and effective alternative topical treatment for skin and nail psoriasis.

Rare and Common Variants in CARD14, Encoding an Epidermal Regulator of NF-kappaB, in Psoriasis

PubMed Central

Jordan, Catherine T.; Cao, Li; Roberson, Elisha D.O.; Duan, Shenghui; Helms, Cynthia A.; Nair, Rajan P.; Duffin, Kristina Callis; Stuart, Philip E.; Goldgar, David; Hayashi, Genki; Olfson, Emily H.; Feng, Bing-Jian; Pullinger, Clive R.; Kane, John P.; Wise, Carol A.; Goldbach-Mansky, Raphaela; Lowes, Michelle A.; Peddle, Lynette; Chandran, Vinod; Liao, Wilson; Rahman, Proton; Krueger, Gerald G.; Gladman, Dafna; Elder, James T.; Menter, Alan; Bowcock, Anne M.

2012-01-01

Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5× higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-α) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 × 10−6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw∗0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease. PMID:22521419

Membrane cofactor protein (CD46) is a keratinocyte receptor for the M protein of the group A streptococcus.

PubMed

Okada, N; Liszewski, M K; Atkinson, J P; Caparon, M

1995-03-28

The pathogenic Gram-positive bacterium Streptococcus pyogenes (group A streptococcus) is the causative agent of numerous suppurative diseases of human skin. The M protein of S. pyogenes mediates the adherence of the bacterium to keratinocytes, the most numerous cell type in the epidermis. In this study, we have constructed and analyzed a series of mutant M proteins and have shown that the C repeat domain of the M molecule is responsible for cell recognition. The binding of factor H, a serum regulator of complement activation, to the C repeat region of M protein blocked bacterial adherence. Factor H is a member of a large family of complement regulatory proteins that share a homologous structural motif termed the short consensus repeat. Membrane cofactor protein (MCP), or CD46, is a short consensus repeat-containing protein found on the surface of keratinocytes, and purified MCP could competitively inhibit the adherence of S. pyogenes to these cells. Furthermore, the M protein was found to bind directly to MCP, whereas mutant M proteins that lacked the C repeat domain did not bind MCP, suggesting that recognition of MCP plays an important role in the ability of the streptococcus to adhere to keratinocytes.

IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation.

PubMed

Ma, Hak-Ling; Liang, Spencer; Li, Jing; Napierata, Lee; Brown, Tom; Benoit, Stephen; Senices, Mayra; Gill, Davinder; Dunussi-Joannopoulos, Kyriaki; Collins, Mary; Nickerson-Nutter, Cheryl; Fouser, Lynette A; Young, Deborah A

2008-02-01

Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. We report on a psoriasis-like disease model, which is induced by the transfer of CD4(+)CD45RB(hi)CD25(-) cells to pathogen-free scid/scid mice. Psoriasis-like lesions had elevated levels of antimicrobial peptide and proinflammatory cytokine mRNA. Also, similar to psoriasis, disease progression in this model was dependent on the p40 common to IL-12 and IL-23. To investigate the role of IL-22, a Th17 cytokine, in disease progression, mice were treated with IL-22-neutralizing antibodies. Neutralization of IL-22 prevented the development of disease, reducing acanthosis (thickening of the skin), inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of IL-22 into the skin of normal mice induced both antimicrobial peptide and proinflammatory cytokine gene expression. Our data suggest that IL-22, which acts on keratinocytes and other nonhematopoietic cells, is required for development of the autoreactive Th17 cell-dependent disease in this model of skin inflammation. We propose that IL-22 antagonism might be a promising therapy for the treatment of human psoriasis.

Psoriasis pathogenesis and the development of novel targeted immune therapies.

PubMed

Hawkes, Jason E; Chan, Tom C; Krueger, James G

2017-09-01

Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell-mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a "feed forward" inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Association of Psoriasis With the Risk for Type 2 Diabetes Mellitus and Obesity.

PubMed

Lønnberg, Ann Sophie; Skov, Lone; Skytthe, Axel; Kyvik, Kirsten Ohm; Pedersen, Ole Birger; Thomsen, Simon Francis

2016-07-01

Psoriasis has been shown to be associated with overweight and type 2 diabetes mellitus. The genetic association is unclear. To examine the association among psoriasis, type 2 diabetes mellitus, and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) in twins. This cross-sectional, population-based twin study included 34 781 Danish twins, 20 to 71 years of age. Data from a questionnaire on psoriasis was validated against hospital discharge diagnoses of psoriasis and compared with hospital discharge diagnoses of type 2 diabetes mellitus and self-reported BMI. Data were collected in the spring of 2002. Data were analyzed from January 1 to October 31, 2014. Crude and adjusted odds ratios (ORs) were calculated for psoriasis in relation to type 2 diabetes mellitus, increasing BMI, and obesity in the whole population of twins and in 449 psoriasis-discordant twins. Variance component analysis was used to measure genetic and nongenetic effects on the associations. Among the 34 781 questionnaire respondents, 33 588 with complete data were included in the study (15 443 men [46.0%]; 18 145 women [54.0%]; mean [SD] age, 44.5 [7.6] years). After multivariable adjustment, a significant association was found between psoriasis and type 2 diabetes mellitus (odds ratio [OR], 1.53; 95% CI, 1.03-2.27; P = .04) and between psoriasis and increasing BMI (OR, 1.81; 95% CI, 1.28-2.55; P = .001 in individuals with a BMI>35.0). Among psoriasis-discordant twin pairs, the association between psoriasis and obesity was diluted in monozygotic twins (OR, 1.43; 95% CI, 0.50-4.07; P = .50) relative to dizygotic twins (OR, 2.13; 95% CI, 1.03-4.39; P = .04). Variance decomposition showed that additive genetic factors accounted for 68% (95% CI, 60%-75%) of the variance in the susceptibility to psoriasis, for 73% (95% CI, 58%-83%) of the variance in susceptibility to type 2 diabetes mellitus, and for 74% (95% CI, 72%-76%) of the variance in BMI

Acute Generalized Erythrodermic Pustular Psoriasis Associated with Bupropion/Naltrexone (Contrave®).

PubMed

Singh, Priyanka A; Cassel, Kerry P; Moscati, Ronald M; Eckersley, David

2017-04-01

We report a case of erythrodermic pustular psoriasis associated with initiation of bupropion/naltrexone (Contrave®; Orexigen Therapeutics, La Jolla, CA) in a patient with no history of psoriasis. A 55-year-old woman was transferred to our tertiary medical center from a community hospital for possible Stevens-Johnson syndrome 3 weeks after initiation of bupropion/naltrexone. The patient was admitted to the burn unit for wound treatment and hydration. She received intravenous cyclosporine during the admission that resulted in acute kidney injury and the therapy was discontinued. The skin biopsy ruled out Stevens-Johnson syndrome and was more consistent with generalized pustular psoriasis. After discharge, the patient followed up with her dermatologist. She was diagnosed with acute generalized and erythrodermic psoriasis and the patient was restarted on cyclosporine 100 mg twice a day. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Few case reports of bupropion-induced generalized pustular psoriasis and erythrodermic psoriasis in patients with a history of psoriasis have been reported. To our knowledge, acute generalized erythrodermic pustular psoriasis associated with bupropion/naltrexone has not been reported in a patient without history of psoriasis. Due to increases in obesity and increases in prescribing of bupropion/naltrexone SR, health care providers should be aware of this possible severe adverse reaction. Published by Elsevier Inc.

Anti-psoriatic effects of indigo naturalis on the proliferation and differentiation of keratinocytes with indirubin as the active component.

PubMed

Lin, Yin-Ku; Leu, Yann-Lii; Yang, Sien-Hung; Chen, Hsiao-Wen; Wang, Chin-Ting; Pang, Jong-Hwei Su

2009-06-01

Indigo naturalis has shown efficacy in treating psoriasis in our previous clinical studies. To investigate the potential effect of indigo naturalis on regulating keratinocyte proliferation and differentiation. Skin samples from six patients were analyzed for proliferating cell nuclear antigen (PCNA) and involucrin expression by immunohistochemical staining. In addition, indigo naturalis extracts from 10 to 500 microg/ml were added to cultured keratinocytes and cell viability determined. Real-time RT-PCR, Western blotting analysis and indirect immunofluorescent labeling were used to investigate the messenger (m)RNA and protein expressions of PCNA and involucrin. Finally, high-performance liquid chromatography (HPLC) was used to identify major components of indigo naturalis and their in vitro effects compared. Immunohistochemical results demonstrated decreased PCNA and increased involucrin in psoriatic lesions after indigo naturalis treatment. Cultured keratinocytes decreased after indigo naturalis treatment, while G(0)/G(1) arrest was observed to dose-dependently increase. Staining revealed decreased PCNA-stained nuclei and increased cytosolic involucrin in treated keratinocytes. Decreased PCNA and increased involucrin at both the mRNA and protein levels were confirmed. Both major components, indirubin and indigo, could cause G(0)/G(1) phase arrest; however, only indirubin modulated the expressions of PCNA and involucrin similar to indigo naturalis. Together, these findings indicate that the anti-psoriatic effects of indigo naturalis are mediated, at least in part, by modulating the proliferation and differentiation of keratinocytes, with indirubin as the major active component.

Throat infections are associated with exacerbation in a substantial proportion of patients with chronic plaque psoriasis

PubMed Central

Thorleifsdottir, Ragna H.; Eysteinsdottir, Jenna H.; Olafsson, Jon H.; Sigurdsson, Martin I.; Johnston, Andrew; Valdimarsson, Helgi; Sigurgeirsson, Bardur

2016-01-01

Streptococcal throat infections are known to trigger or exacerbate psoriasis, and several studies support the benefit of tonsillectomy. To evaluate the potential of tonsillectomy as a treatment, we used a retrospective study-specific questionnaire to assess the proportion of psoriasis patients with sore throat-associated psoriasis exacerbations. Our survey sampled 275 psoriasis patients. 42% of patients with plaque psoriasis reported sore throat-associated psoriasis exacerbations, and 72% of patients with confirmed streptococcal infections reported aggravation. Notably, women and early onset psoriasis patients were more likely to report psoriasis exacerbation after a sore throat (p<0.001, p=0.046 respectively). Other psoriasis aggravation factors were more common in patients with sore throat-associated exacerbations (p<0.01). 49% of tonsillectomized patients reported subsequent improvement and had more frequent sore throat-associated aggravation of psoriasis than patients who did not improve after tonsillectomy (p=0.015). These findings suggest a closer association between sore throats, streptococcal throat infections and plaque psoriasis than previously reported. PMID:26984718

Throat Infections are Associated with Exacerbation in a Substantial Proportion of Patients with Chronic Plaque Psoriasis.

PubMed

Thorleifsdottir, Ragna H; Eysteinsdóttir, Jenna H; Olafsson, Jón H; Sigurdsson, Martin I; Johnston, Andrew; Valdimarsson, Helgi; Sigurgeirsson, Bardur

2016-08-23

Streptococcal throat infections are known to trigger or exacerbate psoriasis, and several studies support the benefit of tonsillectomy. To evaluate the potential of tonsillectomy as a treatment, we used a retrospective study-specific questionnaire to assess the proportion of psoriasis patients with sore throat-associated psoriasis exacerbations. Our survey sampled 275 psoriasis patients. Of patients with plaque psoriasis, 42% reported sore throat-associated psoriasis exacerbations, and of patients with confirmed streptococcal infections, 72% reported aggravation. Notably, women and patients with early onset psoriasis were more likely to report psoriasis exacerbation after a sore throat (p < 0.001, p = 0.046, respectively). Other psoriasis aggravation factors were more common in patients with sore throat-associated exacerbations (p < 0.01). Of tonsillectomized patients, 49% reported subsequent improvement and had more frequent sore throat-associated aggravation of psoriasis than patients who did not improve after tonsillectomy (p = 0.015). These findings suggest a closer association between sore throats, streptococcal throat infections and plaque psoriasis than reported previously.

[Current Topics on Vitamin D. The vitamin D functions in keratinocytes and its therapeutic applications].

PubMed

Sawatsubashi, Shun

2015-03-01

1,25 (OH) 2D and calcium have been shown to promote epidermal keratinocyte differentiation and prevent proliferation. These prodifferentiation and antiproliferative effects of 1,25 (OH) 2D have led to its clinical use in the treatment of psoriasis. However, the mechanism of vitamin D action on keratinocytes remains largely unknown. While the actions of calcium and the vitamin D receptor signaling pathways on epidermal keratinocyte differentiation are redundant, their effects on the hair follicle are not. In this review, we discuss how the vitamin D and its receptor contribute to skin and hair follicle homeostasis.

No association of psoriasis with autoimmune thyroiditis.

PubMed

Vassilatou, E; Papadavid, E; Papastamatakis, P; Alexakos, D; Koumaki, D; Katsimbri, P; Hadjidakis, D; Dimitriadis, G; Rigopoulos, D

2017-01-01

Common autoimmune diseases tend to coexist in the same patients. Few studies have examined the possible association between autoimmune thyroiditis and psoriasis or psoriatic arthritis (PsA), with inconsistent results. To investigate the prevalence of autoimmune thyroiditis in psoriatic patients with or without PsA, living in an iodine-sufficient area. We studied prospectively, 114 psoriatic patients with disease duration of 5-38 years, 30 of them with PsA, and 286 age- and body mass index (BMI)-matched subjects without psoriasis or known thyroid disease or autoimmune disease. A detailed medical history was obtained from all participants and clinical examination and laboratory evaluation was performed. Psoriasis severity was assessed with Psoriasis Area and Severity Index (PASI). Autoimmune thyroiditis was defined by the presence of positive autoantibodies to thyroid peroxidase and/or thyroglobulin. There was no difference in the prevalence of autoimmune thyroiditis between psoriatic patients and controls (20.2% vs. 19.6%). The prevalence of autoimmune thyroiditis in male and female psoriatic patients was similar (9.6% and 10.5% respectively), in contrast to the increased, as expected, prevalence in female vs. male controls (14.7% vs. 4.9%, P < 0.01). Detected cases with hypothyroidism due to autoimmune thyroiditis were similar in psoriatic patients and controls (7.9% and 7.0% respectively). Autoimmune thyroiditis in psoriatic patients was not related with age of psoriasis onset, psoriasis duration, PASI score, PsA and obesity. These data support that psoriatic patients with or without PsA do not have an increased risk for autoimmune thyroiditis. © 2016 European Academy of Dermatology and Venereology.

Kaposi's Sarcoma-Associated Herpesvirus Can Productively Infect Primary Human Keratinocytes and Alter Their Growth Properties

PubMed Central

Cerimele, Francesca; Curreli, Francesca; Ely, Scott; Friedman-Kien, Alvin E.; Cesarman, Ethel; Flore, Ornella

2001-01-01

Previous studies have shown the presence of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) DNA in endothelial cells, in keratinocytes in the basal layer of the epidermis overlying plaque-stage nodular lesions of cutaneous Kaposi's sarcoma (KS), and in the epithelial cells of eccrine glands within KS lesions. We infected primary cell cultures of human keratinocytes with KSHV/HHV8. At 6 days post infection, transcription of viral genes was detected by reverse transcriptase PCR (RT-PCR), and protein expression was documented by an immunofluorescence assay with an anti-LANA monoclonal antibody. To determine whether the viral lytic cycle was inducible by chemical treatment, KSHV/HHV8-infected keratinocytes were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and RT-PCR was performed to confirm the transcription of lytic genes such as open reading frame 26, (which encodes a capsid protein). Finally, to assess infectious viral production, other primary human cells (human umbilical vein endothelial cells), were infected with concentrated supernatant of KSHV-infected, TPA-induced keratinocytes and the presence of viral transcripts was confirmed by RT-PCR. The uninfected keratinocytes senesced 3 to 5 weeks after mock infection, while the KSHV/HHV8-infected keratinocytes continued to proliferate and to date are still in culture. However, 8 weeks after infection, viral genomes were no longer detectable by nested PCR. Although the previously KSHV/HHV8-infected keratinocytes still expressed epithelial markers, they acquired new characteristics such as contact inhibition loss, telomerase activity, anchorage-independent growth, and changes in cytokine production. These results show that KSHV/HHV8, like other herpesviruses, can infect and replicate in epithelial cells in vitro and suggest that in vivo these cells may play a significant role in the establishment of KSHV/HHV8 infection and viral transmission. PMID:11160746

Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases.

PubMed

Ishibashi, Toru; Ichikawa, Miki; Sato, Bunpei; Shibata, Shinji; Hara, Yuichi; Naritomi, Yuji; Okazaki, Ken; Nakashima, Yasuharu; Iwamoto, Yukihide; Koyanagi, Samon; Hara, Hiroshi; Nagao, Tetsuhiko

2015-08-01

Psoriasis, a chronic inflammatory skin disease, is caused by infiltrating lymphocytes and associated cytokines, including tumor necrosis factor (TNF)α, interleukin (IL)-6, and IL-17. Effective treatments, including pathogenesis-based biological agents against psoriasis, are currently under development. Although the role of reactive oxygen species (ROS) in the pathogenesis of psoriasis has been investigated, it remains to be fully elucidated; ROS-targeted therapeutic strategies are also lacking at present. Therefore, the objective of the present study was to assess whether H2, a ROS scavenger, has a therapeutic effect on psoriasis-associated inflammation by reducing hydroxyl radicals or peroxynitrite in the immunogenic psoriasis cascade. Three methods were used to administer H2: Drop infusion of saline containing 1 ppm H2 (H2-saline), inhalation of 3% H2 gas, and drinking of water containing a high concentration (5-7-ppm) of H2 (high-H2 water). Treatment efficacy was estimated using the disease activity score 28 (DAS28) system, based on C-reactive protein levels, and the psoriasis area and severity index (PASI) score, determined at baseline and following each H2 treatment. Furthermore, levels of TNFα, IL-6, and IL-17 were analyzed. The DAS28 and PASI score of the three patients decreased during H2 treatment, regardless of the administration method. The psoriatic skin lesions almost disappeared at the end of the treatment. IL-6 levels decreased during H2 treatment in Case 1 and 2. IL-17, whose concentration was high in Case 1, was reduced following H2 treatment, and TNFα also decreased in Case 1. In conclusion, H2 administration reduced inflammation associated with psoriasis in the three cases examined and it may therefore be considered as a treatment strategy for psoriasis-associated skin lesions and arthritis.

A hemidesmosomal protein regulates actin dynamics and traction forces in motile keratinocytes

PubMed Central

Hiroyasu, Sho; Colburn, Zachary T.; Jones, Jonathan C. R.

2016-01-01

During wound healing of the skin, keratinocytes disassemble hemidesmosomes and reorganize their actin cytoskeletons in order to exert traction forces on and move directionally over the dermis. Nonetheless, the transmembrane hemidesmosome component collagen XVII (ColXVII) is found in actin-rich lamella, situated behind the lamellipodium. A set of actin bundles, along which ColXVII colocalizes with actinin4, is present at each lamella. Knockdown of either ColXVII or actinin4 not only inhibits directed migration of keratinocytes but also relieves constraints on actin bundle retrograde movement at the site of lamella, such that actin bundle movement is enhanced more than 5-fold. Moreover, whereas control keratinocytes move in a stepwise fashion over a substrate by generating alternating traction forces, of up to 1.4 kPa, at each flank of the lamellipodium, ColXVII knockdown keratinocytes fail to do so. In summary, our data indicate that ColXVII-actinin4 complexes at the lamella of a moving keratinocyte regulate actin dynamics, thereby determining the direction of cell movement.—Hiroyasu, S., Colburn, Z. T., Jones, J. C. R. A hemidesmosomal protein regulates actin dynamics and traction forces in motile keratinocytes. PMID:26936359

Proteomic Analyses of NF1-Interacting Proteins in Keratinocytes

DTIC Science & Technology

2015-04-01

and knockout mice further confirmed the interactions suggested by the proteomic analyses. In relation to the development of psoriasis -like symptoms...in the NF1 null epidermis, we analyzed NF1 expression in a mouse model of psoriasis (imiquimod-induced psoriasis -like skin inflammation) and...knockout of epidermal NF1 to elucidate the molecular underpinnings of psoriasis . 15. SUBJECT TERMS neurofibromin-1 (NF1), psoriasis , inflammation

IL-22 is required for Th17 cell–mediated pathology in a mouse model of psoriasis-like skin inflammation

PubMed Central

Ma, Hak-Ling; Liang, Spencer; Li, Jing; Napierata, Lee; Brown, Tom; Benoit, Stephen; Senices, Mayra; Gill, Davinder; Dunussi-Joannopoulos, Kyriaki; Collins, Mary; Nickerson-Nutter, Cheryl; Fouser, Lynette A.; Young, Deborah A.

2008-01-01

Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. We report on a psoriasis-like disease model, which is induced by the transfer of CD4+CD45RBhiCD25– cells to pathogen-free scid/scid mice. Psoriasis-like lesions had elevated levels of antimicrobial peptide and proinflammatory cytokine mRNA. Also, similar to psoriasis, disease progression in this model was dependent on the p40 common to IL-12 and IL-23. To investigate the role of IL-22, a Th17 cytokine, in disease progression, mice were treated with IL-22–neutralizing antibodies. Neutralization of IL-22 prevented the development of disease, reducing acanthosis (thickening of the skin), inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of IL-22 into the skin of normal mice induced both antimicrobial peptide and proinflammatory cytokine gene expression. Our data suggest that IL-22, which acts on keratinocytes and other nonhematopoietic cells, is required for development of the autoreactive Th17 cell–dependent disease in this model of skin inflammation. We propose that IL-22 antagonism might be a promising therapy for the treatment of human psoriasis. PMID:18202747

Granulocyte colony-stimulating-factor-induced psoriasiform dermatitis resembles psoriasis with regard to abnormal cytokine expression and epidermal activation.

PubMed

Mössner, R; Beckmann, I; Hallermann, C; Neumann, C; Reich, K

2004-06-01

Psoriasis is a chronic inflammatory skin disorder characterized by accumulation of Th1-type T cells and neutrophils, regenerative keratinocyte proliferation and differentiation, and enhanced epidermal production of antimicrobial peptides. The underlying cause is unknown, but there are some similarities with the immunologic defense program against bacteria. Development of psoriasiform skin lesions has been reported after administration of granulocyte colony-stimulating factor (G-CSF), a cytokine induced in monocytes by bacterial antigens. To further investigate the relation between this type of cytokine-induced dermatitis and psoriasis, we analyzed the cutaneous cytokine profile [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), IL-12p35 and p40, and IL-8] and expression of markers of epidermal activation [Ki-67, cytokeratin-16, major histocompatibility complex (MHC) class II, intercellular adhesion molecule-1 (ICAM-1)] in a patient who developed G-CSF-induced psoriasiform dermatitis by using quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistology. The histologic picture resembled psoriasis with regard to epidermal hyperparakeratosis and the accumulation of lymphocytes in the upper corium. CD8(+) T cells were found to infiltrate the epidermis which was associated with an aberrant expression of Ki-67, cytokeratin-16, MHC class II, and ICAM-1 on adjacent keratinocytes. As compared to normal skin (n = 7), there was an increased expression of TNF-alpha, IL-12p40, and IL-8, a decreased expression of TGF-beta1, and a lack of IL-10, similar to the findings in active psoriasis (n = 8). Therefore, G-CSF may cause a lymphocytic dermatitis that, similar to psoriasis, is characterized by a pro-inflammatory Th1-type cytokine milieu and an epidermal phenotype indicative of aberrant maturation and acquisition of non-professional immune functions.

Indirubin, an acting component of indigo naturalis, inhibits EGFR activation and EGF-induced CDC25B gene expression in epidermal keratinocytes.

PubMed

Hsieh, Wan-Ling; Lin, Yin-Ku; Tsai, Chi-Neu; Wang, Ta-Min; Chen, Tzu-Ya; Pang, Jong-Hwei S

2012-08-01

Topical indigo naturalis ointment is clinically proved to be an effective therapy for plaque-type psoriasis. Indirubin, as the active component of indigo naturalis, inhibits cell proliferation of epidermal keratinocytes. However, the detailed underlying mechanism is not fully understood. To further investigate the anti-proliferating effects of indigo naturalis and indirubin on epidermal keratinocytes. The decreased expression of CDC25B in indigo naturalis- or indirubin-treated epidermal keratinocytes, as revealed by cDNA microarray analysis, was studied. The CDC25B expression was examined under different serum concentrations and compared between primary and immortalized keratinocytes. The activation of EGFR and the effect of EGF on the cell proliferation and CDC25B expression were also investigated in epidermal keratinocytes. RT/real-time PCR and western blot method were used to analyze the CDC25B expression at the mRNA and protein levels, respectively. Indigo naturalis and indirubin were confirmed to down-regulate CDC25B expression significantly at both the mRNA and protein levels. The growth-dependent expression of CDC25B was demonstrated by the increased expression in serum-stimulated and immortalized keratinocytes. The activation of EGF receptor, known to be highly expressed in psoriatic lesions, was inhibited by indigo naturalis or indirubin. The cell proliferation and CDC25B expression of epidermal keratinocytes were induced by EGF alone and confirmed to be inhibited by indigo naturalis or indirubin. Except being a common therapeutic target in various cancers, CDC25B also plays an important role in the hyper-proliferation of epidermal keratinocytes which can be suppressed by anti-psoriatic drug indigo naturalis and its component, indirubin. Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era

PubMed Central

2014-01-01

Background Genome-scale studies of psoriasis have been used to identify genes of potential relevance to disease mechanisms. For many identified genes, however, the cell type mediating disease activity is uncertain, which has limited our ability to design gene functional studies based on genomic findings. Methods We identified differentially expressed genes (DEGs) with altered expression in psoriasis lesions (n = 216 patients), as well as candidate genes near susceptibility loci from psoriasis GWAS studies. These gene sets were characterized based upon their expression across 10 cell types present in psoriasis lesions. Susceptibility-associated variation at intergenic (non-coding) loci was evaluated to identify sites of allele-specific transcription factor binding. Results Half of DEGs showed highest expression in skin cells, although the dominant cell type differed between psoriasis-increased DEGs (keratinocytes, 35%) and psoriasis-decreased DEGs (fibroblasts, 33%). In contrast, psoriasis GWAS candidates tended to have highest expression in immune cells (71%), with a significant fraction showing maximal expression in neutrophils (24%, P < 0.001). By identifying candidate cell types for genes near susceptibility loci, we could identify and prioritize SNPs at which susceptibility variants are predicted to influence transcription factor binding. This led to the identification of potentially causal (non-coding) SNPs for which susceptibility variants influence binding of AP-1, NF-κB, IRF1, STAT3 and STAT4. Conclusions These findings underscore the role of innate immunity in psoriasis and highlight neutrophils as a cell type linked with pathogenetic mechanisms. Assignment of candidate cell types to genes emerging from GWAS studies provides a first step towards functional analysis, and we have proposed an approach for generating hypotheses to explain GWAS hits at intergenic loci. PMID:24885462

Omega-3 fatty acids as pharmacotherapeutics in psoriasis: current status and scope of nanomedicine in its effective delivery.

PubMed

Rahman, Mahfoozur; Beg, Sarwar; Ahmad, Mohammad Zaki; Kazmi, Imran; Ahmed, Aziz; Rahman, Ziyaur; Ahmad, Farhan Jalees; Akhter, Sohail

2013-06-01

Psoriasis is a multifactorial autoimmune skin disorder based on irregularities of the T- cell function. The abnormal keratinocyte hyper proliferation in psoriasis arises due to the activation of T-cells which produces rich amount of arachidonic acid leads to generation of various proinflammatory mediators like PGs, LTs, cytokines and adhesion molecules via MAPK/AP-1, EARK1/2 and protein kinase-C (PKCs) activation pathways. Incorporation of naturally occuring bioactives like, omega (ω)-3 fatty acids (i.e., EPA and DHA) in a dose dependent manner results in inhibition of various pro-inflammatory mediators and metabolization of EPA and DHA leads to dampening of inflammation and higher resolution of the skin abnromalities. These all due to the promotion of the synthesis of ω-3 PUFA-derived lipid mediators viz namely resolvins and protectins. These have been widely used alone or in combination with other drugs in the treatment of psoriasis. Despite of their meritorious visages, the use of these bioactives is associated with several hiccups like higher unstability and vulnerable to degradation due to lipid peroxidation, poor and incosistent bioavilability by oral and topical administration. The potential use of nanomedicines in the delivery of such bioactives has gained wider attention owing to their promising bioavailability enhancement characteristics, improved stability and better efficacy. The present review gives an extensive account on ω-3 fatty acids (EPA and DHA) starting from seedling to apex, including biosynthesis, metabolites, and its mechanism of action in psoriasis. Moreover, barriers in the effective delivery of ω-3 fatty acids and how nanomedicines can be fit in the scope of its therapeutic delivery in psoriasis have also been addressed. Despite numerous advantages, application of EPA-DHA as ω-3 fatty acids therapeutics in the management of psoriasis are still at an initial stage. Nanomedicines approach to achieve high bioavailable delivery with

Incoming human papillomavirus 16 genome is lost in PML protein-deficient HaCaT keratinocytes.

PubMed

Bienkowska-Haba, Malgorzata; Luszczek, Wioleta; Keiffer, Timothy R; Guion, Lucile G M; DiGiuseppe, Stephen; Scott, Rona S; Sapp, Martin

2017-05-01

Human papillomaviruses (HPVs) target promyelocytic leukemia (PML) nuclear bodies (NBs) during infectious entry and PML protein is important for efficient transcription of incoming viral genome. However, the transcriptional down regulation was shown to be promoter-independent in that heterologous promoters delivered by papillomavirus particles were also affected. To further investigate the role of PML protein in HPV entry, we used small hairpin RNA to knockdown PML protein in HaCaT keratinocytes. Confirming previous findings, PML knockdown in HaCaT cells reduced HPV16 transcript levels significantly following infectious entry without impairing binding and trafficking. However, when we quantified steady-state levels of pseudogenomes in interphase cells, we found strongly reduced genome levels compared with parental HaCaT cells. Because nuclear delivery was comparable in both cell lines, we conclude that viral pseudogenome must be removed after successful nuclear delivery. Transcriptome analysis by gene array revealed that PML knockdown in clonal HaCaT cells was associated with a constitutive interferon response. Abrogation of JAK1/2 signaling prevented genome loss, however, did not restore viral transcription. In contrast, knockdown of PML protein in HeLa cells did not affect HPV genome delivery and transcription. HeLa cells are transformed by HPV18 oncogenes E6 and E7, which have been shown to interfere with the JAK/Stat signaling pathway. Our data imply that PML NBs protect incoming HPV genomes. Furthermore, they provide evidence that PML NBs are key regulators of the innate immune response in keratinocytes. Promyelocytic leukemia nuclear bodies (PML NBs) are important for antiviral defense. Many DNA viruses target these subnuclear structures and reorganize them. Reorganization of PML NBs by viral proteins is important for establishment of infection. In contrast, HPVs require the presence of PML protein for efficient transcription of incoming viral genome. Our

Influence of extracellular matrix proteins on human keratinocyte attachment, proliferation and transfer to a dermal wound model.

PubMed

Dawson, R A; Goberdhan, N J; Freedlander, E; MacNeil, S

1996-03-01

The aim of this study was to investigate whether prior culture of cells on ECM proteins might positively influence the performance of keratinocytes when cells are transferred to a dermal in vitro wound bed model. Keratinocytes were cultured using a method for producing cultured epithelial autografts for severely burned patients (essentially using Green's medium, a mitogen-rich medium containing fetal calf serum, cholera toxin, EGF, insulin, transferrin and triiodothyronine). Cells were cultured either on irradiated 3T3 fibroblasts (as in the standard Rheinwald and Green technique) or, alternatively, on collagen I, collagen IV, matrigel, RGD, vitronectin or fibronectin. Under these conditions matrigel, collagen I and IV enhanced initial attachment, RGD, vitronectin, fibronectin and irradiated 3T3 fibroblasts did not. Proliferation of cells was positively influenced by matrigel, collagen I and IV and irradiated 3T3 fibroblasts; of these, however, only matrigel and 3T3 fibroblasts had sustained significant effects on keratinocyte proliferation over 4 days. Cells on fibronectin showed significantly reduced proliferation. An acellular non-viable dermis was then used to mimic the homograft allodermis onto which cultured epithelial autograft sheets are grafted clinically and cells cultured on the various ECM proteins for 96 h were transferred to this in vitro wound model. None of the substrates enhanced keratinocyte performance on this model. It was concluded that under these conditions some ECM proteins can significantly affect keratinocyte attachment and, to a lesser extent, proliferation but that the culture of keratinocytes on these ECM proteins does not appear to confer any lasting benefit to the attachment of these keratinocytes to an in vitro wound-bed model.

Psoriasis is associated with decreased plasma adiponectin levels independently of cardiometabolic risk factors

PubMed Central

Li, R. C.; Krishnamoorthy, P.; DerOhannessian, S.; Doveikis, J.; Wilcox, M.; Thomas, P.; Rader, D. J.; Reilly, M. P.; Voorhees, A. Van; Gelfand, J. M.; Mehta, N. N.

2013-01-01

Summary Background Psoriasis is an inflammatory skin disease that may be associated with an adverse cardiometabolic profile including modulated plasma adiponectin and leptin levels. Whether these levels are independent of cardiometabolic risk factors, which are also prevalent in psoriasis, is not known. Methods A consecutive sample of 122 participants with varying degrees of psoriasis severity, and a random sample of 134 participants without psoriasis were recruited for this case–control study. Cardiometabolic risk factors including traditional cardiovascular risk factors, waist circumference, insulin resistance, and total plasma adiponectin and leptin were measured. Total plasma adiponectin and leptin levels were compared in unadjusted and adjusted analyses by psoriasis status. Results Participants with psoriasis had mostly mild disease and were mainly on topical therapies, but still had a more adverse cardiometabolic profile compared with those without psoriasis. Furthermore, plasma adiponectin levels were significantly lower in participants with psoriasis than those without {7.13 µg/mL [interquartile range (IQR) 4.9–11.3) vs. 14.5 µg/mL (IQR 8.4–24.1); P < 0.001]}. Plasma leptin (ng/mL) levels were higher in the psoriasis group but this did not reach statistical significance [11.3 (IQR 6.4–21.8) vs. 9.8 (IQR 4.9–20.5); P = 0.07]. In multivariable modelling, plasma adiponectin levels were still negatively associated with psoriasis status after adjusting for waist size (% difference = −41.2%, P < 0.001), insulin resistance (% difference = −39.5%, P < 0.001) and both waist size and insulin resistance (% difference = −38.5%, P < 0.001) Conclusion Plasma levels of adiponectin were lower in psoriasis, and this relationship persisted after adjusting for cardiometabolic risk factors known to decrease adiponectin levels. These findings suggest that inflammation present in psoriasis may be associated with adipose tissue dysfunction; however, direct

The role of IL 23 in the treatment of psoriasis.

PubMed

Puig, Lluís

2017-06-01

The IL-23/IL-17 axis is currently considered to be crucial in the pathogenesis of psoriasis. Human IL-23 is primarily produced by antigen-presenting cells and induces and maintains differentiation of Th17 cells and Th22 cells, a primary cellular source of proinflammatory cytokines such as IL-17 and IL-22, which mediate the epidermal hyperplasia, keratinocyte immune activation and tissue inflammation inherent in psoriasis. Agents that target the p40 subunit common to both IL-12 and IL-23 have shown robust clinical activity, but selectivity for IL-23p19 could offer advantages in efficacy and safety with respect to anti-p40 blockade. Areas covered: Relevant references regarding the role of the IL-23/IL-17 pathway in the pathogenesis of psoriasis/psoriatic arthritis and clinical trials with IL-23p40 and IL-23p19 blocking agents were obtained through a literature search in MEDLINE/Pubmed for articles published until November 2016. Moreover, ongoing registered clinical trials (RCTs) of moderate-to-severe psoriasis and psoriatic arthritis were searched through clinicaltrials.gov website, and a manual search was made for pertinent communications at the 2016 American Academy of Dermatology and European Academy of Dermatology and Venereology meetings. Expert commentary: There are potential advantages in selective blockade of the IL23-specific p19 subunit with respect to distal blockade of IL-17A or its receptor. Acting upstream in the IL-23/IL-17 cytokine pathway is likely to reduce the expression of multiple pro-inflammatory cytokines acting on keratinocytes -including IL-17F, IL-21 and IL-22-, in addition to IL-17A. On the other hand, safety data thus far suggest that these drugs might be devoid of some adverse effects of IL-17A blockade that seem to be class related, such as mucocutaneous Candida infections or triggering or worsening of inflammatory bowel disease. Specific IL-23p19 blockade with high-affinity monoclonal antibodies seems to be able to induce long

Autoantibodies to BP180 associated with bullous pemphigoid release interleukin-6 and interleukin-8 from cultured human keratinocytes.

PubMed

Schmidt, E; Reimer, S; Kruse, N; Jainta, S; Bröcker, E B; Marinkovich, M P; Giudice, G J; Zillikens, D

2000-11-01

Bullous pemphigoid is an inflammatory subepidermal blistering disease that is associated with auto- antibodies to the keratinocyte surface protein, BP180. In addition to the binding of autoantibodies, the infiltration of inflammatory cells is necessary for blister formation. Cytokines, including interleukin-6 and interleukin-8, have been implicated in the disease process of both human and experimental murine bullous pemphigoid. This study was aimed at testing the hypothesis that the binding of anti-BP180 antibodies to their target antigen triggers a signal transduction event that results in the secretion of these pro-inflammatory cytokines. Consistent with this hypothesis, treatment of cultured normal human epidermal keratinocytes with bullous pemphigoid IgG, but not control IgG, led to increased levels of interleukin-6 and interleukin-8, but not interleukin-1alpha, interleukin-1beta, tumor necrosis factor-alpha, interleukin-10, or monocyte chemoattractant protein-1, in the culture medium. This effect was concentration- and time-dependent and was abolished by depleting the bullous pemphigoid IgG of reactivity to two distinct epitopes on the BP180 NC16A domain. Upregulation of interleukin-6 and interleukin-8 was found at both protein and mRNA levels. In addition, bullous pemphigoid IgG did not induce the release of interleukin-6 and interleukin-8 from BP180-deficient keratinocytes obtained from a patient with generalized atrophic benign epidermolysis bullosa. These data indicate that bullous pemphigoid-associated autoantibodies to the human BP180 ectodomain trigger a signal transducing event that leads to expression and secretion of interleukin-6 and interleukin-8 from human keratinocytes.

Moderate-to-vigorous physical activity in individuals with psoriasis: associations with body surface area and subjective disease severity.

PubMed

Wilson, P B

2013-10-01

Psoriasis is associated with serious comorbidities such as cardiovascular disease, type 2 diabetes, and metabolic syndrome. These comorbidities are related to low physical activity in the general population. Limited research has evaluated physical activity in psoriasis, and thus, the purpose of this investigation was to compare physical activity between individuals with and without psoriasis as well as explore the associations between measures of psoriasis severity and physical activity. Cross-sectional study using data from the 2003-2006 National Health and Nutrition Examination Survey. Self-reported psoriasis diagnosis and psoriasis severity were regressed on moderate/vigorous physical activity, as measured objectively by accelerometers. Measures of psoriasis severity included rating of psoriasis as a problem in life and body surface area involvement. A total of 4316 individuals had data on psoriasis, moderate/vigorous physical activity, and relevant covariates, with 3.6% (population weighted) of participants (N.=117) reporting a diagnosis of psoriasis. A psoriasis diagnosis was not associated with moderate/vigorous physical activity, and furthermore, body surface area involvement was not associated with moderate/vigorous physical activity among participants with psoriasis. However, every tertile increase in psoriasis as a problem in life was associated with 28% less moderate/vigorous physical activity, which remained significant after adjusting for covariates and removing outliers. While a diagnosis of psoriasis and body surface area involvement do not appear to be associated with less moderate/vigorous physical activity, individuals that rate their psoriasis to be a large problem engage in less moderate/vigorous physical activity.

IL-22/STAT3-Induced Increases in SLURP1 Expression within Psoriatic Lesions Exerts Antimicrobial Effects against Staphylococcus aureus.

PubMed

Moriwaki, Yasuhiro; Takada, Kiyoko; Nagasaki, Toshinori; Kubo, Natsuki; Ishii, Tomohiro; Kose, Kazuaki; Kageyama, Taihei; Tsuji, Shoutaro; Kawashima, Koichiro; Misawa, Hidemi

2015-01-01

SLURP1 is the causal gene for Mal de Meleda (MDM), an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma and transgressive keratosis. Moreover, although SLURP1 likely serves as an important proliferation/differentiation factor in keratinocytes, the possible relation between SLURP1 and other skin diseases, such as psoriasis and atopic dermatitis, has not been studied, and the pathophysiological control of SLURP1 expression in keratinocytes is largely unknown. Our aim was to examine the involvement of SLURP1 in the pathophysiology of psoriasis using an imiquimod (IMQ)-induced psoriasis model mice and normal human epidermal keratinocytes (NHEKs). SLURP1 expression was up-regulated in the skin of IMQ-induced psoriasis model mice. In NHEKs stimulated with the inflammatory cytokines IL-17, IL-22 and TNF-α, which are reportedly expressed in psoriatic lesions, SLURP1 mRNA expression was significantly up-regulated by IL-22 but not the other two cytokines. The stimulatory effect of IL-22 was completely suppressed in NHEKs treated with a STAT3 inhibitor or transfected with siRNA targeting STAT3. Because IL-22 induces production of antimicrobial proteins in epithelial cells, the antibacterial activity of SLURP1 was assessed against Staphylococcus aureus (S. aureus), which is known to be associated with disease severity in psoriasis. SLURP1 significantly suppressed the growth of S. aureus. These results indicate SLURP1 participates in pathophysiology of psoriasis by regulating keratinocyte proliferation and differentiation, and by suppressing the growth of S. aureus.

Turmeric tonic as a treatment in scalp psoriasis: A randomized placebo-control clinical trial.

PubMed

Bahraini, Parichehr; Rajabi, Mehdi; Mansouri, Parvin; Sarafian, Golnaz; Chalangari, Reza; Azizian, Zahra

2018-06-01

Psoriasis is an autoimmune and recurrent chronic inflammatory skin disorder with a strong genetic basis. The characteristic features are hyperproliferation of keratinocytes, leading to redness, thickening, and scaling of the epidermis followed by itching and the appearance of lesions, which in most cases can affect the patients both medically and psychologically. The scalp is one of the most common sites for psoriasis. This condition is predominantly managed with steroids, which are associated with various side effects. Turmeric (Curcuma longa L.), a spice commonly used throughout the world, has been shown to exhibit anti-inflammatory, antimicrobial, antioxidant, and antineoplastic properties. It has been reported to exhibit inhibitory activity on potassium channels in T cells and plays a key role in psoriasis. We were prompted to investigate the turmeric tonic as an immune modulation and anti-inflammatory therapy on scalp psoriasis. Forty patients with mild-to-moderate scalp psoriasis who fulfilled the inclusion criteria were randomly allocated into two groups. The case group received turmeric tonic twice a day for 9 weeks, whereas the other group received a placebo applied in the same manner. Patients were evaluated at the following points: baseline, weeks 3, 6, and 9. The dermatology life quality index (DLQI) questionnaire and PASI (psoriasis area & severity index) scores, as well as medical photos before, during and after treatment were also evaluated. The probable adverse effects were also recorded and reported. Compared to the placebo, turmeric tonic significantly reduced the erythema, scaling and induration of lesions (PASI score), and also improved the patients' quality of life (P value < .05). The clinical effects of turmeric tonic on scalp psoriasis were satisfactory overall. This formulation could be considered as a treatment for scalp psoriasis. © 2018 Wiley Periodicals, Inc.

Genetic Epidemiology of Psoriasis

PubMed Central

Gupta, Rashmi; Debbaneh, Maya G.; Liao, Wilson

2014-01-01

Psoriasis is a chronic, inflammatory, immune-mediated skin condition with a prevalence of 0-11.8% across the world. It is associated with a number of cardiovascular, metabolic, and autoimmune disease co-morbidities. Psoriasis is a multifactorial disorder, influenced by both genetic and environmental factors. Its genetic basis has long been established through twin studies and familial clustering. The association of psoriasis with the HLA-Cw6 allele has been shown in many studies. Recent genome-wide association studies have identified a large number of other genes associated with psoriasis. Many of these genes regulate the innate and adaptive immune system. These findings indicate that a dysregulated immune system may play a major role in the pathogenesis of psoriasis. In this article, we review the clinical and genetic epidemiology of psoriasis with a brief description of the pathogenesis of disease. PMID:25580373

Activation of T-cell Protein-tyrosine Phosphatase Suppresses Keratinocyte Survival and Proliferation following UVB Irradiation*

PubMed Central

Lee, Hyunseung; Morales, Liza D.; Slaga, Thomas J.; Kim, Dae Joon

2015-01-01

Chronic exposure to UV radiation can contribute to the development of skin cancer by promoting protein-tyrosine kinase (PTK) signaling. Studies show that exposure to UV radiation increases the ligand-independent activation of PTKs and induces protein-tyrosine phosphatase (PTP) inactivation. In the present work, we report that T-cell PTP (TC-PTP) activity is stimulated during the initial response to UVB irradiation, which leads to suppression of keratinocyte cell survival and proliferation via the down-regulation of STAT3 signaling. Our results show that TC-PTP-deficient keratinocyte cell lines expressed a significantly increased level of phosphorylated STAT3 after exposure to low dose UVB. This increase corresponded with increased cell proliferation in TC-PTP-deficient keratinocytes following UVB irradiation. Loss of TC-PTP also reduced UVB-induced apoptosis. Corroborating with these results, overexpression of TC-PTP in keratinocyte cell lines yielded a decrease in phosphorylated STAT3 levels, which corresponded with a significant decrease in cell proliferation in response to low dose UVB. We demonstrate that TC-PTP activity was increased upon UVB exposure, and overexpression of TC-PTP in keratinocyte cell lines further increased its activity in the presence of UVB. Treatment of TC-PTP-deficient keratinocytes with the STAT3 inhibitor STA21 significantly reduced cell viability following UVB exposure in comparison with untreated TC-PTP-deficient keratinocytes, confirming that the effect of TC-PTP on cell viability is mediated by STAT3 dephosphorylation. Combined, our results indicate that UVB-mediated activation of TC-PTP plays an important role in the STAT3-dependent regulation of keratinocyte cell proliferation and survival. Furthermore, these results suggest that TC-PTP may be a novel potential target for the prevention of UVB-induced skin cancer. PMID:25406309

Psoriasis: new comorbidities*

PubMed Central

Machado-Pinto, Jackson; Diniz, Michelle dos Santos; Bavoso, Nádia Couto

2016-01-01

Psoriasis is a chronic inflammatory disease associated with several comorbidities. A few decades ago, it was considered an exclusive skin disease but today it is considered a multisystem disease. It is believed that 73% of psoriasis patients have at least one comorbidity. Studies have demonstrated the association of psoriasis with inflammatory bowel disease, uveitis, psychiatric disorders, metabolic syndrome and its components and cardiovascular diseases. The systemic inflammatory state seems to be the common denominator for all these comorbidities. This work aims at presenting a review of the current literature on some new comorbidities that are associated with psoriasis as osteoporosis, obstructive sleep apnea and chronic obstructive pulmonary disease. While there is still controversy, many studies already point to a possible bone involvement in patients with psoriasis, especially in the male group, generally less affected by osteoporosis. Psoriasis and chronic obstructive pulmonary disease present some risk factors in common as obesity, smoking and physical inactivity. Besides, both diseases are associated with the metabolic syndrome. These factors could be potential confounders in the association of the two diseases. Further prospective studies with control of those potential confounders should be developed in an attempt to establish causality. Existing data in the literature suggest that there is an association between obstructive sleep apnea and psoriasis, but studies performed until now have involved few patients and had a short follow-up period. It is, therefore, premature to assert that there is indeed a correlation between these two diseases. PMID:26982772

Delphinidin, a dietary antioxidant, induces human epidermal keratinocyte differentiation but not apoptosis: studies in submerged and three-dimensional epidermal equivalent models.

PubMed

Chamcheu, Jean Christopher; Afaq, Farrukh; Syed, Deeba N; Siddiqui, Imtiaz A; Adhami, Vaqar M; Khan, Naghma; Singh, Sohinderjit; Boylan, Brendan T; Wood, Gary S; Mukhtar, Hasan

2013-05-01

Delphinidin (Del), [3,5,7,3'-,4'-,5'-hexahydroxyflavylium], an anthocyanidin and a potent antioxidant abundantly found in pigmented fruits and vegetables exhibits proapoptotic effects in many cancer cells. Here, we determined the effect of Del on growth, apoptosis and differentiation of normal human epidermal keratinocytes (NHEKs) in vitro in submerged cultures and examined its effects in a three-dimensional (3D) epidermal equivalent (EE) model that permits complete differentiation reminiscent of in vivo skin. Treatment of NHEKs with Del (10-40 μm; 24-48 h) significantly enhanced keratinocyte differentiation. In Del-treated cells, there was marked increase in human involucrin (hINV) promoter activity with simultaneous increase in the mRNA and protein expressions of involucrin and other epidermal differentiation markers including procaspase-14 and transglutaminase-1 (TGM1), but without any effect on TGM2. Del treatment of NHEKs was associated with minimal decrease in cell viability, which was not associated with apoptosis as evident by lack of modulation of caspases, apoptosis-related proteins including Bcl-2 family of proteins and poly(ADP-ribose) polymerase cleavage. To establish the in vivo relevance of our observations in submerged cultures, we then validated these effects in a 3D EE model, where Del was found to significantly enhance cornification and increase the protein expression of cornification markers including caspase-14 and keratin 1. For the first time, we show that Del induces epidermal differentiation using an experimental system that closely mimics in vivo human skin. These observations suggest that Del could be a useful agent for dermatoses associated with epidermal barrier defects including aberrant keratinization, hyperproliferation or inflammation observed in skin diseases like psoriasis and ichthyoses. © 2013 John Wiley & Sons A/S.

Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis

PubMed Central

Zuo, Xianbo; Sun, Liangdan; Yin, Xianyong; Gao, Jinping; Sheng, Yujun; Xu, Jinhua; Zhang, Jianzhong; He, Chundi; Qiu, Ying; Wen, Guangdong; Tian, Hongqing; Zheng, Xiaodong; Liu, Shengxiu; Wang, Wenjun; Li, Weiran; Cheng, Yuyan; Liu, Longdan; Chang, Yan; Wang, Zaixing; Li, Zenggang; Li, Longnian; Wu, Jianping; Fang, Ling; Shen, Changbing; Zhou, Fusheng; Liang, Bo; Chen, Gang; Li, Hui; Cui, Yong; Xu, Aie; Yang, Xueqin; Hao, Fei; Xu, Limin; Fan, Xing; Li, Yuzhen; Wu, Rina; Wang, Xiuli; Liu, Xiaoming; Zheng, Min; Song, Shunpeng; Ji, Bihua; Fang, Hong; Yu, Jianbin; Sun, Yongxin; Hui, Yan; Zhang, Furen; Yang, Rongya; Yang, Sen; Zhang, Xuejun

2015-01-01

Genome-wide association studies (GWASs) have reproducibly associated ∼40 susceptibility loci with psoriasis. However, the missing heritability is evident and the contributions of coding variants have not yet been systematically evaluated. Here, we present a large-scale whole-exome array analysis for psoriasis consisting of 42,760 individuals. We discover 16 SNPs within 15 new genes/loci associated with psoriasis, including C1orf141, ZNF683, TMC6, AIM2, IL1RL1, CASR, SON, ZFYVE16, MTHFR, CCDC129, ZNF143, AP5B1, SYNE2, IFNGR2 and 3q26.2-q27 (P<5.00 × 10−08). In addition, we also replicate four known susceptibility loci TNIP1, NFKBIA, IL12B and LCE3D–LCE3E. These susceptibility variants identified in the current study collectively account for 1.9% of the psoriasis heritability. The variant within AIM2 is predicted to impact protein structure. Our findings increase the number of genetic risk factors for psoriasis and highlight new and plausible biological pathways in psoriasis. PMID:25854761

Accumulating Evidence for the Association and Shared Pathogenic Mechanisms between Psoriasis and Cardiovascular–Related Co-morbidities

PubMed Central

Shlyankevich, Julia; Mehta, Nehal N.; Krueger, James G.; Strober, Bruce; Gudjonsson, Johann E.; Qureshi, Abrar A.; Tebbey, Paul W.; Kimball, Alexandra Boer

2014-01-01

The International Psoriasis Council (IPC), a global non-profit organization dedicated to advancing psoriasis research and treatment, led an initiative to better define the association of various cardiometabolic comorbidities with psoriasis. In November 2013, a workshop was held in Boston, MA. By assembling a panel of global dermatology, immunology and cardiovascular experts, the objective was to better define the current status of the science that explains the association of psoriasis with various cardiometabolic-related comorbidities. IPC has played a historical role in associating psoriasis with various comorbidities by integrating multidisciplinary expertise to advance the scientific and clinical knowledge through publications and clinical trials. This report synthesizes the current understanding of psoriasis with various cardiometabolic risk factors by exploring the potential shared pathogenic mechanisms and genetic connectivity. PMID:25149424

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

PubMed

Mohan, Girish C; Zhang, Huayi; Bao, Lei; Many, Benjamin; Chan, Lawrence S

2017-01-01

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-1β, 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.

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

PubMed Central

Bao, Lei; Many, Benjamin; Chan, Lawrence S.

2017-01-01

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-1β, 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. PMID:28323859

Specific TRPC6 Channel Activation, a Novel Approach to Stimulate Keratinocyte Differentiation*S⃞

PubMed Central

Müller, Margarethe; Essin, Kirill; Hill, Kerstin; Beschmann, Heike; Rubant, Simone; Schempp, Christoph M.; Gollasch, Maik; Boehncke, W. Henning; Harteneck, Christian; Müller, Walter E.; Leuner, Kristina

2008-01-01

The protective epithelial barrier in our skin undergoes constant regulation, whereby the balance between differentiation and proliferation of keratinocytes plays a major role. Impaired keratinocyte differentiation and proliferation are key elements in the pathophysiology of several important dermatological diseases, including atopic dermatitis and psoriasis. Ca2+ influx plays an essential role in this process presumably mediated by different transient receptor potential (TRP) channels. However, investigating their individual role was hampered by the lack of specific stimulators or inhibitors. Because we have recently identified hyperforin as a specific TRPC6 activator, we investigated the contribution of TRPC6 to keratinocyte differentiation and proliferation. Like the endogenous differentiation stimulus high extracellular Ca2+ concentration ([Ca2+]o), hyperforin triggers differentiation in HaCaT cells and in primary cultures of human keratinocytes by inducing Ca2+ influx via TRPC6 channels and additional inhibition of proliferation. Knocking down TRPC6 channels prevents the induction of Ca2+- and hyperforin-induced differentiation. Importantly, TRPC6 activation is sufficient to induce keratinocyte differentiation similar to the physiological stimulus [Ca2+]o. Therefore, TRPC6 activation by hyperforin may represent a new innovative therapeutic strategy in skin disorders characterized by altered keratinocyte differentiation. PMID:18818211

Remission of Psoriasis in a Patient with Hepatocellular Carcinoma Treated with Sorafenib.

PubMed

Antoniou, Efstathios A; Koutsounas, Ioannis; Damaskos, Christos; Koutsounas, Sotiris

Psoriasis is a chronic, immune-mediated and angiogenesis-dependent disease. Activated keratinocytes in psoriatic lesions produce pro-angiogenic cytokines, including vascular endothelial growth factor (VEGF), which binds to vascular endothelial growth factor receptor (VEGFR) and promotes cell proliferation and angiogenesis. Sorafenib (BAY 43-9006) is a molecular multikinase inhibitor of RAF kinase, platelet-derived growth factor (PDGF), VEGFR-1, -2, -3, platelet-derived growth factor receptor (PDGFR)-β and c-Kit. This molecule inhibits tumor cell proliferation and angiogenesis and it is currently approved for the treatment of hepatocellular carcinoma (HCC). We present the complete remission of resistant psoriasis in a hepatitis C virus (HCV)-infected cirrhotic patient who was treated with sorafenib, for recurrent HCC. Several targeted therapies have demonstrated efficacy against psoriasis. More research and well-designed studies, both in novel drugs and those already marketed for other indications, are needed to determine their value as potential novel therapies for psoriasis. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Activation of the Low Molecular Weight Protein Tyrosine Phosphatase in Keratinocytes Exposed to Hyperosmotic Stress

PubMed Central

Cavalheiro, Renan P.; Machado, Daisy; Cruz, Bread L. G.; Paredes-Gamero, Edgar J.; Gomes-Marcondes, Maria C. C.; Zambuzzi, Willian F.; Vasques, Luciana; Nader, Helena B.; Souza, Ana Carolina S.; Justo, Giselle Z.

2015-01-01

Herein, we provide new contribution to the mechanisms involved in keratinocytes response to hyperosmotic shock showing, for the first time, the participation of Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP) activity in this event. We reported that sorbitol-induced osmotic stress mediates alterations in the phosphorylation of pivotal cytoskeletal proteins, particularly Src and cofilin. Furthermore, an increase in the expression of the phosphorylated form of LMWPTP, which was followed by an augment in its catalytic activity, was observed. Of particular importance, these responses occurred in an intracellular milieu characterized by elevated levels of reduced glutathione (GSH) and increased expression of the antioxidant enzymes glutathione peroxidase and glutathione reductase. Altogether, our results suggest that hyperosmostic stress provides a favorable cellular environment to the activation of LMWPTP, which is associated with increased expression of antioxidant enzymes, high levels of GSH and inhibition of Src kinase. Finally, the real contribution of LMWPTP in the hyperosmotic stress response of keratinocytes was demonstrated through analysis of the effects of ACP1 gene knockdown in stressed and non-stressed cells. LMWPTP knockdown attenuates the effects of sorbitol induced-stress in HaCaT cells, mainly in the status of Src kinase, Rac and STAT5 phosphorylation and activity. These results describe for the first time the participation of LMWPTP in the dynamics of cytoskeleton rearrangement during exposure of human keratinocytes to hyperosmotic shock, which may contribute to cell death. PMID:25781955

Generalized Pustular Psoriasis and Hepatic Dysfunction Associated with Oral Terbinafine Therapy

PubMed Central

Kim, Byung-Soo; Jwa, Seung-Wook; Jang, Bong-Seok; Kim, Moon-Bum; Oh, Chang-Keun; Kwon, Yoo-Wook; Kwon, Kyung-Sool

2007-01-01

We report a case of 61-yr-old man with stable psoriasis who progressively developed generalized pustular eruption, erythroderma, fever, and hepatic dysfunction following oral terbinafine. Skin biopsy was compatible with pustular psoriasis. After discontinuation of terbinafine and initiating topical corticosteroid and calcipotriol combination with narrow band ultraviolet B therapy, patient'S condition slowly improved until complete remission was reached 2 weeks later. The diagnosis of generalized pustular psoriasis (GPP) induced by oral terbinafine was made. To our knowledge, this is the first report of GPP accompanied by hepatic dysfunction associated with oral terbinafine therapy. PMID:17297275

Effects of Wannachawee Recipe with Antipsoriatic Activity on Suppressing Inflammatory Cytokine Production in HaCaT Human Keratinocytes

PubMed Central

Na Takuathung, Mingkwan; Wongnoppavich, Ariyaphong; Pitchakarn, Pornsiri; Panthong, Ampai; Khonsung, Parirat; Soonthornchareonnon, Noppamas

2017-01-01

Psoriasis is a chronic inflammatory and immune-mediated skin disease. The pathogenesis involves T cells activation via the IL-23/Th17 axis. Conventional treatments of psoriasis have adverse events influencing patients' adherence. Wannachawee Recipe (WCR) has been effectively used as Thai folk remedy for psoriasis patients; however, preclinical evidence defining how WCR works is still lacking. This study defined mechanisms for its antiproliferation and anti-inflammatory effects in HaCaT cells. The cytotoxicity and antiproliferation results from SRB and CCK-8 assays showed that WCR inhibited the growth and viability of HaCaT cells in a concentration-dependent manner. The distribution of cell cycle phases determined by flow cytometry showed that WCR did not interrupt cell cycle progression. Interestingly, RT-qPCR revealed that WCR significantly decreased the mRNA expression of IL-1β, IL-6, IL-8, IL-17A, IL-22, IL-23, and TNF-α but induced IL-10 expression in TNF-α- and IFN-γ-induced HaCaT cells. At the protein level determined by ELISA, WCR significantly reduced the secretion of IL-17A, IL-22, and IL-23. The WCR at low concentrations was proved to possess anti-inflammatory effect without cytotoxicity and it did not interfere with cell cycle of keratinocytes. This is the first study to provide convincing evidence that WCR is a potential candidate for development of effective psoriasis therapies. PMID:28900461

Effects of Wannachawee Recipe with Antipsoriatic Activity on Suppressing Inflammatory Cytokine Production in HaCaT Human Keratinocytes.

PubMed

Na Takuathung, Mingkwan; Wongnoppavich, Ariyaphong; Pitchakarn, Pornsiri; Panthong, Ampai; Khonsung, Parirat; Chiranthanut, Natthakarn; Soonthornchareonnon, Noppamas; Sireeratawong, Seewaboon

2017-01-01

Psoriasis is a chronic inflammatory and immune-mediated skin disease. The pathogenesis involves T cells activation via the IL-23/Th17 axis. Conventional treatments of psoriasis have adverse events influencing patients' adherence. Wannachawee Recipe (WCR) has been effectively used as Thai folk remedy for psoriasis patients; however, preclinical evidence defining how WCR works is still lacking. This study defined mechanisms for its antiproliferation and anti-inflammatory effects in HaCaT cells. The cytotoxicity and antiproliferation results from SRB and CCK-8 assays showed that WCR inhibited the growth and viability of HaCaT cells in a concentration-dependent manner. The distribution of cell cycle phases determined by flow cytometry showed that WCR did not interrupt cell cycle progression. Interestingly, RT-qPCR revealed that WCR significantly decreased the mRNA expression of IL-1 β , IL-6, IL-8, IL-17A, IL-22, IL-23, and TNF- α but induced IL-10 expression in TNF- α - and IFN- γ -induced HaCaT cells. At the protein level determined by ELISA, WCR significantly reduced the secretion of IL-17A, IL-22, and IL-23. The WCR at low concentrations was proved to possess anti-inflammatory effect without cytotoxicity and it did not interfere with cell cycle of keratinocytes. This is the first study to provide convincing evidence that WCR is a potential candidate for development of effective psoriasis therapies.

Cytokine-induced CEACAM1 expression on keratinocytes is characteristic for psoriatic skin and contributes to a prolonged lifespan of neutrophils.

PubMed

Rahmoun, Massilva; Molès, Jean-Pierre; Pedretti, Nathalie; Mathieu, Marc; Fremaux, Isabelle; Raison-Peyron, Nadia; Lecron, Jean-Claude; Yssel, Hans; Pène, Jérôme

2009-03-01

Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell-surface glycoprotein, belonging to the carcinoembryonic antigen family, expressed by human neutrophils, epithelial cells, activated T and NK cells. CEACAM1 is expressed as a cell-surface molecule with different isoforms or can be secreted as a soluble protein. Here, we show that keratinocytes in the outer epidermal layer of psoriatic skin express CEACAM1, unlike those in healthy skin or in cutaneous lesions of patients with atopic or nummular dermatitis. Stimulation of primary human keratinocytes or in vitro reconstituted epidermis with culture supernatants of activated psoriatic lesion-infiltrating T cells, IFN-gamma or oncostatin M, but not IL-17, induced the expression of transcripts for the CEACAM1-long and -short isoforms and cell-surface CEACAM1, whereas soluble CEACAM1 was not produced. The uppermost layers of the epidermis in psoriatic lesions also contain neutrophils, a cell type with inflammatory and antimicrobial properties. Coculture of CEACAM1-expressing keratinocytes or CHO transfectants with neutrophils delayed spontaneous apoptosis of the latter cells. These results show that cytokine-induced cell-surface expression of CEACAM1 by keratinocytes in the context of a psoriatic environment might contribute to the persistence of neutrophils and thus to ongoing inflammation and the decreased propensity for skin infection, typical for patients with psoriasis.

Healthcare costs in psoriasis and psoriasis sub-groups over time following psoriasis diagnosis.

PubMed

Al Sawah, Sarah; Foster, Shonda A; Goldblum, Orin M; Malatestinic, William N; Zhu, Baojin; Shi, Nianwen; Song, Xue; Feldman, Steven R

2017-09-01

To quantify healthcare costs in patients with psoriasis overall and in psoriasis patient sub-groups, by level of disease severity, presence or absence of psoriatic arthritis, or use of biologics. Administrative data from Truven Health Analytics MarketScan Research Database were used to select adult patients with psoriasis from January 2009 to January 2014. The first psoriasis diagnosis was set as the index date. Patients were required to have ≥6 months of continuous enrollment with medical and pharmacy benefits pre-index and ≥12 months post-index. Patients were followed from index until the earliest of loss to follow-up or study end. All-cause healthcare costs and outpatient pharmacy costs were calculated for the overall psoriasis cohort and for the six different psoriasis patient sub-groups: (a) patients with moderate-to-severe disease and mild disease, (b) patients with psoriatic arthritis and those without, and (c) patients on biologics and those who are not. Costs are presented per-patient-per-year (PPPY) and by years 1, 2, 3, 4, and 5 of follow-up, expressed in 2014 US dollars. A total of 108,790 psoriasis patients were selected, with a mean age of 46.0 years (52.7% females). Average follow-up was 962 days. All-cause healthcare costs were $12,523 PPPY. Outpatient pharmacy costs accounted for 38.6% of total costs. All-cause healthcare costs were highest for patients on biologics ($29,832), then for patients with psoriatic arthritis ($23,427) and those with moderate-to-severe disease ($21,481). Overall, all-cause healthcare costs and outpatient pharmacy costs presented an upward trend over a 5-year period. Psoriasis is associated with significant economic burden, which increases over time as the disease progresses. Patients with moderate-to-severe psoriasis, those with psoriatic arthritis, or use of biologics contributes to higher healthcare costs. Psoriasis-related pharmacy expenditure is the largest driver of healthcare costs in patients with psoriasis.

Allele-specific cytokine responses at the HLA-C locus: implications for psoriasis.

PubMed

Hundhausen, Christian; Bertoni, Anna; Mak, Rose K; Botti, Elisabetta; Di Meglio, Paola; Clop, Alex; Laggner, Ute; Chimenti, Sergio; Hayday, Adrian C; Barker, Jonathan N; Trembath, Richard C; Capon, Francesca; Nestle, Frank O

2012-03-01

Psoriasis is an inflammatory skin disorder that is inherited as a complex trait. Genetic studies have repeatedly highlighted HLA-C as the major determinant for psoriasis susceptibility, with the Cw*0602 allele conferring significant disease risk in a wide range of populations. Despite the potential importance of HLA-C variation in psoriasis, either via an effect on peptide presentation or immuno-inhibitory activity, allele-specific expression patterns have not been investigated. Here, we used reporter assays to characterize two regulatory variants, which virtually abolished the response to tumor necrosis factor (TNF)-α (rs2524094) and IFN-γ (rs10657191) in HLA-Cw*0602 and a cluster of related alleles. We validated these findings through the analysis of HLA-Cw*0602 expression in primary keratinocytes treated with TNF-α and IFN-γ. Finally, we showed that HLA-Cw*0602 transcripts are not increased in psoriatic skin lesions, despite highly elevated TNF-α levels. Thus, our findings demonstrate the presence of allele-specific differences in HLA-C expression and indicate that HLA-Cw*0602 is unresponsive to upregulation by key proinflammatory cytokines in psoriasis. These data pave the way for functional studies into the pathogenic role of the major psoriasis susceptibility allele.

Allele-specific cytokine responses at the HLA-C locus, implications for psoriasis

PubMed Central

Hundhausen, Christian; Bertoni, Anna; Mak, Rose K; Botti, Elisabetta; Di Meglio, Paola; Clop, Alex; Laggner, Ute; Chimenti, Sergio; Hayday, Adrian C; Barker, Jonathan N; Trembath, Richard C; Capon, Francesca; Nestle, Frank O

2011-01-01

Psoriasis is an inflammatory skin disorder that is inherited as a complex trait. Genetic studies have repeatedly highlighted HLA-C as the major determinant for psoriasis susceptibility, with the Cw*0602 allele conferring significant disease risk in a wide-range of populations. Despite the potential importance of HLA-C variation in psoriasis, either via an effect on peptide presentation or immuno-inhibitory activity, allele-specific expression patterns have not been investigated. Here, we used reporter assays to characterize two regulatory variants, which virtually abolished the response to TNF-α (rs2524094) and IFN-γ (rs10657191) in HLA-Cw*0602 and a cluster of related alleles. We validated these findings through the analysis of HLA-Cw*0602 expression in primary keratinocytes treated with TNF-α and IFN-γ. Finally, we showed that HLA-Cw*0602 transcripts are not increased in psoriatic skin lesions, despite highly elevated TNF-α levels. Thus, our findings demonstrate the presence of allele-specific differences in HLA-C expression and indicate that HLA-Cw*0602 is unresponsive to up-regulation by key pro-inflammatory cytokines in psoriasis. These data pave the way for functional studies into the pathogenic role of the major psoriasis susceptibility allele. PMID:22113476

Generalised pustular psoriasis, psoriatic arthritis and nephrotic syndrome associated with systemic amyloidosis.

PubMed

David, M; Abraham, D; Weinberger, A; Feuerman, E J

1982-09-01

The case report is presented of a psoriatic patient with arthropathy, generalised pustular psoriasis and nephrotic syndrome, in whom systemic amyloidosis developed. The literature reports 13 cases of psoriasis associated with amyloidosis, 3 of whom suffered from pustular psoriasis as does our case. With the addition of our case, 12 of these 14 had concomitant arthropathy. This seems to suggest that arthritis is an important factor in the appearance of amyloidosis. Rectal biopsy and/or renal biopsy may be helpful in establishing the diagnosis of amyloidosis relatively early in patients with psoriatic arthritis.

miR-24 and miR-205 expression is dependent on HPV onco-protein expression in keratinocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

McKenna, Declan J., E-mail: dj.mckenna@ulster.ac.uk; Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast BT9 7BL; Patel, Daksha, E-mail: d.patel@qub.ac.uk

2014-01-05

A screen of microRNA (miRNA) expression following differentiation in human foreskin keratinocytes (HFKs) identified changes in several miRNAs, including miR-24 and miR-205. We investigated how expression of Human Papilloma Virus Type-16 (HPV16) onco-proteins E6 and E7 affected expression of miR-24 and miR-205 during proliferation and differentiation of HFKs. We show that the induction of both miR-24 and miR-205 observed during differentiation of HFKs is lost in HFKs expressing E6 and E7. We demonstrate that the effect on miR-205 is due to E7 activity, as miR-205 expression is dependent on pRb expression. Finally, we provide evidence that miR-24 effects in themore » cell may be due to targeting of cyclin dependent kinase inhibitor p27. In summary, these results indicate that expression of both miR-24 and miR-205 are impacted by E6 and/or E7 expression, which may be one mechanism by which HPV onco-proteins can disrupt the balance between proliferation and differentiation in keratinocytes. - Highlights: • miR-24 and miR-205 are induced during keratinocyte differentiation. • This induction is lost in keratinocytes expressing HPV onco-proteins E6 and E7. • miR-205 is dependent upon pRb expression. • miR-24 targets p27 in cycling keratinocytes.« less

HLA-C and guttate psoriasis.

PubMed

Mallon, E; Bunce, M; Savoie, H; Rowe, A; Newson, R; Gotch, F; Bunker, C B

2000-12-01

Psoriasis is a heterogeneous disease in its clinical expression. Both genetic and environmental factors are thought to contribute to the pathogenesis of the inflammatory and hyperproliferative components of the typical skin lesions. Predisposing genetic influences include associations with human leucocyte antigens (HLA) of which that with HLA-Cw6 is the strongest. Guttate psoriasis is a specific clinical manifestation of psoriasis frequently associated with group A beta-haemolytic streptococcal throat infection. We set out to determine whether further clinical subdivision of psoriasis is associated with tighter correlation with HLA-C alleles. We determined the HLA-C locus genotype of 29 caucasian patients with guttate psoriasis presenting consecutively with guttate psoriasis associated with a history of a sore throat and/or an antistreptolysin O titre > 200 IU mL-1. Polymerase chain reaction typing using sequence-specific primers was used to detect all known HLA-C alleles. These data were compared with a control population of 604 random caucasian cadaver donors. All patients (100%) with guttate psoriasis carried the Cw*0602 allele compared with 20% of the control population (odds ratio = infinity; 95% confidence limits 25.00-infinity; Pcorrected < 0.0000002). This result is consistent with HLA-Cw*0602 playing a part directly in the pathogenesis of guttate psoriasis.

Psoriasis: the future.

PubMed

Menter, M Alan; Griffiths, Christopher E M

2015-01-01

The umbrella term psoriasis is now understood to incorporate several distinct phenotypes or endotypes along the disease spectrum that in turn will dictate different therapies. A stratified medicine approach to psoriasis using this clinical information coupled with pharmacogenomic and immunologic data will become more widely acceptable in the future. Comorbidities associated with psoriasis, such as diabetes, depression, and Crohn disease, and the debate about the interdependence of psoriasis and cardiovascular disease will also dictate future research and holistic and management plans for this complex disease.

Association Between Psoriasis and Subclinical Atherosclerosis: A Meta-Analysis.

PubMed

Fang, Na; Jiang, Menglin; Fan, Yu

2016-05-01

The association between psoriasis and carotid intima-media thickness (CIMT) or impaired flow-mediated dilation (FMD) remains controversial. We aimed to evaluate the extent of subclinical atherosclerosis as measured by CIMT and FMD in patients with psoriasis by conducting a meta-analysis.A systematic literature search was performed using PubMed, Embase, Cochrane databases, China National Knowledge Infrastructure, and VIP databases up to February 2015. Observational studies investigating CIMT or FMD in patients with psoriasis and controls were eligible. Psoriatic patients and controls were at least age- and sex-matched. Random-effects analysis was used to estimate the weighted mean difference (WMD) and 95% confidence interval (CI) between psoriatic patients and controls.A total of 20 studies were identified and analyzed. Meta-analysis showed that psoriatic patients had a significantly thicker CIMT (WMD 0.11 mm; 95% CI 0.08-0.15) and lower FMD (WMD -2.79%; -4.14% to -1.43%) than those in controls. Subgroup analysis indicated that psoriatic arthritis appeared to have less impaired FMD (WMD -2.45%) and thinner CIMT (WMD 0.10 mm). Psoriatic patients with mean age >45 years had much thicker CIMT (WMD 0.13 mm). The impaired FMD (WMD -3.99%) seemed more pronounced in psoriatic patients with mean age <45 years.This meta-analysis suggests that patients with psoriasis are associated with excessive risk of subclinical atherosclerosis. Screening and monitoring CIMT and brachial artery FMD may be recommended to identify a subgroup of psoriatic patients at higher risk for cardiovascular events.

Nonlinear cellular dynamics of keratinocytes in normal and psoriatic epidermis under action of UV radiation

NASA Astrophysics Data System (ADS)

Stolnitz, Mikhail M.; Medvedev, Boris A.; Gribko, Tatyana V.

2004-05-01

The semi-phenomenological model of epidermal cell dynamics is submitted. The model takes into account three types of basal layer keratinocytes (stem, transient amplifying, terminally differentiated), distribution of first two types cells on mitotic cycle stages and resting states, keratinocytes-lymphocytes interactions that provide a positive feedback loop, influence of more differentiated cells on their progenitors that provide a negative feedback loop. Simplified model are developed and its stationary solutions are received. The opportunity of interpretation of some received modes as corresponding to various stages of psoriasis is discussed. Influence of UV-radiation on transitions between various modes of epidermis functioning is qualitatively analyzed.

Drug-induced Fanconi syndrome associated with fumaric acid esters treatment for psoriasis: a case series.

PubMed

Balak, Deepak M W; Bouwes Bavinck, Jan Nico; de Vries, Aiko P J; Hartman, Jenny; Neumann, Hendrik A Martino; Zietse, Robert; Thio, Hok Bing

2016-02-01

Fumaric acid esters (FAEs), an oral immunomodulating treatment for psoriasis and multiple sclerosis, have been anecdotally associated with proximal renal tubular dysfunction due to a drug-induced Fanconi syndrome. Few data are available on clinical outcomes of FAE-induced Fanconi syndrome. Descriptive case series with two cases of Fanconi syndrome associated with FAE treatment diagnosed at two Dutch university nephrology departments, three cases reported at the Dutch and German national pharmacovigilance databases and six previously reported cases. All 11 cases involved female patients with psoriasis. The median age at the time of onset was 38 years [interquartile range (IQR) 37-46]. Patients received long-term FAEs treatment with a median treatment duration of 60 months (IQR 28-111). Laboratory tests were typically significant for low serum levels of phosphate and uric acid, while urinalysis showed glycosuria and proteinuria. Eight (73%) patients had developed a hypophosphataemic osteomalacia and three (27%) had pathological bone fractures. All patients discontinued FAEs, while four (36%) patients were treated with supplementation of phosphate and/or vitamin D. Five (45%) patients had persisting symptoms despite FAEs discontinuation. FAEs treatment can cause drug-induced Fanconi syndrome, but the association has been reported infrequently. Female patients with psoriasis treated long term with FAEs seem to be particularly at risk. Physicians treating patients with FAEs should be vigilant and monitor for the potential occurrence of Fanconi syndrome. Measurement of the urinary albumin:total protein ratio is a suggested screening tool for tubular proteinuria in Fanconi syndrome.

Anti-apoptotic effects of suppressor of cytokine signaling 3 and 1 in psoriasis

PubMed Central

Madonna, S; Scarponi, C; Pallotta, S; Cavani, A; Albanesi, C

2012-01-01

Because of their genetically determined capacity to respond to pro-inflammatory stimuli, keratinocytes have a crucial role in the pathogenesis of psoriasis. Upon IFN-γ and TNF-α exposure, psoriatic keratinocytes express exaggerated levels of inflammatory mediators, and show aberrant hyperproliferation and terminal differentiation. The thickening of psoriasic skin also results from a peculiar resistance of keratinocytes to cytokine-induced apoptosis. In this study, we investigated on the molecular mechanisms concurring to the resistance of psoriatic keratinocytes to cell death, focusing on the role having suppressor of cytokine signaling (SOCS)1 and SOCS3, two molecules abundantly expressed in IFN-γ/TNF-α-activated psoriatic keratinocytes, in sustaining anti-apoptotic pathways. We found that SOCS1 and SOCS3 suppress cytokine-induced apoptosis by sustaining the activation of the PI3K/AKT pathway in keratinocytes. The latter determines the activation of the anti-apoptotic NF-κB cascade and, in parallel, the inhibition of the pro-apoptotic BAD function in keratinocytes. For the first time, we report that phosphorylated AKT and phosphorylated BAD are strongly expressed in lesional psoriatic skin, compared with healthy or not lesional skin, and they strictly correlate to the high expression of SOCS1 and SOCS3 molecules in the psoriatic epidermis. Finally, the depletion of SOCS1 and SOCS3, as well as the chemical inactivation of PI3K activity in psoriatic keratinocytes, definitively unveils the role of PI3K/AKT cascade on the resistance of diseased keratinocytes to apoptosis. PMID:22739986

Psoriasis and metabolic syndrome.

PubMed

Sales, Rita; Torres, Tiago

2014-01-01

Psoriasis is a chronic, systemic inflammatory disease associated with several cardiometabolic comorbidities, such as obesity, insulin resistance, dyslipidemia, and hypertension, and with clinically significant increased risk of cardiovascular disease and cardiovascular mortality. These comorbidities are components of the metabolic syndrome. Multiple epidemiologic studies have revealed a high prevalence of metabolic syndrome in patients with psoriasis compared with other skin diseases. Genetic susceptibility and overlapping inflammatory pathways may be potential biologic links underlying this association. Understanding the interrelationship between these conditions is important for the management of psoriasis and its associated comorbidities. This review will focus on the range of these comorbidities, with emphasis on the metabolic syndrome, aiming to encourage physicians to screen patients with psoriasis for cardiometabolic disorders and risk factors.

Advanced oxidative protein products induced human keratinocyte apoptosis through the NOX-MAPK pathway.

PubMed

Sun, Baihui; Ding, Ruoting; Yu, Wenlin; Wu, Yanhong; Wang, Bulin; Li, Qin

2016-07-01

Impaired wound healing is a major diabetes-related complication. Keratinocytes play an important role in wound healing. Multiple factors have been proposed that can induce dysfunction in keratinocytes. The focus of present research is at a more specific molecular level. We investigated the role of advanced oxidative protein products (AOPPs) in inducing human immortalized keratinocyte (HaCaT) cell apoptosis and the cellular mechanism underlying the proapoptotic effect of AOPPs. HaCaT cells were treated with increasing concentrations of AOPP-human serum albumin or for increasing time durations. The cell viability was measured using the thiazolyl blue tetrazolium bromide method, and flow cytometry was used to assess the rate of cell apoptosis. A loss of mitochondrial membrane potential (MMP) and an increase in intracellular reactive oxygen species (ROS) were observed through a confocal laser scanning microscope system, and the level of ROS generation was determined using a microplate reader. Nicotinamide adenine dinucleotide phosphate oxidase (NOX)4, extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and apoptosis-related downstream protein interactions were investigated using the Western blot analysis. We found that AOPPs triggered HaCaT cell apoptosis and MMP loss. After AOPP treatment, intracellular ROS generation increased in a time- and dose-dependent manner. Proapoptotic proteins, such as Bax, caspase 9/caspase 3, and poly(ADP-ribose) polymerase (PARP)-1 were activated, whereas anti-apoptotic Bcl-2 protein was downregulated. AOPPs also increased NOX4, ERK1/2, and p38 MAPK expression. Taken together, these findings suggest that extracellular AOPP accumulation triggered NOX-dependent ROS production, which activated ERK1/2 and p38 MAPK, and induced HaCaT cell apoptosis by activating caspase 3 and PARP-1.

Sumoylation Dynamics During Keratinocyte Differentiation

PubMed Central

Deyrieux, Adeline F.; Rosas-Acosta, Germán; Ozbun, Michelle A.; Wilson, Van G.

2012-01-01

Summary SUMO modification regulates the activity of numerous transcription factors that have a direct role in cell cycle progression, apoptosis, cellular proliferation, and development, but its role in differentiation processes is less clear. Keratinocyte differentiation requires the coordinated activation of a series of transcription factors, and as several critical keratinocyte transcription factors are known to be SUMO substrates, we investigated the role of sumoylation in keratinocyte differentiation. In a human keratinocyte cell line model (HaCaT cells), calcium-induced differentiation led to the transient and coordinated transcriptional activation of the genes encoding critical sumoylation system components, including SAE1, SAE2, Ubc9, SENP1, Miz-1 (PIASxβ), SUMO2, and SUMO3. The increased gene expression resulted in higher levels of the respective proteins and changes in the pattern of sumoylated substrate proteins during the differentiation process. Similar to the HaCaT results, stratified human foreskin keratinocytes showed an upregulation of Ubc9 in the suprabasal layers. Lastly, abrogation of sumoylation by Gam1 expression severely disrupted normal HaCaT differentiation, consistent with an important role for sumoylation in the proper progression of this biological process. PMID:17164289

The association between psoriasis and health-related quality of life, work productivity, and healthcare resource use in Brazil.

PubMed

DiBonaventura, Marco; Carvalho, André Vicente Esteves de; Souza, Cacilda da Silva; Squiassi, Haline Bianca; Ferreira, Cristina Nunes

2018-03-01

Psoriasis is a chronic, immune mediated inflammatory condition that affects a significant amount of the global population. Yet geographic variability in the consequences of psoriasis warrants region-level analyses. The current study contributes to the psoriasis outcomes literature by offering a comprehensive assessment of the humanistic and economic burden in Brazil. The 2012 Brazil National Health and Wellness Survey (N=12,000) was used to assess health-related quality of life (Short Form-12, version 2), work productivity, and healthcare resource use associated with experiencing psoriasis vs. no psoriasis, along with varying levels of psoriasis severity. A total of 210 respondents reported diagnosis of psoriasis (N=157, 42, and 11 reporting mild, moderate, and severe psoriasis, respectively). Compared with controls, respondents with psoriasis reported diminished mental component summary scores and health utilities, as well as increased presenteeism, activity impairment, and physician visits over the past six months, adjusting for covariates. Among those with psoriasis, physical health decreased as psoriasis severity increased. Although work productivity and healthcare resource utilization did not differ with psoriasis severity, the high rates of productivity loss (e.g. 45.5% presenteeism in the severe psoriasis group) suggest an economic burden. Cost analyses were not performed, and cross-sectional patient-reported data limit causal conclusions and may reflect reporting biases. Nevertheless, these results suggest a significant burden to patients with psoriasis across both humanistic and economic outcomes. The association between psoriasis and mental health aspects and health utilities were particularly strong and exceeded what would be considered clinically meaningful.

The histamine-synthesizing enzyme histidine decarboxylase is upregulated by keratinocytes in atopic skin.

PubMed

Gutowska-Owsiak, D; Greenwald, L; Watson, C; Selvakumar, T A; Wang, X; Ogg, G S

2014-10-01

Histamine is an abundant mediator accumulating in the skin of atopic patients, where it is thought to be derived from immune cells. While keratinocytes express histidine decarboxylase (HDC), levels of the enzyme in normal or diseased epidermis and factors that influence its expression in human keratinocytes are not known. To assess levels of HDC in inflammatory skin diseases and factors influencing its expression. Normal and filaggrin-insufficient human keratinocytes, organotypic epidermal models and skin samples were investigated for the expression of HDC. The effect of cytokines, bacterial and allergen stimuli exposure and functional changes in differentiation were evaluated in vitro. We detected abundant expression of the HDC protein in all models studied; expression was increased in atopic skin samples. Filaggrin-insufficient keratinocytes maintained HDC levels, but exposure of keratinocytes to thymic stromal lymphopoietin, tumour necrosis factor-α, lipopolysaccharide (LPS) and house dust mite (HDM) extract increased HDC expression in vitro. Furthermore, filaggrin expression in cultured keratinocytes increased following histamine depletion. Keratinocytes express abundant HDC protein, and the levels increase in atopic skin. LPS, HDM and cytokines, which are implicated in allergic inflammation, promote the expression of the enzyme and upregulate histamine levels in keratinocytes. Actively produced histamine influences keratinocyte differentiation, suggesting functional relevance of the axis to atopic dermatitis. The findings therefore identify a new point of therapeutic intervention. © 2014 British Association of Dermatologists.

In vivo relative quantitative proteomics reveals HMGB1 as a downstream mediator of oestrogen-stimulated keratinocyte migration.

PubMed

Shin, Jung U; Noh, Ji Yeon; Lee, Ju Hee; Lee, Won Jai; Yoo, Jong Shin; Kim, Jin Young; Kim, Hyeran; Jung, Inhee; Jin, Shan; Lee, Kwang Hoon

2015-06-01

It is known that oestrogen influences skin wound healing by modulating the inflammatory response, cytokine expression and extracellular matrix deposition; accelerating re-epithelialization; and stimulating angiogenesis. To identify novel proteins associated with effects of oestrogen on keratinocyte, stable isotope labelling by amino acids in cell culture (SILAC)-based mass spectrometry was performed. Using SILAC, quantification of 1085 proteins was achieved. Among these proteins, 60 proteins were upregulated and 32 proteins were downregulated. Among significantly upregulated proteins, high-mobility group protein B1 (HMGB1) has been further evaluated for its role in the effect of oestrogen on keratinocytes. HMGB1 expression was strongly induced in oestrogen-treated keratinocytes in dose- and time-dependent manner. Further, HMGB1 was able to significantly accelerate the rate of HaCaT cell migration. To determine whether HMGB1 is involved in E2-induced HaCaT cell migration, cells were transfected with HMGB1 siRNA. Knockdown of HMGB1 blocked oestrogen-induced keratinocyte migration. Collectively, these experiments demonstrate that HMGB1 is a novel downstream mediator of oestrogen-stimulated keratinocyte migration. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Drug-induced Fanconi syndrome associated with fumaric acid esters treatment for psoriasis: a case series

PubMed Central

Balak, Deepak M.W.; Bouwes Bavinck, Jan Nico; de Vries, Aiko P.J.; Hartman, Jenny; Neumann, Hendrik A. Martino; Zietse, Robert; Thio, Hok Bing

2016-01-01

Background Fumaric acid esters (FAEs), an oral immunomodulating treatment for psoriasis and multiple sclerosis, have been anecdotally associated with proximal renal tubular dysfunction due to a drug-induced Fanconi syndrome. Few data are available on clinical outcomes of FAE-induced Fanconi syndrome. Methods Descriptive case series with two cases of Fanconi syndrome associated with FAE treatment diagnosed at two Dutch university nephrology departments, three cases reported at the Dutch and German national pharmacovigilance databases and six previously reported cases. Results All 11 cases involved female patients with psoriasis. The median age at the time of onset was 38 years [interquartile range (IQR) 37–46]. Patients received long-term FAEs treatment with a median treatment duration of 60 months (IQR 28–111). Laboratory tests were typically significant for low serum levels of phosphate and uric acid, while urinalysis showed glycosuria and proteinuria. Eight (73%) patients had developed a hypophosphataemic osteomalacia and three (27%) had pathological bone fractures. All patients discontinued FAEs, while four (36%) patients were treated with supplementation of phosphate and/or vitamin D. Five (45%) patients had persisting symptoms despite FAEs discontinuation. Conclusions FAEs treatment can cause drug-induced Fanconi syndrome, but the association has been reported infrequently. Female patients with psoriasis treated long term with FAEs seem to be particularly at risk. Physicians treating patients with FAEs should be vigilant and monitor for the potential occurrence of Fanconi syndrome. Measurement of the urinary albumin:total protein ratio is a suggested screening tool for tubular proteinuria in Fanconi syndrome. PMID:26798466

Dermatophytes activate skin keratinocytes via mitogen-activated protein kinase signaling and induce immune responses.

PubMed

Achterman, Rebecca R; Moyes, David L; Thavaraj, Selvam; Smith, Adam R; Blair, Kris M; White, Theodore C; Naglik, Julian R

2015-04-01

Dermatophytes cause superficial and cutaneous fungal infections in immunocompetent hosts and invasive disease in immunocompromised hosts. However, the host mechanisms that regulate innate immune responses against these fungi are largely unknown. Here, we utilized commercially available epidermal tissues and primary keratinocytes to assess (i) damage induction by anthropophilic, geophilic, and zoophilic dermatophyte strains and (ii) the keratinocyte signaling pathways, transcription factors, and proinflammatory responses induced by a representative dermatophyte, Trichophyton equinum. Initially, five dermatophyte species were tested for their ability to invade, cause tissue damage, and induce cytokines, with Microsporum gypseum inducing the greatest level of damage and cytokine release. Using T. equinum as a representative dermatophyte, we found that the mitogen-activated protein kinase (MAPK) pathways were predominantly affected, with increased levels of phospho-p38 and phospho-Jun N-terminal protein kinase (JNK) but decreased levels of phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2). Notably, the NF-κB and PI3K pathways were largely unaffected. T. equinum also significantly increased expression of the AP-1-associated transcription factor, c-Fos, and the MAPK regulatory phosphatase, MKP1. Importantly, the ability of T. equinum to invade, cause tissue damage, activate signaling and transcription factors, and induce proinflammatory responses correlated with germination, indicating that germination may be important for dermatophyte virulence and host immune activation. Copyright © 2015, Achterman et al.

Psoriasis associated with idiopathic CD4+ T-cell lymphopenia: a regulatory T-cell defect?

PubMed

Baroudjian, B; Viguier, M; Battistella, M; Beneton, N; Pagès, C; Gener, G; Bégon, E; Bachelez, H

2014-07-01

Idiopathic CD4(+) lymphocytopenia (ICL) is a rare immunodeficiency syndrome of unknown origin for which the increased risks of opportunistic infections and of malignancies have been well established; however, skin dysimmune diseases, including psoriasis, have been scarcely reported up to now. We report herein the severe course of psoriasis in four patients with ICL, and show evidence for a defect in the skin recruitment of regulatory CD4(+) FoxP3(+) T cells. These data raise the apparent paradigm of the occurrence of a severe immunomediated disease together with a profound T-cell defect, a model that might also apply to other immune deficiencies associated with psoriasis. © 2014 British Association of Dermatologists.

Psoriasis: the visible killer.

PubMed

Torres, Tiago; Bettencourt, Nuno

2014-02-01

Psoriasis is a common chronic inflammatory disease associated with serious comorbidities. In recent years, increased mortality due to cardiovascular disease (myocardial infarction and stroke) has been documented in patients with severe psoriasis. Patients with psoriasis have a higher prevalence of traditional cardiovascular risk factors such as diabetes, hypertension, dyslipidemia and obesity, but it has been suggested that the chronic inflammatory nature of psoriasis is also a contributing and potentially an independent risk factor for the development of cardiovascular disease. The authors highlight the need for early identification and treatment of psoriasis-related comorbidities and cardiovascular disease, as well as effective treatment of psoriasis, in order to reduce the underlying systemic inflammation, and also the importance of a multidisciplinary approach of severe psoriasis patients to optimize the diagnosis, monitoring and treatment of various comorbidities, so as to prevent cardiovascular events. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Palmoplantar psoriasis is associated with greater impairment of health-related quality of life compared to moderate-to-severe plaque psoriasis

PubMed Central

Chung, Jina; Duffin, Kristina Callis; Takeshita, Junko; Shin, Daniel B.; Krueger, Gerald G.; Robertson, Andrew D.; Troxel, Andrea B.; Van Voorhees, Abby S.; Edson-Heredia, Emily; Gelfand, Joel M.

2014-01-01

Background The impact of palmoplantar psoriasis on health-related quality of life (QoL) is largely unknown. Objective To compare clinical characteristics and patient-reported outcomes between patients with palmoplantar psoriasis and moderate-to-severe plaque psoriasis. Methods We conducted a cross-sectional study of patients with plaque psoriasis (N=1,153) and palmoplantar psoriasis (N=66) currently receiving systemic or light treatment for psoriasis. Results Patients with palmoplantar psoriasis were more likely to report Dermatology Life Quality Index scores that correspond to at least a moderate impact on QoL (odds ratio [OR] 2.08; 95% confidence interval [CI], 1.20-3.61); problems with mobility (OR 1.98; 95% CI, 1.10-3.58), self-care (OR 3.12; 95% CI, 1.24-7.86), and usual activities (OR 2.47; 95% CI, 1.44-4.22) on the European Quality of Life-5 Dimensions questionnaire; and heavy topical prescription use of at least twice daily in the preceding week (OR 2.81; 95% CI, 1.63-4.85) than those with plaque psoriasis. Limitations Our assessment tools may not account for all dimensions of health-related QoL affected by palmoplantar disease, and these results may not be generalizable to patients with milder forms of psoriasis. Conclusion Patients with palmoplantar psoriasis suffer from greater health-related QoL impairment and are more likely to report heavy use of topical prescriptions than those with moderate-to-severe plaque psoriasis. PMID:24894455

β-Defensin-2 Protein Is a Serum Biomarker for Disease Activity in Psoriasis and Reaches Biologically Relevant Concentrations in Lesional Skin

PubMed Central

Jansen, Patrick A. M.; Rodijk-Olthuis, Diana; Hollox, Edward J.; Kamsteeg, Marijke; Tjabringa, Geuranne S.; de Jongh, Gys J.; van Vlijmen-Willems, Ivonne M. J. J.; Bergboer, Judith G. M.; van Rossum, Michelle M.; de Jong, Elke M. G. J.; den Heijer, Martin; Evers, Andrea W. M.; Bergers, Mieke; Armour, John A. L.

2009-01-01

Background Previous studies have extensively documented antimicrobial and chemotactic activities of beta-defensins. Human beta-defensin-2 (hBD-2) is strongly expressed in lesional psoriatic epidermis, and recently we have shown that high beta-defensin genomic copy number is associated with psoriasis susceptibility. It is not known, however, if biologically and pathophysiologically relevant concentrations of hBD-2 protein are present in vivo, which could support an antimicrobial and proinflammatory role of beta-defensins in lesional psoriatic epidermis. Methodology/Principal Findings We found that systemic levels of hBD-2 showed a weak but significant correlation with beta defensin copy number in healthy controls but not in psoriasis patients with active disease. In psoriasis patients but not in atopic dermatitis patients, we found high systemic hBD-2 levels that strongly correlated with disease activity as assessed by the PASI score. Our findings suggest that systemic levels in psoriasis are largely determined by secretion from involved skin and not by genomic copy number. Modelling of the in vivo epidermal hBD-2 concentration based on the secretion rate in a reconstructed skin model for psoriatic epidermis provides evidence that epidermal hBD-2 levels in vivo are probably well above the concentrations required for in vitro antimicrobial and chemokine-like effects. Conclusions/Significance Serum hBD-2 appears to be a useful surrogate marker for disease activity in psoriasis. The discrepancy between hBD-2 levels in psoriasis and atopic dermatitis could explain the well known differences in infection rate between these two diseases. PMID:19266104

Dynamic thiol/disulfide homeostasis and effects of smoking on homeostasis parameters in patients with psoriasis.

PubMed

Emre, Selma; Demirseren, Duriye Deniz; Alisik, Murat; Aktas, Akin; Neselioglu, Salim; Erel, Ozcan

2017-12-01

Recently, increased reactive oxygen species (ROS), reduced antioxidant capacity, and oxidative stress have been suggested in the pathogenesis of psoriasis. The aim of this study to evaluate the thiol/disulfide homeostasis in patients with psoriasis. Ninety patients with psoriasis who did not receive any systemic treatment in the last six  months were included in the study. Seventy-six age and gender-matched healthy volunteers served as control group. Thiol/disulfide homeostasis was measured in venous blood samples obtained from patient and control groups. Native thiol and total thiol levels were significantly higher in patients than in control group. When thiol/disulfide hemostasis parameters and clinical and demographic characteristics were compared, a negative correlation was detected between native thiol and total thiol with age. The levels of total thiols had also negative correlation with PASI and duration of the disease. When we divided the patients into smokers and non-smokers, native thiol and total thiol levels were significantly higher in smokers than in controls, whereas native thiol and total thiol levels were comparable in non-smoker patients and controls. Thiol/disulfide balance shifted towards thiol in psoriasis patients and this may be responsible for increased keratinocyte proliferation in the pathogenesis of psoriasis.

Guttate psoriasis

MedlinePlus

Psoriasis - guttate; Group A streptococcus - guttate psoriasis; Strep throat - guttate psoriasis ... Guttate psoriasis is a type of psoriasis . Guttate psoriasis is usually seen in people younger than 30, especially in ...

Serum lipocalin-2 levels are increased in patients with psoriasis.

PubMed

Kamata, M; Tada, Y; Tatsuta, A; Kawashima, T; Shibata, S; Mitsui, H; Asano, Y; Sugaya, M; Kadono, T; Kanda, N; Watanabe, S; Sato, S

2012-04-01

The protein lipocalin (LCN)-2 is known to be related to insulin resistance, obesity and atherosclerotic diseases. Psoriasis is an inflammatory skin disease related to metabolic syndrome. The aim of this study was to examine the relationship between serum LCN2 levels and indicators for metabolic syndrome and inflammatory cytokine levels in patients with psoriasis. Serum LCN2 levels were measured in patients with psoriasis, atopic dermatitis (AD) or bullous pemphigoid (BP), and compared with those of healthy controls. Serum LCN2 levels were also compared with several indicators for metabolic syndrome, and with serum levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-α, two markers of inflammation. Serum LCN2 levels in patients with psoriasis were significantly higher than those of healthy controls, but there was no significant correlation between serum LCN2 and body mass index. Serum LCN2 levels also correlated with serum IL-6 and TNF-α levels in patients with psoriasis. Serum LCN2 levels are a general indicator for increased inflammation in the patients with psoriasis. © The Author(s). CED © 2012 British Association of Dermatologists.

Characterization of keratinocyte differentiation induced by ascorbic acid: protein kinase C involvement and vitamin C homeostasis.

PubMed

Savini, Isabella; Catani, Maria Valeria; Rossi, Antonello; Duranti, Guglielmo; Melino, Gerry; Avigliano, Luciana

2002-02-01

Epidermal keratinocytes undergo differentiation in response to several stimuli to form the cornified envelope, a structure that contributes to the barrier function of skin. Although differentiation has been extensively analyzed, the precise role of vitamin C during this process is still not defined. Ascorbic acid, besides acting as a radical scavenger, has been shown to promote mesenchymal differentiation. In this study, we found that keratinocytes grown in ascorbate-supplemented medium developed a differentiated phenotype, as demonstrated by enhanced expression of marker genes and increase in cornified envelope content. The pro-differentiating effects of ascorbate were mediated by the protein-kinase-C-dependent induction of activating protein 1 DNA binding activity; indeed, down-modulation of protein kinase C activity abolished differentiation triggered by ascorbic acid. Although vitamin C appeared to regulate the same signaling pathway modulated by calcium, a classical in vitro inducer of epidermal differentiation, nonetheless terminally differentiated keratinocytes exhibited different ascorbate homeostasis and cellular antioxidant status. Indeed, we found that, unlike calcium, differentiation promoted by ascorbate was accompanied by (i) an enhanced ascorbate transport, due to overexpression of specific transporters, (ii) a great efficiency of dehydroascorbate uptake, and (iii) an increase in glutathione content with respect to proliferating cells. Ascorbic acid may be useful to promote epidermal differentiation, avoiding depletion of hydrophilic antioxidant stores.

Psychological differences between early- and late-onset psoriasis: a study of personality traits, anxiety and depression in psoriasis.

PubMed

Remröd, C; Sjöström, K; Svensson, A

2013-08-01

Onset of psoriasis may occur at any age. Early negative experiences often influence personality development, and may lead to physical disease, anxiety and depression in adulthood. Knowledge about onset of psoriasis and psychopathology is limited. To examine whether patients with early-onset psoriasis differ psychologically from patients with late-onset psoriasis, regarding personality traits, anxiety and depression. A descriptive cross-sectional study was conducted among 101 consecutively recruited outpatients with psoriasis. A psychosocial interview was performed followed by self-assessment of validated questionnaires: Swedish Universities Scales of Personality (SSP), Spielberger State-Trait Anxiety Inventory and Beck Depression Inventory. Psoriasis severity was assessed by the Psoriasis Area and Severity Index. Patients with early-onset psoriasis (age < 20 years) were significantly more anxious and depressed than patients with late-onset psoriasis. In multiple linear regression models, younger age at onset of psoriasis was a significant determinant of higher scores of four personality traits: SSP-embitterment, -trait irritability, -mistrust and -verbal trait aggression. Our results indicate that early detection of psychological vulnerability when treating children and adolescents with psoriasis seems to be of great importance. Traits of psychological vulnerability and pessimistic personality traits were found to be significantly associated with the early onset of psoriasis, but not with disease duration in this study. These traits may be seen as a consequence of psoriasis, and/or as individual traits modulating and impairing clinical course and efforts to cope with psoriasis. © 2013 The Authors BJD © 2013 British Association of Dermatologists.

Bathing in carbon dioxide-enriched water alters protein expression in keratinocytes of skin tissue in rats.

PubMed

Kälsch, Julia; Pott, Leona L; Takeda, Atsushi; Kumamoto, Hideo; Möllmann, Dorothe; Canbay, Ali; Sitek, Barbara; Baba, Hideo A

2017-04-01

Beneficial effects of balneotherapy using naturally occurring carbonated water (CO 2 enriched) have been known since the Middle Ages. Although this therapy is clinically applied for peripheral artery disease and skin disorder, the underlying mechanisms are not fully elucidated.Under controlled conditions, rats were bathed in either CO 2 -enriched water (CO 2 content 1200 mg/L) or tap water, both at 37 °C, for 10 min daily over 4 weeks. Proliferation activity was assessed by Ki67 immunohistochemistry of the epidermis of the abdomen. The capillary density was assessed by immunodetection of isolectin-positive cells. Using cryo-fixed abdominal skin epidermis, follicle cells and stroma tissue containing capillaries were separately isolated by means of laser microdissection and subjected to proteomic analysis using label-free technique. Differentially expressed proteins were validated by immunohistochemistry.Proliferation activity of keratinocytes was not significantly different in the epidermis after bathing in CO 2 -enriched water, and also, capillary density did not change. Proteomic analysis revealed up to 36 significantly regulated proteins in the analyzed tissue. Based on the best expression profiles, ten proteins were selected for immunohistochemical validation. Only one protein, far upstream element binding protein 2 (FUBP2), was similarly downregulated in the epidermis after bathing in CO 2 -enriched water with both techniques. Low FUBP2 expression was associated with low c-Myc immune-expression in keratinocytes.Long-term bathing in CO 2 -enriched water showed a cellular protein response of epithelial cells in the epidermis which was detectable by two different methods. However, differences in proliferation activity or capillary density were not detected in the normal skin.

Compounds of psoriasis with obesity and overweight.

PubMed

Owczarczyk-Saczonek, Agnieszka; Placek, Waldemar

2017-08-24

Many epidemiological studies have confirmed the relationship of obesity and psoriasis, and it is believed that obesity is an independent risk factor for its development and is associated with a worse prognosis. Furthermore, the reduction of body weight, using low-calorie diet combined with exercise, reduces the severity of psoriasis.Visceral adipose tissue is the largest endocrine organ, producing proinflammatory cytokines (TNF-α, IL-6, IL-17) and adipokines (adiponectin, omentin, chemerin). They participate in the development of dyslipidemia, insulin resistance, diabetes, and consequently of the cardiovascular diseases. Macrophages of visceral adipose tissue have a special role and they increase significantly in obesity. They are responsible for the development of inflammation in adipose tissue and produce inflammatory cytokines (TNF alpha, IL-6, Il-8, Il-17, Il-18, MCP-1) and other adipokines: resistin, visfatin, retinol-binding protein 4. This explains the concept of «psoriatic march «and observations of the frequent coexistence of psoriasis with obesity. Inflammation associated with systemic disease, fanned by pro-inflammatory cytokines and adipokines produced by the visceral adipose tissue lead to the development of insulin resistance, endothelial cell damage. Endothelial dysfunction predisposes to the formation of atherosclerotic plaques and faster development of cardiovascular events. Complication of obesity is the development of non-alcoholic fatty liver disease (NAFLD), which states twice as likely in patients with plaque psoriasis and is associated with the severity of the disease. Another consequence is the development of depression. Probably the proinflammatory cytokines can interact with metabolism of neurotransmitters. Obesity also has a significant impact on the treatment of psoriasis, increasing the risk of adverse effects of systemic drugs, reducing the efficacy of biological agents which dose should be adjusted to the weight of the patient. It

Psoriasis: classical and emerging comorbidities*

PubMed Central

de Oliveira, Maria de Fátima Santos Paim; Rocha, Bruno de Oliveira; Duarte, Gleison Vieira

2015-01-01

Psoriasis is a chronic inflammatory systemic disease. Evidence shows an association of psoriasis with arthritis, depression, inflammatory bowel disease and cardiovascular diseases. Recently, several other comorbid conditions have been proposed as related to the chronic inflammatory status of psoriasis. The understanding of these conditions and their treatments will certainly lead to better management of the disease. The present article aims to synthesize the knowledge in the literature about the classical and emerging comorbidities related to psoriasis. PMID:25672294

Exosomes released by keratinocytes modulate melanocyte pigmentation

PubMed Central

Cicero, Alessandra Lo; Delevoye, Cédric; Gilles-Marsens, Floriane; Loew, Damarys; Dingli, Florent; Guéré, Christelle; André, Nathalie; Vié, Katell; van Niel, Guillaume; Raposo, Graça

2015-01-01

Cells secrete extracellular vesicles (EVs), exosomes and microvesicles, which transfer proteins, lipids and RNAs to regulate recipient cell functions. Skin pigmentation relies on a tight dialogue between keratinocytes and melanocytes in the epidermis. Here we report that exosomes secreted by keratinocytes enhance melanin synthesis by increasing both the expression and activity of melanosomal proteins. Furthermore, we show that the function of keratinocyte-derived exosomes is phototype-dependent and is modulated by ultraviolet B. In sum, this study uncovers an important physiological function for exosomes in human pigmentation and opens new avenues in our understanding of how pigmentation is regulated by intercellular communication in both healthy and diseased states. PMID:26103923

Serum irisin levels in patients with psoriasis.

PubMed

Baran, Anna; Myśliwiec, Hanna; Kiluk, Paulina; Świderska, Magdalena; Flisiak, Iwona

2017-06-01

Irisin has been proposed to regulate metabolic diseases such as obesity, diabetes or metabolic syndrome which are common comorbidities in psoriasis. The aim of this study was to evaluate the serum irisin level in psoriasis and elucidate possible associations with disease activity, inflammatory or metabolic parameters and topical treatment. Thirty-seven individuals with active plaque-type psoriasis and 15 healthy controls were enrolled. Blood samples were collected before and after two weeks of therapy. Serum irisin concentrations were examined by enzyme-linked immunosorbent assay (ELISA). The results were correlated with psoriasis area and severity index (PASI), body mass index (BMI), inflammatory and biochemical markers, lipid profile and effectiveness of topical treatment. Irisin serum levels were insignificantly increased in psoriatic patients in comparison to the controls (p = 0.38). No significant correlations between investigated adipokine and several indicators of metabolic disorders, nor BMI (p = 0.37) or PASI (p = 0.5) were found. Significant positive correlations with C-reactive protein (CRP) (0.009), lipocalin-2 (p = 0.02), age (p = 0.02) and disease duration (p = 0.008) were noted. After topical treatment, serum irisin level did not significantly change (p = 0.31), despite clinical improvement. Irisin might be a marker of inflammation in psoriatic patients, but may not be a reliable indicator of metabolic conditions, severity of psoriasis nor efficacy of antipsoriatic treatment.

The association between etanercept serum concentration and psoriasis severity is highly age-dependent.

PubMed

Detrez, Iris; Van Steen, Kristel; Segaert, Siegfried; Gils, Ann

2017-06-01

The association between etanercept serum concentration and psoriasis disease severity is poorly investigated, and currently etanercept serum concentration monitoring that is aiming to optimize the psoriasis treatment lacks evidence. In this prospective study, we investigated the relation between etanercept exposure and disease severity via measuring etanercept concentrations at five consecutive time points in 56 psoriasis patients. Disease severity assessments included the Psoriasis Area and Severity Index (PASI), body surface area (BSA) and Physician Global Assessment (PGA), and etanercept and anti-etanercept antibody concentrations were determined every 3 months for a period of 1 year. The present study demonstrated that the association between etanercept concentration and psoriasis severity is age-dependent: when patients were stratified into three groups, patients in the youngest age group (-50 years) showed a lower PASI at a higher etanercept concentration (β = -0.26), whereas patients in the oldest age group (+59 years) showed the opposite trend (β =0.22). Similar age effects were observed in the relation of etanercept concentration with BSA ( P =0.02) and PGA ( P =0.02). The influence of age and length of time in therapy on the etanercept concentration-disease severity relation was unaffected by body mass index (BMI) or any other possible confounder. Incidence of anti-etanercept antibodies was low (2%). The age-dependent relation between etanercept serum concentrations is both unexpected and intriguing and needs further investigation. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Serum YKL-40 as a potential biomarker of inflammation in psoriasis.

PubMed

Baran, Anna; Myśliwiec, Hanna; Szterling-Jaworowska, Malgorzata; Kiluk, Paulina; Świderska, Magdalena; Flisiak, Iwona

2018-02-01

YKL-40 is an inflammatory glycoprotein associated with atherosclerosis, cardiovascular disease, diabetes or metabolic syndrome which are common comorbidities in psoriasis. The aim of the study was to assess serum YKL-40 level in psoriasis and elucidate possible associations with disease activity, inflammatory or metabolic parameters and treatment. A total of 37 individuals with active plaque-type psoriasis and 15 healthy controls were enrolled. Blood samples were collected before and after 2 weeks of therapy. Serum YKL-40 concentrations were evaluated by enzyme-linked immunosorbent assay (ELISA). The results were correlated with Psoriasis Area and Severity Index (PASI), body mass index (BMI), inflammatory and biochemical markers, lipid profile and topical therapy. Median YKL-40 serum levels were significantly increased in psoriatic patients in comparison to the controls (p < .0001). No significant correlations between investigated protein and metabolic parameters as BMI (p = .19), glucose (p = .32) nor lipids levels were found. Significant positive relation with CRP (p = .003) or alanine aminotransferase (p = .04) and no correlation with PASI (p = .2) were noted. Serum YKL-40 level remained unchanged (p = .5) after topical treatment, despite clinical improvement. YKL-40 might be a biomarker of psoriasis and inflammation in psoriatic patients, but not a reliable indicator of metabolic conditions, severity of psoriasis nor efficacy of the treatment.

Systematic review and meta-analysis of the association between psoriasis and metabolic syndrome.

PubMed

Rodríguez-Zúñiga, Milton José Max; García-Perdomo, Herney Andrés

2017-10-01

Several studies have shown a relationship between psoriasis and metabolic syndrome (MS), but no meta-analysis has been restricted to studies that adjusted for confounders. To determine the association between psoriasis and MS. A systematic review and meta-analysis of observational studies on psoriasis and MS in adults was performed from MEDLINE, Scopus, SciELO, Google Scholar, Science Direct, and LILACS from inception to January 2016. We performed a random effects model meta-analysis for those studies reporting adjusted odds ratios (ORs) with 95% confidence intervals (CIs). The subgroup analysis was related to geographic location, diagnosis criteria and risk of bias. In all, 14 papers including a total of 25,042 patients with psoriasis were analyzed. We found that MS was present in 31.4% of patients with psoriasis (OR, 1.42; 95% CI, 1.28-1.65). Middle Eastern studies (in Israel, Turkey, and Lebanon) (OR, 1.76, 95% CI, 0.86-2.67) reported a greater risk for MS than European studies (in Germany, Italy, the United Kingdom, Norway, and Denmark) (OR, 1.40; 95% CI, 1.25-1.55). Few adjusted studies existed, and there was inconsistency between publications. Because of the increased risk for MS, clinicians should consider screening patients with psoriasis for metabolic risk factors. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Oral candidiasis in patients with psoriasis: correlation of oral examination and cytopathological evaluation with psoriasis disease severity and treatment.

PubMed

Picciani, Bruna Lavinas Sayed; Michalski-Santos, Bruna; Carneiro, Sueli; Sampaio, Ana Luisa; Avelleira, Joao Carlos Regazzi; Azulay, David Rubem; Pinto, Jane Marcy Neffa; Dias, Eliane Pedra

2013-06-01

Infections are known to trigger and exacerbate psoriasis. Although oral candidiasis is often clinically diagnosed, it is not always confirmed by laboratory tests such as oral cytopathology. The aims of this study were to determine the prevalence of oral candidiasis in patients with psoriasis through clinical and cytopathological diagnosis and to investigate the association between oral candidiasis and psoriasis with regards to the severity of the clinical presentation and the type of treatment for psoriasis. A total of 140 patients with psoriasis and 140 healthy control subjects received an oral examination. Scrapings of the tongue were also obtained for a cytopathological examination. The oral examination and the results of the cytopathological smear revealed 37 (26%) cases of candidiasis in the patients with psoriasis and no cases of candidiasis in the healthy control subjects. There was no correlation between the type of psoriasis treatment and the presence of oral candidiasis (P = .616). There was a statistically significant association (P = .033) between the clinical severity of psoriasis and the presence of Candida. This study was limited by the small number of subjects and the lack of follow-up to determine the development of psoriasis after treatment for oral candidiasis. The presence of oral candidiasis is higher in patients with psoriasis and it is associated with disease severity. This increased presence of oral candidiasis was apparent despite any type of treatment for the psoriasis. Cytopathology to rule out oral candidiasis should be used in the routine medical workup of patients with psoriasis. Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Clinical, Diagnostic, and Therapeutic Implications in Psoriasis Associated With Cardiovascular Disease.

PubMed

Bonanad, C; González-Parra, E; Rivera, R; Carrascosa, J M; Daudén, E; Olveira, A; Botella-Estrada, R

2017-11-01

In recent years the concept of psoriasis as a systemic disease has gained acceptance due to its association with numerous comorbid conditions, particularly atherosclerosis and cardiovascular disease. Several studies have shown that patients with psoriasis, especially younger patients and those with more severe forms of psoriasis or with psoriatic arthritis, have a higher prevalence of risk factors and metabolic syndrome, as well as an increased risk of major cardiovascular events such as myocardial infarction, cerebrovascular disease, and peripheral arterial disease. Furthermore, it remains unclear which of the current treatments might be more effective in reducing cardiovascular risk in these patients. It is therefore important for dermatologists to be aware of this increased risk, to be able to detect modifiable risk factors early and, when appropriate, refer patients to other specialists for the prevention of major cardiovascular events. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Induction of senescence pathways in Kindler syndrome primary keratinocytes.

PubMed

Piccinni, E; Di Zenzo, G; Maurelli, R; Dellambra, E; Teson, M; Has, C; Zambruno, G; Castiglia, D

2013-05-01

Individuals with Kindler syndrome (KS) have loss-of-function mutations in the FERMT1 gene that encodes the focal adhesion component kindlin-1. The major clinical manifestation of KS is epidermal atrophy (premature skin ageing). This phenotypic feature is thought to be related to the decreased proliferation rate of KS keratinocytes; nevertheless, molecular mediators of such abnormal behaviour have not been fully elucidated. To investigate how kindlin-1 deficiency affects the proliferative potential of primary human keratinocytes. We serially cultivated nine primary KS keratinocyte strains until senescence and determined their lifespan and colony-forming efficiency (CFE) at each serial passage. The expression of molecular markers of stemness and cellular senescence were investigated by immunoblotting using cell extracts of primary keratinocyte cultures from patients with KS and healthy donors. In another set of experiments, kindlin-1 downregulation in normal keratinocytes was obtained by small interfering RNA (siRNA) technology. We found that KS keratinocytes exhibited a precocious senescence and strongly reduced clonogenic potential. Moreover, KS cultures showed a strikingly increased percentage of aborted colonies (paraclones) already at early passages indicating an early depletion of stem cells. Immunoblotting analysis of KS keratinocyte extracts showed reduced levels of the stemness markers p63 and Bmi-1, upregulation of p16 and scant amounts of hypophosphorylated Rb protein, which indicated cell cycle-arrested status. Treatment of normal human primary keratinocytes with siRNA targeting kindlin-1 proved that its deficiency was directly responsible for p63, Bmi-1 and pRb downregulation and p16 induction. Our data directly implicate kindlin-1 in preventing premature senescence of keratinocytes. © 2013 The Authors. BJD © 2013 British Association of Dermatologists.

Oncostatin M overexpression induces skin inflammation but is not required in the mouse model of imiquimod-induced psoriasis-like inflammation.

PubMed

Pohin, Mathilde; Guesdon, William; Mekouo, Adela Andrine Tagne; Rabeony, Hanitriniaina; Paris, Isabelle; Atanassov, Hristo; Favot, Laure; Mcheik, Jiad; Bernard, François-Xavier; Richards, Carl D; Amiaud, Jérôme; Blanchard, Frédéric; Lecron, Jean-Claude; Morel, Franck; Jégou, Jean-François

2016-07-01

Oncostatin M (OSM) has been reported to be overexpressed in psoriasis skin lesions and to exert proinflammatory effects in vitro on human keratinocytes. Here, we report the proinflammatory role of OSM in vivo in a mouse model of skin inflammation induced by intradermal injection of murine OSM-encoding adenovirus (AdOSM) and compare with that induced by IL-6 injection. Here, we show that OSM potently regulates the expression of genes involved in skin inflammation and epidermal differentiation in murine primary keratinocytes. In vivo, intradermal injection of AdOSM in mouse ears provoked robust skin inflammation with epidermal thickening and keratinocyte proliferation, while minimal effect was observed after AdIL-6 injection. OSM overexpression in the skin increased the expression of the S100A8/9 antimicrobial peptides, CXCL3, CCL2, CCL5, CCL20, and Th1/Th2 cytokines, in correlation with neutrophil and macrophage infiltration. In contrast, OSM downregulated the expression of epidermal differentiation genes, such as cytokeratin-10 or filaggrin. Collectively, these results support the proinflammatory role of OSM when it is overexpressed in the skin. However, OSM expression was not required in the murine model of psoriasis induced by topical application of imiquimod, as demonstrated by the inflammatory phenotype of OSM-deficient mice or wild-type mice treated with anti-OSM antibodies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Intense THz pulses down-regulate genes associated with skin cancer and psoriasis: a new therapeutic avenue?

PubMed Central

Titova, Lyubov V.; Ayesheshim, Ayesheshim K.; Golubov, Andrey; Rodriguez-Juarez, Rocio; Woycicki, Rafal; Hegmann, Frank A.; Kovalchuk, Olga

2013-01-01

Terahertz (THz) radiation lies between the infrared and microwave regions of the electromagnetic spectrum and is non-ionizing. We show that exposure of artificial human skin tissue to intense, picosecond-duration THz pulses affects expression levels of numerous genes associated with non-melanoma skin cancers, psoriasis and atopic dermatitis. Genes affected by intense THz pulses include nearly half of the epidermal differentiation complex (EDC) members. EDC genes, which are mapped to the chromosomal human region 1q21, encode for proteins that partake in epidermal differentiation and are often overexpressed in conditions such as psoriasis and skin cancer. In nearly all the genes differentially expressed by exposure to intense THz pulses, the induced changes in transcription levels are opposite to disease-related changes. The ability of intense THz pulses to cause concerted favorable changes in the expression of multiple genes implicated in inflammatory skin diseases and skin cancers suggests potential therapeutic applications of intense THz pulses. PMID:23917523

The Spanish Psoriasis Patients' Association According to Its Members: Cross-Sectional Descriptive Study of Members' Opinions of the Association's Functions.

PubMed

González-de Paz, L; Ribera, M; Gratacós-Masmitjà, J; Ros, S; Blanch Mur, C; Alfonso-Zamora, S

2016-11-01

Patient associations form part of health care systems, but little is known about how their members' view the functionality of these associations and whether they endorse their goals and activities. To study how the members of the leading Spanish association of patients with psoriasis and their relatives view the group's functioning. Survey study using a self-administered questionnaire answered by members of the association (total membership, 26 349 persons). The credibility of the association and respondents' confidence in and satisfaction with it were studied and compared with their attitudes toward other agents in the health care system. A Rasch model was used to analyze respondents' ranking of functions. Analysis of variance was used to study between-group differences. A total of 746 members participated (response rate 2.83%). The association's credibility was rated in second place, after that of specialists who treat psoriasis. Support for the association functions was good (7.53 on a scale of 0 to 10). The function the members rated highest was the raising of societal awareness of psoriasis and its problems. Rated lowest were functions related to personal services for members. Educational level was the only participant factor associated with significant differences in evaluations (P<.05). The psoriasis association contributes by disseminating information about the disease and patient care, and it serves to represent patients. Health professionals and institutions should take the association into account in their efforts to deal with the disease and in designing effective policies. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Effect of Wnt3a on Keratinocytes Utilizing in Vitro and Bioinformatics Analysis

PubMed Central

Nam, Ju-Suk; Chakraborty, Chiranjib; Sharma, Ashish Ranjan; Her, Young; Bae, Kee-Jeong; Sharma, Garima; Doss, George Priya; Lee, Sang-Soo; Hong, Myung-Sun; Song, Dong-Keun

2014-01-01

Wingless-type (Wnt) signaling proteins participate in various cell developmental processes. A suppressive role of Wnt5a on keratinocyte growth has already been observed. However, the role of other Wnt proteins in proliferation and differentiation of keratinocytes remains unknown. Here, we investigated the effects of the Wnt ligand, Wnt3a, on proliferation and differentiation of keratinocytes. Keratinocytes from normal human skin were cultured and treated with recombinant Wnt3a alone or in combination with the inflammatory cytokine, tumor necrosis factor α (TNFα). Furthermore, using bioinformatics, we analyzed the biochemical parameters, molecular evolution, and protein–protein interaction network for the Wnt family. Application of recombinant Wnt3a showed an anti-proliferative effect on keratinocytes in a dose-dependent manner. After treatment with TNFα, Wnt3a still demonstrated an anti-proliferative effect on human keratinocytes. Exogenous treatment of Wnt3a was unable to alter mRNA expression of differentiation markers of keratinocytes, whereas an altered expression was observed in TNFα-stimulated keratinocytes. In silico phylogenetic, biochemical, and protein–protein interaction analysis showed several close relationships among the family members of the Wnt family. Moreover, a close phylogenetic and biochemical similarity was observed between Wnt3a and Wnt5a. Finally, we proposed a hypothetical mechanism to illustrate how the Wnt3a protein may inhibit the process of proliferation in keratinocytes, which would be useful for future researchers. PMID:24686518

Oral administration of acarbose ameliorates imiquimod-induced psoriasis-like dermatitis in a mouse model.

PubMed

Chen, Hsin-Hua; Chao, Ya-Hsuan; Chen, Der-Yuan; Yang, Deng-Ho; Chung, Ting-Wen; Li, Yi-Rong; Lin, Chi Chen

2016-04-01

Psoriasis is a chronic autoimmune disease of undefined etiology that involves dysregulated interplay between immune cells and keratinocytes. Acarbose was found to decrease inflammatory parameters in diabetic patients in addition to its anti-diabetic effects. Here, we report that imiquimod (IMQ)-induced epidermal hyperplasia and psoriasis like-inflammation were significantly inhibited by acarbose treatment. Real-time PCR showed that mRNA levels of the cytokines TNF-α, IL-6, IL-1β IL-17A, and IL-22 in skin were also decreased significantly by acarbose. In addition, we found that acarbose reduced infiltration of CD3(+) T cells and GR-1(+) neutrophils in lesional skin and also reduced the percentage of IL-17-producing CD4(+) T cells (Th17) and IL-17- and IL-22-producing γδ T cells in the spleen. In contrast, acarbose increased the frequency of IL-10-producing CD4(+) regulator Tr1 T cells in the spleen and small intestine. These results indicate that oral administration of acarbose can attenuate the severity of imiquimod-induced psoriasis with local and systemic anti-inflammatory and immune modulation effects, thus suggesting that acarbose is an effective therapeutic strategy for psoriasis regulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Human Primary Keratinocytes as a Tool for the Analysis of Caspase-1-Dependent Unconventional Protein Secretion.

PubMed

Strittmatter, Gerhard E; Garstkiewicz, Martha; Sand, Jennifer; Grossi, Serena; Beer, Hans-Dietmar

2016-01-01

Inflammasomes comprise a group of protein complexes, which activate the protease caspase-1 upon sensing a variety of stress factors. Active caspase-1 in turn cleaves and thereby activates the pro-inflammatory cytokines prointerleukin (IL)-1β and -18, and induces unconventional protein secretion (UPS) of mature IL-1β, IL-18, as well as of many other proteins involved in and required for induction of inflammation. Human primary keratinocytes (HPKs) represent epithelial cells able to activate caspase-1 in an inflammasome-dependent manner upon irradiation with a physiological dose of ultraviolet B (UVB) light. Here, we describe the isolation of keratinocytes from human skin, their cultivation, and induction of caspase-1-dependent UPS upon UVB irradiation as well as its siRNA- and chemical-mediated inhibition. In contrast to inflammasome activation of professional immune cells, UVB-irradiated HPKs represent a robust and physiological cell culture system for the analysis of UPS induced by active caspase-1.

Keratinocyte differentiation is regulated by the Rho and ROCK signaling pathway.

PubMed

McMullan, Rachel; Lax, Siân; Robertson, Vicki H; Radford, David J; Broad, Simon; Watt, Fiona M; Rowles, Alison; Croft, Daniel R; Olson, Michael F; Hotchin, Neil A

2003-12-16

The epidermis comprises multiple layers of specialized epithelial cells called keratinocytes. As cells are lost from the outermost epidermal layers, they are replaced through terminal differentiation, in which keratinocytes of the basal layer cease proliferating, migrate upwards, and eventually reach the outermost cornified layers. Normal homeostasis of the epidermis requires that the balance between proliferation and differentiation be tightly regulated. The GTP binding protein RhoA plays a fundamental role in the regulation of the actin cytoskeleton and in the adhesion events that are critically important to normal tissue homeostasis. Two central mediators of the signals from RhoA are the ROCK serine/threonine kinases ROCK-I and ROCK-II. We have analyzed ROCK's role in the regulation of epidermal keratinocyte function by using a pharmacological inhibitor and expressing conditionally active or inactive forms of ROCK-II in primary human keratinocytes. We report that blocking ROCK function results in inhibition of keratinocyte terminal differentiation and an increase in cell proliferation. In contrast, activation of ROCK-II in keratinocytes results in cell cycle arrest and an increase in the expression of a number of genes associated with terminal differentiation. Thus, these results indicate that ROCK plays a critical role in regulating the balance between proliferation and differentiation in human keratinocytes.

Balneotherapy in Psoriasis Rehabilitation

PubMed Central

PÉTER, IVÁN; JAGICZA, ANNA; AJTAY, ZÉNÓ; BONCZ, IMRE; KISS, ISTVÁN; SZENDI, KATALIN; KUSTÁN, PÉTER; NÉMETH, BALÁZS

2017-01-01

Background/Aim: This study aimed to report a balneotherapy-based psoriasis rehabilitation protocol and assess its effectivity. Patients and Methods: Eighty psoriatic patients who underwent a 3-week-long inward balneotherapy-based rehabilitation were enrolled. Psoriasis Area and Severity Index (PASI) score and high sensitivity C-reactive protein (CRP) were determined on admission and before discharge. Results: The mean PASI score and CRP level –determined on admission and before discharge– decreased significantly after the 3-week-long rehabilitation 7.15±7.3 vs. 2.62±3.05 (p<0.001) and 4.1±3.8 vs. 3.5±3.1 (p=0.026). A negative correlation was found between PASI delta and the number of spa therapies received (r=–0.228). Conclusion: After completing the 3-week-long spa therapy based rehabilitation, both PASI score and CRP levels showed improvement of psoriasis. The complex spa therapy used during the rehabilitation is an effective tool to reduce the symptoms of psoriasis and improve the patient’s well-being. PMID:29102940

Balneotherapy in Psoriasis Rehabilitation.

PubMed

Péter, Iván; Jagicza, Anna; Ajtay, Zénó; Boncz, Imre; Kiss, István; Szendi, Katalin; Kustán, Péter; Németh, Balázs

2017-01-01

This study aimed to report a balneotherapy-based psoriasis rehabilitation protocol and assess its effectivity. Eighty psoriatic patients who underwent a 3-week-long inward balneotherapy-based rehabilitation were enrolled. Psoriasis Area and Severity Index (PASI) score and high sensitivity C-reactive protein (CRP) were determined on admission and before discharge. The mean PASI score and CRP level -determined on admission and before discharge-decreased significantly after the 3-week-long rehabilitation 7.15±7.3 vs. 2.62±3.05 (p<0.001) and 4.1±3.8 vs. 3.5±3.1 (p=0.026). A negative correlation was found between PASI delta and the number of spa therapies received (r=-0.228). After completing the 3-week-long spa therapy based rehabilitation, both PASI score and CRP levels showed improvement of psoriasis. The complex spa therapy used during the rehabilitation is an effective tool to reduce the symptoms of psoriasis and improve the patient's well-being. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Low-concentration hydrogen peroxide can upregulate keratinocyte intracellular calcium and PAR-2 expression in a human keratinocyte-melanocyte co-culture system.

PubMed

Li, Jian; Tang, Lu-Yan; Fu, Wen-Wen; Yuan, Jin; Sheng, You-Yu; Yang, Qin-Ping

2016-12-01

Hydrogen peroxide (H 2 O 2 ) may have a biphasic effect on melanin synthesis and melanosome transfer. High H 2 O 2 concentrations are involved in impaired melanosome transfer in vitiligo. However, low H 2 O 2 concentration promotes the beneficial proliferation and migration of melanocytes. The aim of this study was to explore low H 2 O 2 and its mechanism in melanosome transfer, protease-activated receptor-2 (PAR-2) expression and calcium balance. Melanosomes were fluorescein-labeled for clear visualization of their transfer. The expression of protease-activated receptor-2 (PAR-2) in keratinocytes was determined by western blot analysis. Flow cytometry was employed to evaluate the effects of H 2 O 2 on calcium levels in keratinocytes. Fluorescence microscopy showed the upregulation of melanosome transfer into keratinocytes following 0.3 mM H 2 O 2 treatment in the co-cultures rather than in the untreated control groups, which was associated with higher expression of PAR-2 protein and increased calcium concentration. The addition of a PAR-2 antagonist inhibited the positive activity of H 2 O 2 and calcium flow in keratinocytes. When calcium flow was blocked by a calcium chelator, the addition of H 2 O 2 did not increase the PAR-2 expression level in keratinocytes, therefore, inhibiting dendrite formation and melanosome transfer. Low H 2 O 2 concentration promotes melanosome transfer with increased PAR-2 expression level and calcium concentration in keratinocytes. In addition, the interaction between melanocytes and keratinocytes is more beneficial to enhance calcium levels in keratinocytes which mediate melanin transfer. Moreover, low H 2 O 2 concentration promotes dendrite formation, in which extracellular calcium and Par-2 were involved.

Association between psoriasis and leisure-time physical activity: findings from the National Health and Nutrition Examination Survey.

PubMed

Do, Young Kyung; Lakhani, Naheed; Malhotra, Rahul; Halstater, Brian; Theng, Colin; Østbye, Truls

2015-02-01

Despite evidence that physical activity can reduce the cardiometabolic risk of patients with psoriasis, these patients may engage in less physical activity than those without psoriasis. The aim of this study was to examine the association of the extent of psoriatic skin lesions with the likelihood of participating in leisure-time moderate to vigorous physical activity (MVPA) and metabolic equivalent task (MET)-minutes of MVPA amongst those who participated. The National Health and Nutrition Examination Survey (NHANES) is a population-based survey among U.S. adults. A total of 6549 persons aged 20-59 years responded to the 2003-2006 NHANES dermatology questionnaires, which asked about participation in leisure-time MVPA and MET-minutes of MVPA amongst those who participated. Compared with individuals without psoriasis, those with psoriasis were less likely to have engaged in leisure MVPA in the past 30 days, although this association was not statistically significant. Amongst those who participated in leisure-time MVPA, MET-minutes of leisure-time MVPA were lower on average for patients currently having few to extensive cutaneous lesions (but not for those currently having little or no psoriatic patches), relative to individuals never diagnosed with psoriasis by approximately 30%. Clinicians should encourage patients with psoriasis, especially those with more severe disease, to be more physically active; they should help identify and address possible psychological and physical barriers to their patients' physical activity. © 2014 Japanese Dermatological Association.

Fibroblast Growth Factor-Peptide Improves Barrier Function and Proliferation in Human Keratinocytes After Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang Kunzhong; Tian Yeping; Yin Liangjie

2011-09-01

Purpose: Epidermal keratinocytes, which can be severely damaged after ionizing radiation (IR), are rapid turnover cells that function as a barrier, protecting the host from pathogenic invasion and fluid loss. We tested fibroblast growth factor-peptide (FGF-P), a small peptide derived from the receptor-binding domain of FGF-2, as a potential mitigator of radiation effects via proliferation and the barrier function of keratinocytes. Methods and Materials: Keratinocytes isolated from neonatal foreskin were grown on transwells. After being exposed to 0, 5, or 10 Gy IR, the cells were treated with a vehicle or FGF-P. The permeability of IR cells was assessed bymore » using transepithelial electrical resistance (TEER) and a paracellular tracer flux of fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) with Ussing chambers. The cell proliferation was measured with yellow tetrazolium salt (MTT) and tritiated thymidine ([{sup 3}H]-TdR) assays. The phosphorylation of extracellular signal-regulated kinases (ERK) was measured in an enzyme-linked immunosorbent (ELISA)-like assay, and the proteins related to tight junctions (TJ) and adherens junctions (AJ) were examined with Western blotting. We used a mouse model to assess the ability of FGF-P to promote the healing of skin {beta} burns created with a strontium applicator. Results: We found (1) FGF-P reduced the permeability of irradiated keratinocytes, as evidenced by increased TEER and decreased diffusion of FITC-BSA, both associated with the regulation of different proteins and levels of TJ and AJ; and (2) FGF-P enhanced the proliferation of irradiated keratinocytes, as evidenced by increased MTT activity and [{sup 3}H]-TdR incorporation, which was associated with activation of the ERK pathway; and (3) FGF-P promoted the healing of skin {beta} burns. Conclusions: FGF-P enhances the barrier function, including up-regulation of TJ proteins, increases proliferation of human keratinocytes, and accelerates

Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC/IL-17A pathway modulation.

PubMed

Nadeem, Ahmed; Al-Harbi, Naif O; Al-Harbi, Mohamed M; El-Sherbeeny, Ahmed M; Ahmad, Sheikh F; Siddiqui, Nahid; Ansari, Mushtaq A; Zoheir, Khairy M A; Attia, Sabry M; Al-Hosaini, Khaled A; Al-Sharary, Shakir D

2015-09-01

Psoriasis is one of the most common skin disorders characterized by erythematous plaques that result from hyperproliferative keratinocytes and infiltration of inflammatory leukocytes into dermis and epidermis. Recent studies suggest that IL-23/IL-17A/IL-22 cytokine axis plays an important role in the pathogenesis of psoriasis. The small molecule bromodomain and extraterminal domain (BET) inhibitors, that disrupt interaction of BET proteins with acetylated histones have recently demonstrated efficacy in various models of inflammation through suppression of several pathways, one of them being synthesis of IL-17A/IL-22 which primarily depends on transcription factor, retinoic acid receptor-related orphan receptor C (RORC). However, the efficacy and mechanistic aspect of a BET inhibitor in mouse model of skin inflammation has not been explored previously. Therefore, this study investigated the role of BET inhibitor, JQ-1 in mouse model of psoriasis-like inflammation. Mice were topically applied imiquimod (IMQ) to develop psoriasis-like inflammation on the shaved back and ear followed by assessment of skin inflammation (myeloperoxidase activity, ear thickness, and histopathology), RORC and its signature cytokines (IL-17A/IL-22). JQ-1 suppressed IMQ-induced skin inflammation as reflected by a decrease in ear thickness/myeloperoxidase activity, and RORC/IL-17A/IL-22 expression. Additionally, a RORα/γ agonist SR1078 was utilized to investigate the role of RORC in BET-mediated skin inflammation. SR1078 reversed the protective effect of JQ-1 on skin inflammation at both histological and molecular levels in the IMQ model. The current study suggests that BET bromodomains are involved in psoriasis-like inflammation through induction of RORC/IL-17A pathway. Therefore, inhibition of BET bromodomains may provide a new therapy against skin inflammation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ski protein levels increase during in vitro progression of HPV16-immortalized human keratinocytes and in cervical cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Yi; Pirisi, Lucia; Creek, Kim E., E-mail: creekk@sccp.sc.edu

2013-09-15

We compared the levels of the Ski oncoprotein, an inhibitor of transforming growth factor-beta (TGF-β) signaling, in normal human keratinocytes (HKc), HPV16 immortalized HKc (HKc/HPV16), and differentiation resistant HKc/HPV16 (HKc/DR) in the absence and presence of TGF-β. Steady-state Ski protein levels increased in HKc/HPV16 and even further in HKc/DR, compared to HKc. TGF-β treatment of HKc, HKc/HPV16, and HKc/DR dramatically decreased Ski. TGF-β-induced Ski degradation was delayed in HKc/DR. Ski and phospho-Ski protein levels are cell cycle dependent with maximal Ski expression and localization to centrosomes and mitotic spindles during G2/M. ShRNA knock down of Ski in HKc/DR inhibited cellmore » proliferation. More intense nuclear and cytoplasmic Ski staining and altered Ski localization were found in cervical cancer samples compared to adjacent normal tissue in a cervical cancer tissue array. Overall, these studies demonstrate altered Ski protein levels, degradation and localization in HPV16-transformed human keratinocytes and in cervical cancer. - Highlights: • Ski oncoprotein levels increase during progression of HPV16-transformed cells. • Ski and phospho-Ski protein levels are cell cycle dependent. • Ski knock-down in HPV16-transformed keratinocytes inhibited cell proliferation. • Cervical cancer samples overexpress Ski.« less

Epidemiology and treatment of psoriasis: a Brazilian perspective

PubMed Central

Duarte, Gleison V; Porto-Silva, Larissa; de Oliveira, Maria de Fátima Paim

2015-01-01

Psoriasis is a chronic immune-mediated systemic disease that is influenced by genetic and environmental factors, is associated with comorbidities, and has a negative impact on the quality of life of affected individuals. The prevalence of psoriasis varies among different ethnic groups, but this topic has not been studied in Brazil to date. In this review, we evaluate the epidemiology and treatment of psoriasis from a Brazilian perspective. We focused on studies that involved Brazilian subjects. The prevalence of psoriasis in Brazil is estimated to be 2.5%, but no population study has been performed previously. Environmental factors, such as tropical climate, in association with genetic factors, such as miscegenation, may exert a beneficial impact on the course and frequency of psoriasis in Brazil. A number of studies have advanced our understanding of the cardiovascular, ophthalmic, and oral comorbidities that are associated with psoriasis. Concerns about biological therapy, such as endemic leprosy, human T-cell lymphotropic virus (HTLV), and tuberculosis infections, are discussed. The nonavailability of treatment options for psoriasis in the public health system contradicts the Brazilian Society of Dermatology guidelines, stimulating the judicialization of access to medicines in psoriasis care. PMID:29387582

Association of Psoriasis and Metabolic Syndrome in Latin America: A Systematic Review and Meta-Analysis.

PubMed

Rodríguez-Zúñiga, M J M; Cortez-Franco, F; Quijano-Gomero, E

2017-05-01

Meta-analyses have found evidence of a relationship between psoriasis and metabolic syndrome, but Latin American populations have not been included. We performed a systematic review and meta-analysis of observational studies including adults with psoriasis and metabolic syndrome indexed in Medline, Scopus, SciELO, Google Scholar, Science Direct, and LILACS between 1980 and 2016. We computed pooled odds ratios (OR) with a random effects model and analyzed subgroups according to patient variables used in the studies. Five studies with a total of 241 patients with psoriasis were found; 46.5% of the patients also had metabolic syndrome (pooled OR, 2.63; 95% CI: 1.11-6.23; P=.03). In studies using the Adult Treatment Panel III (ATP-III) criteria for metabolic syndrome, the pooled OR was similar at 3.97 (95% CI: 1.27-21.42). Studies that included patients with chronic and severe disease detected higher risk for metabolic syndrome (pooled OR, 6.65; 95% CI: 3.32-13.31). Limitations are that few studies have been done in Latin America, heterogeneity was high, and inconsistency was found across studies. The association between psoriasis and metabolic syndrome is high in Latin America. The association is stronger when psoriasis is chronic and severe and when the ATP-III criteria are used for diagnosis. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.

PubMed

Sa, Susan M; Valdez, Patricia A; Wu, Jianfeng; Jung, Kenneth; Zhong, Fiona; Hall, Linda; Kasman, Ian; Winer, Jane; Modrusan, Zora; Danilenko, Dimitry M; Ouyang, Wenjun

2007-02-15

IL-19, IL-20, IL-22, IL-24, and IL-26 are members of the IL-10 family of cytokines that have been shown to be up-regulated in psoriatic skin. Contrary to IL-10, these cytokines signal using receptor complex R1 subunits that are preferentially expressed on cells of epithelial origin; thus, we henceforth refer to them as the IL-20 subfamily cytokines. In this study, we show that primary human keratinocytes (KCs) express receptors for these cytokines and that IL-19, IL-20, IL-22, and IL-24 induce acanthosis in reconstituted human epidermis (RHE) in a dose-dependent manner. These cytokines also induce expression of the psoriasis-associated protein S100A7 and keratin 16 in RHE and cause persistent activation of Stat3 with nuclear localization. IL-22 had the most pronounced effects on KC proliferation and on the differentiation of KCs in RHE, inducing a decrease in the granular cell layer (hypogranulosis). Furthermore, gene expression analysis performed on cultured RHE treated with these cytokines showed that IL-19, IL-20, IL-22, and IL-24 regulate many of these same genes to variable degrees, inducing a gene expression profile consistent with inflammatory responses, wound healing re-epithelialization, and altered differentiation. Many of these genes have also been found to be up-regulated in psoriatic skin, including several chemokines, beta-defensins, S100 family proteins, and kallikreins. These results confirm that IL-20 subfamily cytokines are important regulators of epidermal KC biology with potentially pivotal roles in the immunopathology of psoriasis.

Sirt1 Protects against Oxidative Stress-Induced Apoptosis in Fibroblasts from Psoriatic Patients: A New Insight into the Pathogenetic Mechanisms of Psoriasis.

PubMed

Becatti, Matteo; Barygina, Victoria; Mannucci, Amanda; Emmi, Giacomo; Prisco, Domenico; Lotti, Torello; Fiorillo, Claudia; Taddei, Niccolò

2018-05-25

Psoriasis, a multisystem chronic disease characterized by abnormal keratinocyte proliferation, has an unclear pathogenesis where systemic inflammation and oxidative stress play mutual roles. Dermal fibroblasts, which are known to provide a crucial microenvironment for epidermal keratinocyte function, represented the selected experimental model in our study which aimed to clarify the potential role of SIRT1 in the pathogenetic mechanisms of the disease. We firstly detected the presence of oxidative stress (lipid peroxidation and total antioxidant capacity), significantly reduced SIRT1 expression level and activity, mitochondrial damage and apoptosis (caspase-3, -8 and -9 activities) in psoriatic fibroblasts. Upon SIRT1 activation, redox balance was re-established, mitochondrial function was restored and apoptosis was no longer evident. Furthermore, we examined p38, ERK and JNK activation, which was strongly altered in psoriatic fibroblasts, in response to SIRT1 activation and we measured caspase-3 activity in the presence of specific MAPK inhibitors demonstrating the key role of the SIRT1 pathway against apoptotic cell death via MAPK modulation. Our results clearly demonstrate the involvement of SIRT1 in the protective mechanisms related to fibroblast injury in psoriasis. SIRT1 activation exerts an active role in restoring both mitochondrial function and redox balance via modulation of MAPK signaling. Hence, SIRT1 can be proposed as a specific tool for the treatment of psoriasis.

Pustular psoriasis: pathophysiology and current treatment perspectives

PubMed Central

Benjegerdes, Katie E; Hyde, Kimberly; Kivelevitch, Dario; Mansouri, Bobbak

2016-01-01

Psoriasis vulgaris is a chronic inflammatory disease that classically affects skin and joints and is associated with numerous comorbidities. There are several clinical subtypes of psoriasis including the uncommon pustular variants, which are subdivided into generalized and localized forms. Generalized forms of pustular psoriasis include acute generalized pustular psoriasis, pustular psoriasis of pregnancy, and infantile and juvenile pustular psoriasis. Localized forms include acrodermatitis continua of Hallopeau and palmoplantar pustular psoriasis. These subtypes vary in their presentations, but all have similar histopathologic characteristics. The immunopathogenesis of each entity remains to be fully elucidated and some debate exists as to whether these inflammatory pustular dermatoses should be classified as entities distinct from psoriasis vulgaris. Due to the rarity of these conditions and the questionable link to the common, plaque-type psoriasis, numerous therapies have shown variable results and most entities remain difficult to treat. With increasing knowledge of the pathogenesis of these variants of pustular psoriasis, the development and use of biologic and other immunomodulatory therapies holds promise for the future of successfully treating pustular variants of psoriasis. PMID:29387600

Streptococcal throat infections and exacerbation of chronic plaque psoriasis: a prospective study.

PubMed

Gudjonsson, J E; Thorarinsson, A M; Sigurgeirsson, B; Kristinsson, K G; Valdimarsson, H

2003-09-01

Guttate psoriasis has a well-known association with streptococcal throat infections but the effects of these infections in patients with chronic psoriasis remains to be evaluated in a prospective study. To determine whether streptococcal throat infections are more common in and can cause exacerbation in patients with chronic psoriasis. Two hundred and eight patients with chronic plaque psoriasis and 116 unrelated age-matched household controls were followed for 1 year. At recruitment all patients were examined, their disease severity scored and throat swabs taken. Patients and corresponding controls were then re-examined and tested for streptococcal colonization whenever they reported sore throat or exacerbation of their psoriasis during the study period. The psoriasis patients reported sore throat significantly more often than controls (61 of 208 vs. three of 116, P < 0.0001), and beta-haemolytic streptococci of Lancefield groups A, C and G (M protein-positive streptococci) were more often cultured from the patients than the controls (19 of 208 vs. one of 116, P = 0.003). A significant exacerbation of psoriasis (P = 0.004) was observed only if streptococci were isolated and the patients were assessed 4 days or later after the onset of sore throat. No difference was observed between groups A, C or G streptococci in this respect. This study confirms anecdotal and retrospective reports that streptococcal throat infections can cause exacerbation of chronic plaque psoriasis. It is concluded that psoriasis patients should be encouraged to report sore throat to their physician and that early treatment of streptococcal throat infections might be beneficial in psoriasis. A controlled trial for assessing potential benefits of tonsillectomy in patients with severe psoriasis should also be considered.

Association of β-defensin copy number and psoriasis in three cohorts of European origin

PubMed Central

Stuart, Philip E; Hüffmeier, Ulrike; Nair, Rajan P; Palla, Raquel; Tejasvi, Trilokraj; Schalkwijk, Joost; Elder, James T; Reis, Andre; Armour, John AL

2012-01-01

A single previous study has demonstrated significant association of psoriasis with copy number of beta-defensin genes, using DNA from psoriasis cases and controls from Nijmegen and Erlangen. In this study we attempted to replicate that finding in larger new cohorts from Erlangen (N = 2017) and Michigan (N = 5412), using improved methods for beta-defensin copy number determination based on the paralog ratio test (PRT), and enhanced methods of analysis and association testing implemented in the CNVtools resource. We demonstrate that the association with psoriasis found in the discovery sample is maintained after applying improved typing and analysis methods (p = 5.5 × 10−4, OR = 1.25). We also find that the association is replicated in 2616 cases and 2526 controls from Michigan, although at reduced significance (p = 0.014), but not in new samples from Erlangen (1396 cases and 621 controls, p = 0.38). Meta-analysis across all cohorts suggests a nominally significant association (p = 6.6 × 10−3/2 × 10−4) with an effect size (OR = 1.081) much lower than found in the discovery study (OR = 1.32). This reduced effect size and significance on replication is consistent with a genuine but weak association. PMID:22739795

Psoriasis and Comorbid Diseases Part I. Epidemiology

PubMed Central

Takeshita, Junko; Grewal, Sungat; Langan, Sinéad M.; Mehta, Nehal N.; Ogdie, Alexis; Van Voorhees, Abby S.; Gelfand, Joel M.

2017-01-01

Psoriasis is a common chronic inflammatory disease of the skin that is increasingly being recognized as a systemic inflammatory disorder. Psoriatic arthritis is a well-known comorbidity of psoriasis. A rapidly expanding body of literature in various populations and settings supports additional associations between psoriasis and cardiometabolic disease, gastrointestinal disease, kidney disease, malignancies, infections, and mood disorders. The pathogenesis of comorbid disease in psoriasis patients remains unknown; however, shared inflammatory pathways, cellular mediators, genetic susceptibility, and common risk factors are hypothesized to be contributing elements. As additional psoriasis comorbidities continue to emerge, education of healthcare providers is essential to ensuring comprehensive medical care for patients with psoriasis. PMID:28212759

Clinical characteristics of patients with facial psoriasis in Malaysia.

PubMed

Syed Nong Chek, Sharifah Rosniza; Robinson, Suganthy; Mohd Affandi, Azura; Baharum, Nurakmal

2016-10-01

Psoriasis involving the face is visible and can cause considerable emotional distress to patients. Its presence may also confer a poorer prognosis for the patient. This study sought to evaluate the characteristics of facial psoriasis in Malaysia. A cross-sectional study conducted using data from the Malaysian Psoriasis Registry from 2007 to 2011. Specific risk factors, i.e., age, age of onset, gender, duration of disease, obesity group, body surface area, Dermatology Life Quality Index (DLQI), family history of psoriasis, nail involvement, psoriatic arthritis, phototherapy, systemic therapy, clinic visit, days of work/school, and hospital admission due to psoriasis in the last 6 months were analyzed. A total of 48.4% of patients had facial psoriasis. Variables significantly associated with facial psoriasis are younger age, younger age of onset of psoriasis of ≤ 40 years, male, severity of psoriasis involving >10% of the body surface area, higher DLQI of >10, nail involvement, and history of hospitalization due to psoriasis. This study found that facial psoriasis is not as rare as previously thought. Ambient ultraviolet light, sebum, and contact with chemicals from facial products may reduce the severity of facial psoriasis, but these factors do not reduce the prevalence of facial psoriasis. The association with younger age, younger age of onset, higher percentage of body surface area involvement, higher DLQI of > 10, nail involvement, and hospitalization due to psoriasis support the notion that facial psoriasis is a marker of severe disease. © 2016 The International Society of Dermatology.

Subjective stress reactivity in psoriasis - a cross sectional study of associated psychological traits.

PubMed

Remröd, Charlotta; Sjöström, Karin; Svensson, Åke

2015-05-02

Stress or psychological distress is often described as a causative or maintaining factor in psoriasis. Psychological traits may influence the appraisal, interpretation and coping ability regarding stressful situations. Detailed investigations of psychological traits in relation to stress reactivity in psoriasis are rare. The aim of this study was to examine whether patients with psoriasis who report an association between psychological distress and exacerbation, "stress reactors" (SRs), differ psychologically from those with no stress reactivity "non-stress reactors" (NSRs). This cross-sectional study was conducted among 101 consecutively recruited outpatients with plaque psoriasis. A psychosocial interview was performed including questions concerning stress reactivity in relation to onset and exacerbation. Three validated self-rating scales were used: Spielberger State-Trait Anxiety Inventory (STAI, Form-Y), Beck Depression Inventory (BDI-II) and Swedish Universities Scales of Personality (SSP). Independent samples t-tests, Chi-square tests and one-way ANOVA analyses were used for group comparisons when appropriate. A logistic regression model was designed with SR as the dependent variable. Sixty-four patients (63%) reported a subjective association between disease exacerbation and stress (SRs). Patients defined as SRs reported significantly higher mean scores regarding state and trait anxiety, depression, and also five SSP scale personality traits, i.e. somatic trait anxiety, psychic trait anxiety, stress susceptibility, lack of assertiveness and mistrust, compared with NSRs. In multivariate analysis, SSP-stress susceptibility was the strongest explanatory variable for SR, i.e. OR (95% CI)=1.13 (1.02 - 1.24), p=0.018. According to our results, patients who perceive stress as a causal factor in their psoriasis might have a more vulnerable psychological constitution. This finding suggests important opportunities for clinicians to identify patients who may benefit

HLA-Cw6 homozygosity in plaque psoriasis is associated with streptococcal throat infections and pronounced improvement after tonsillectomy: A prospective case series.

PubMed

Thorleifsdottir, Ragna H; Sigurdardottir, Sigrun L; Sigurgeirsson, Bardur; Olafsson, Jon H; Petersen, Hannes; Sigurdsson, Martin I; Gudjonsson, Johann E; Johnston, Andrew; Valdimarsson, Helgi

2016-11-01

Carriage of the HLA-Cw*0602 allele is associated with a particular set of clinical features and treatment responses in psoriasis. Tonsillectomy can improve psoriasis. We sought to evaluate whether HLA-Cw*0602 predicts a favorable outcome after tonsillectomy of patients with psoriasis. This prospective case series followed up 28 tonsillectomized patients with plaque psoriasis for 24 months. The Psoriasis Area and Severity Index, Psoriasis Disability Index, and Psoriasis Life Stress Inventory were used for assessment. Tonsils were swabbed for bacteria and patients genotyped for HLA-Cw*0602. After tonsillectomy, HLA-Cw*0602 homozygotes showed significantly more improvement, compared with heterozygous and HLA-Cw*0602-negative patients. Thus, Psoriasis Area and Severity Index score was reduced by 82% in the homozygous patients compared with 42% and 31%, respectively (P < .001), Psoriasis Disability Index score improved by 87% compared with 38% and 41%, respectively (P < .001), and Psoriasis Life Stress Inventory score was 82% reduced compared with 60% and 54%, respectively (P < .001). The homozygotes more often had psoriasis onset associated with a throat infection (P = .007) and an increased frequency of streptococcal throat infections per lifetime (P = .038). Few patients were included and some data were retrospective. Homozygous HLA-Cw*0602 carriage in plaque psoriasis may predict a favorable outcome after tonsillectomy. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Relationship Between the Serum Total Bilirubin and Inflammation in Patients With Psoriasis Vulgaris.

PubMed

Zhou, Zhen-Xing; Chen, Jian-Kui; Hong, Yan-Ying; Zhou, Ru; Zhou, Dong-Mei; Sun, Li-Yun; Qin, Wen-Li; Wang, Tian-Cheng

2016-09-01

Psoriasis is a chronic and recurrent inflammatory skin disease. Previous studies have shown that bilirubin has anti-inflammation and antioxidant effects. However, the various roles of bilirubin in psoriasis patients are still unclear. To investigate the serum total bilirubin (TB) level in the individuals with psoriasis vulgaris and further evaluate the relationship between serum TB concentration and C-reactive protein (CRP) to clarify the effect of bilirubin on inflammation. A total of 214 patients with psoriasis vulgaris and 165 age- and gender-matched healthy control subjects were recruited. The peripheral leukocyte count (white blood cell, WBC) and differential, serum biochemical and immunologic indexes including serum TB, immunoglobulin (Ig) G, IgA, IgM, complement C3 and C4 , as well as serum CRP concentrations were measured. Results showed that the serum TB level decreased significantly and peripheral WBC, neutrophil, and serum CRP concentrations increased significantly in patients with psoriasis vulgaris. Meanwhile, the serum CRP was negatively correlated with serum TB levels but positively correlated with peripheral WBC and the Psoriasis Area and Severity Index (PASI). Logistic regression analysis showed that the serum TB was a protective factor for psoriasis vulgaris. The present study suggests that lower serum TB is associated with the enhancement of the inflammatory response in psoriasis vulgaris. Therefore, lower serum TB has a prognostic significance for worsening psoriasis vulgaris. Bilirubin may play a crucial role in inflammation by contributing to the inhibition of the inflammatory response. © 2016 Wiley Periodicals, Inc.

Increased Incidence of Critical Illness in Psoriasis.

PubMed

Marrie, Ruth Ann; Bernstein, Charles N; Peschken, Christine A; Hitchon, Carol A; Chen, Hui; Garland, Allan

Psoriasis is associated with an increased risk of comorbid disease. Despite the recognition of increased morbidity in psoriasis, the effects on health care utilisation remain incompletely understood. Little is known about the risk of intensive care unit (ICU) admission in persons with psoriasis. To compare the incidence of ICU admission and post-ICU mortality rates in a psoriasis population compared with a matched population without psoriasis. Using population-based administrative data from Manitoba, Canada, we identified 40 930 prevalent cases of psoriasis and an age-, sex-, and geographically matched cohort from the general population (n = 150 210). We compared the incidence of ICU admission between populations using incidence rates and Cox regression models adjusted for age, sex, socioeconomic status, and comorbidity and compared mortality after ICU admission. Among incident psoriasis cases (n = 30 150), the cumulative 10-year incidence of ICU admission was 5.6% (95% confidence interval [CI], 5.3%-5.8%), 21% higher than in the matched cohort (incidence rate ratio, 1.21; 95% CI, 1.15-1.27). In the prevalent psoriasis cohort, crude mortality in the ICU was 11.5% (95% CI, 9.9%-13.0%), 32% higher than observed in the matched population admitted to the ICU (8.7%; 95% CI, 8.3%-9.1%). Mortality rates after ICU admission remained elevated at all time points in the psoriasis cohort compared with the matched cohort. Psoriasis is associated with an increased risk for ICU admission and with an increased risk of mortality post-ICU admission.

An Expert's Advice: What To Do If You Have Psoriasis

MedlinePlus

... on. Feature: Living with Psoriasis An Expert's Advice: What To Do If You Have Psoriasis Past Issues / ... the Dermatology Foundation, and the American Skin Association. What is psoriasis? Psoriasis is a chronic (long-term) ...

Differentiation and injury-repair signals modulate the interaction of E2F and pRB proteins with novel target genes in keratinocytes.

PubMed

Chang, Wing Y; Andrews, Joseph; Carter, David E; Dagnino, Lina

2006-08-01

E2F transcription factors are central to epidermal morphogenesis and regeneration after injury. The precise nature of E2F target genes involved in epidermal formation and repair has yet to be determined. Identification of these genes is essential to understand how E2F proteins regulate fundamental aspects of epidermal homeostasis and transformation. We have conducted a genome-wide screen using CpG island microarray analysis to identify novel promoters bound by E2F3 and E2F5 in human keratinocytes. We further characterized several of these genes, and determined that multiple E2F and retinoblastoma (pRb) family proteins associate with them in exponentially proliferating cells. We also assessed the effect on E2F and pRb binding to those genes in response to differentiation induced by bone morphogenetic protein-6 (BMP-6), or to activation of repair mechanisms induced by transforming growth factor-beta (TGF-beta). These studies demonstrate promoter- and cytokine-specific changes in binding profiles of E2F and/or pRb family proteins. For example, E2F1, 3, 4 and p107 were recruited to the N-myc promoter in cells treated with BMP-6, whereas E2F1, 3, 4, 5, p107 and p130 were bound to this promoter in the presence of TGF-beta. Functionally, these different interactions resulted in transcriptional repression by BMP-6 and TGF-beta of the N-myc gene, via mechanisms that involved E2F binding to the promoter and association with pRb-family proteins. Thus, multiple combinations of E2F and pRb family proteins may associate with and transcriptionally regulate a given target promoter in response to differentiation and injury-repair stimuli in epidermal keratinocytes.

Psoriasis Diet: Can Changing Your Diet Treat Psoriasis?

MedlinePlus

... my diet treat psoriasis? Answers from Lawrence E. Gibson, M.D. Although there's no special psoriasis diet, ... or rule out this condition. With Lawrence E. Gibson, M.D. Diet and nutrition. National Psoriasis Foundation. ...

Altered (/sup 125/I)epidermal growth factor binding and receptor distribution in psoriasis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nanney, L.B.; Stoscheck, C.M.; Magid, M.

1986-03-01

Stimulation of growth and differentiation of human epidermis by epidermal growth factor (EGF) is mediated by its binding to specific receptors. Whether EGF receptors primarily mediate cell division or differentiation in hyperproliferative disease such as psoriasis vulgaris is unclear. To study the pathogenesis of psoriasis, 4-mm2 punch biopsy specimens of normal, uninvolved, and involved psoriatic skin were assayed for EGF receptors by autoradiographic, immunohistochemical, and biochemical methods. Using autoradiographic and immunohistochemical methods, basal keratinocytes were found to contain the greatest number of EGF binding sites and immunoreactive receptors as compared to the upper layers of the epidermis in both normalmore » epidermis and psoriatic skin. No EGF receptor differences between normal and psoriatic epidermis were observed in this layer. In the upper layers of the epidermis, a 2-fold increase in EGF binding capacity was observed in psoriatic skin as compared with normal thin or thick skin. Biochemical methods indicated that (/sup 125/I)EGF binding was increased in psoriatic epidermis as compared with similar thickness normal epidermis when measured on a protein basis. Epidermal growth factor was shown to increase phosphorylation of the EGF receptor in skin. EGF receptors retained in the nonmitotic stratum spinosum and parakeratotic stratum corneum may reflect the incomplete, abnormal differentiation that occurs in active psoriatic lesions. Alternatively, retained EGF receptors may play a direct role in inhibiting cellular differentiation in the suprabasal layers.« less

PDTCM: a systems pharmacology platform of traditional Chinese medicine for psoriasis.

PubMed

Wang, Dongmei; Gu, Jiangyong; Zhu, Wei; Luo, Fang; Chen, Lirong; Xu, Xiaojie; Lu, Chuanjian

2017-12-01

Psoriasis is a refractory skin disorder, and usually requires a lifetime control. Traditional Chinese medicine (TCM) is effective and safe for this disease. However, the cellular and molecular mechanisms of TCM remedies for psoriasis are still not fully understood. TCM contains numerous natural products. Natural products have historically been invaluable as a resource of therapeutic agents. Yet, there is no integrated information about active compounds of TCM for psoriasis. We use systems pharmacology methods to develop the Psoriasis Database of Traditional Chinese Medicine (PDTCM). The database covered a number of psoriasis-related information (formulas, TCM, compounds, target proteins, diseases and biomarkers). With these data information, an online platform was constructed Results: PDTCM comprises 38 empirical therapeutic formulas, 34373 compounds from 1424 medicinal plants, 44 psoriasis-related proteins and 76 biomarkers from 111 related diseases. On this platform, users can screen active compounds for a psoriasis-related target and explore molecular mechanisms of TCM. Accordingly, users can also download the retrieved structures and data information with a defined value set. In addition, it helps to get a better understanding of Chinese prescriptions in disease treatment. With the systems pharmacology-based data, PDTCM would become a valuable resource for TCM in psoriasis-related research. Key messages PDTCM platform comprises a great deal of data on TCM and psoriasis. On this platform, users can retrieve and get needed information with systems pharmacology methods, such as active compounds screening, target prediction and molecular mechanisms exploration. It is a tool for psoriasis-related research on natural drugs systematically.

Psoriasis and suicidality: A systematic review and meta-analysis.

PubMed

Singh, Sanminder; Taylor, Catherine; Kornmehl, Heather; Armstrong, April W

2017-09-01

Psoriasis is associated with psychiatric comorbidities; however, the relationship between psoriasis and suicidality is not well understood. To perform a systematic review and meta-analysis that elucidates the relationship between psoriasis and suicidality. Applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we systematically searched the PubMed, EMBASE, PsycINFO, and Cochrane databases. We searched literature published between 1946 and 2017. We identified 18 studies with a total of 1,767,583 participants, of whom 330,207 had psoriasis. On the basis of random effects modeling, the pooled odds ratio (OR) for suicidal ideation among patients with psoriasis was 2.05 (95% confidence interval [CI], 1.54-2.74). Patients with psoriasis were more likely to exhibit suicidal behaviors (combined attempted and completed suicides) with a pooled OR of 1.26 (95% CI, 1.13-1.40). Subgroup analysis showed that patients with psoriasis were more likely to attempt suicides (OR, 1.32; 95% CI, 1.14-1.54) and complete suicide (OR, 1.20; 95% CI, 1.04-1.39) than those without psoriasis. More severe psoriasis and younger age were associated with greater likelihood of suicidality. There are few studies examining suicidality in conjunction with psoriasis severity. Patients with psoriasis have a significantly higher likelihood of suicidal ideation, suicide attempts, and completed suicides. Among patients with psoriasis, those who are younger and whose psoriasis is more severe are at particular risk for suicidality. Copyright © 2017. Published by Elsevier Inc.

Non-invasive measurements to stratify cardiovascular disease risk in psoriasis patients

PubMed

Dickison, Philippa; J Peek, Jonathan; Swain, Grace; D Smith, Saxon

2018-05-01

Psoriasis is associated with cardiovascular disease (CVD) risk factors and mortality. The aims of this study were to identify CVD risk in patients with psoriasis, and to determine their awareness of the comorbidities. Patients with psoriasis and controls had their inter-arm blood pressure, weight, height and waist circumference measured at their routine clinic appointment. Those with psoriasis also completed a survey regarding awareness of the comorbidities. A total of 179 patients with psoriasis and 115 control patients participated in the study. Patients with psoriasis were significantly more likely to be obese (odds ration [OR] 6.3). An inter-arm blood pressure difference >10 mmHg was more likely in patients with psoriasis for systolic (OR 1.9) and diastolic (OR 2.3) readings. Survey data showed that 47 (26.3%) psoriasis patients knew that psoriasis was associated with being overweight. On the basis of anthropologic measurements, patients with psoriasis have a higher risk of CVD, compared with non-psoriasis patients. There is inadequate knowledge among psoriasis patients regarding the comorbidities of psoriasis.

Psoriasis - resources

MedlinePlus

Resources - psoriasis ... The following organizations are good resources for information about psoriasis : American Academy of Dermatology -- www.aad.org/skin-conditions/dermatology-a-to-z/psoriasis National Institute of ...

Effects of Human Mesenchymal Stem Cells Coculture on Calcium-Induced Differentiation of Normal Human Keratinocytes.

PubMed

Sah, Shyam Kishor; Kim, Hae Young; Lee, Ji Hae; Lee, Seong-Wook; Kim, Hyung-Sik; Kim, Yeon-Soo; Kang, Kyung-Sun; Kim, Tae-Yoon

2017-06-01

The influence of mesenchymal stem cells (MSCs) on keratinocytes in altered microenvironments is poorly understood. Here, we cocultured umbilical cord blood-derived MSCs with normal human epidermal keratinocytes to evaluate their paracrine effect in the presence of high extracellular calcium (Ca 2+ ) concentration. High Ca 2+ environment to keratinocytes can disrupt normal skin barrier function due to abnormal/premature differentiation of keratinocytes. Surprisingly, we found that MSCs suppress both proliferation and differentiation of keratinocytes under a high Ca 2+ environment in transforming growth factors β1 (TGFβ1)-dependent manner. Furthermore, we determined that MSCs can regulate the mitogen-activated protein kinases, phosphatidylinositol 3-kinase/protein kinase B, and protein kinase C pathways in Ca 2+ -induced differentiated keratinocytes. Knockdown of TGFβ1 from MSCs results in decreased suppression of differentiation with significantly increased proliferation of keratinocytes compared with control MSCs. MSCs-derived TGFβ1 further induced growth inhibition of keratinocyte in high extracellular Ca 2+ environment as analyzed by a decrease in DNA synthesis, accumulation of phosphorylated retinoblastoma protein, cdc2, and increased mRNA level of p21, and independent of TGFβ1/SMAD pathway. Taken together, we found that MSCs-derived TGFβ1 is a critical regulator of keratinocyte function, and involves multiple proximal signaling cascades. Stem Cells 2017;35:1592-1602. © 2017 AlphaMed Press.

Interleukin (IL)-8 and IL-36γ but not IL-36Ra are related to acrosyringia in pustule formation associated with palmoplantar pustulosis.

PubMed

Xiaoling, Y; Chao, W; Wenming, W; Feng, L; Hongzhong, J

2018-06-12

Palmoplantar pustulosis (PPP) is a refractory, nonbacterial impetigo confined to the palms and soles. Its pathogenesis is still obscure, but it may be associated with the large eccrine sweat glands and pores of palmoplantar skin. PPP is considered to be a localized pustular psoriasis. Interleukin (IL)-8, IL-36γ and IL-36Ra play important roles in the pathogenesis of pustular psoriasis, but their role in PPP is unclear. To evaluate IL-8, IL-36γ and IL-36Ra expression in PPP, and their relationship with acrosyringia and pustule formation. mRNA expression was quantified in skin samples from patients with PPP (n = 7), patients with psoriasis vulgaris (PSV; n = 8) and healthy controls (HCs) (n = 6) by reverse-transcription-real-time PCR. Protein expression was characterized by immunohistochemistry (PPP, n = 17; PSV, n = 14; HCs, n = 12). Sweat ducts, including acrosyringia, were stained for epithelial membrane antigen (EMA). IL-8 mRNA and protein were markedly increased in PPP lesions compared with PSV lesions or HC skin. IL-36γ mRNA and protein were significantly more abundant in PPP lesions than in HC skin. IL-36Ra mRNA was significantly overexpressed in PPP lesions compared with HC skin, but there was no difference in IL-36Ra protein between PPP, PSV and HCs. IL-8 was abundantly expressed by neutrophils in PPP pustules, while IL36Ra was localized in the keratinocytes of PPP, PSV and HC skin. IL-36γ and EMA were colocalized in cells surrounding PPP pustules, and IL-36γ was also expressed in sweat duct cells in the dermis. IL-8, IL-36γ and IL-36Ra are overexpressed in PPP lesions. IL-8, IL-36γ and acrosyringia, rather than IL-36Ra, are associated with pustule formation in PPP. © 2018 British Association of Dermatologists.

17beta-estradiol stimulates the growth of human keratinocytes by inducing cyclin D2 expression.

PubMed

Kanda, Naoko; Watanabe, Shinichi

2004-08-01

Estrogen is reported to prevent age-associated epidermal thinning in the skin. We examined if 17beta-estradiol (E2) may enhance the growth of human keratinocytes, focusing on its effects on the expression of cell cycle-regulatory proteins. E2 enhanced proliferation, bromodeoxyuridine incorporation of keratinocytes, and increased the proportion of cells in the S phase. The E2-induced stimulation of proliferation and bromodeoxyuridine incorporation was suppressed by antisense oligonucleotide against cyclin D2, which induces G1 to S phase progression. E2 increased protein and mRNA levels of cyclin D2, and resultantly enhanced assembly and kinase activities of cyclin D2-cyclin-dependent kinases 4 or 6 complexes. E2 enhanced cyclin D2 promoter activity, and the element homologous to cAMP response element (CRE) on the promoter was responsible for the effect. Cyclin D2 expression was enhanced by antiestrogens, ICI 182,780 and 4-hydroxytamoxifen, and membrane-impermeable bovine serum albumin-conjugated E2, indicating the effects via membrane E2-binding sites. E2 increased the enhancer activity of CRE-like element and the amount of phosphorylated cAMP response element binding protein (CREB) binding this element, and the increases were suppressed by H-89, an inhibitor of cAMP-dependent protein kinase A. H-89 also suppressed E2-induced cyclin D2 expression, proliferation, and bromodeoxyuridine incorporation in keratinocytes. Antisense oligonucleotide against G-protein-coupled receptor GPR30 suppressed the E2-induced increases of phosphorylated CREB, cyclin D2 level, proliferation, and bromodeoxyuridine incorporation in keratinocytes. These results suggest that E2 may stimulate the growth of keratinocytes by inducing cyclin D2 expression via CREB phosphorylation by protein kinase A, dependent on cAMP. These effects of E2 may be mediated via cell surface GPR30.

Dermoscopic features of nail psoriasis treated with biologics.

PubMed

Hashimoto, Yuki; Uyama, Miki; Takada, Yuko; Yoshida, Kenji; Ishiko, Akira

2017-05-01

Although psoriatic nail lesions are small, they cause considerable discomfort for patients and adversely affect quality of life. Few studies have evaluated the dermoscopic features of psoriatic nails. The aim of this study was to clarify the dermoscopic features of nail psoriasis and identify those that reflect psoriatic activity. During biologic treatment of psoriasis, six patients with psoriatic nails twice underwent dermoscopic examination, with an interval of 17-42 weeks. We used the modified Nail Psoriasis Severity Index score and Psoriasis Area and Severity Index score to identify and assess dermoscopic features. We identified 10 dermoscopic findings, of which disappearance of diffuse scaling of the nail plate, transverse step-like notches and splinter hemorrhages of the nail bed, and appearance of erythematous borders of the onycholytic area were associated with improvement in Psoriasis Area and Severity Index score. Dermoscopy can detect nail changes during psoriasis treatment and should be used to evaluate treatment success. © 2017 Japanese Dermatological Association.

Identification of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map.

PubMed

Hewett, Duncan; Samuelsson, Lena; Polding, Joanne; Enlund, Fredrik; Smart, Devi; Cantone, Kathryn; See, Chee Gee; Chadha, Sapna; Inerot, Annica; Enerback, Charlotta; Montgomery, Doug; Christodolou, Chris; Robinson, Phil; Matthews, Paul; Plumpton, Mary; Wahlstrom, Jan; Swanbeck, Gunnar; Martinsson, Tommy; Roses, Allen; Riley, John; Purvis, Ian

2002-03-01

Psoriasis is a chronic inflammatory disease of the skin with both genetic and environmental risk factors. Here we describe the creation of a single-nucleotide polymorphism (SNP) map spanning 900-1200 kb of chromosome 3q21, which had been previously recognized as containing a psoriasis susceptibility locus, PSORS5. We genotyped 644 individuals, from 195 Swedish psoriatic families, for 19 polymorphisms. Linkage disequilibrium (LD) between marker and disease was assessed using the transmission/disequilibrium test (TDT). In the TDT analysis, alleles of three of these SNPs showed significant association with disease (P<0.05). A 160-kb interval encompassing these three SNPs was sequenced, and a coding sequence consisting of 13 exons was identified. The predicted protein shares 30-40% homology with the family of cation/chloride cotransporters. A five-marker haplotype spanning the 3' half of this gene is associated with psoriasis to a P value of 3.8<10(-5). We have called this gene SLC12A8, coding for a member of the solute carrier family 12 proteins. It belongs to a class of genes that were previously unrecognized as playing a role in psoriasis pathogenesis.

Relapsing polychondritis associated with psoriasis vulgaris successfully treated with adalimumab: A case report with published work review.

PubMed

Matsuo, Haruka; Asahina, Akihiko; Fukuda, Takeshi; Umezawa, Yoshinori; Nakagawa, Hidemi

2017-07-01

Relapsing polychondritis (RP) is a rare autoimmune-mediated disease characterized by inflammation involving cartilaginous tissues. We report here a case of RP in a 38-year-old Japanese man with 13-year duration of psoriasis vulgaris treated with topical steroids and vitamin D 3 . The patient presented with tender swelling and erythema of both auricles, and the antibody to type II collagen was detected. The biopsy specimen revealed a dense mixed cell infiltration over the auricular cartilage. We reviewed eight cases with the association of RP and psoriasis, and in all cases the clinical course of psoriasis did not correlate with that of RP. The severity of RP was mild in the majority of cases, and our case was unique in that the patient had no joint symptoms. Adalimumab treatment was effective for both RP and psoriasis. Fat-suppressed contrast-enhanced magnetic resonance imaging was beneficial, not only to demonstrate subclinical inflammation in the nasal septum, but also to subjectively assess the improvement of RP. © 2017 Japanese Dermatological Association.

An evaluation of thiol/disulphide homeostasis in patients with psoriasis

PubMed Central

Yorulmaz, Ahu; Erdogan, Serpil; Cakmak, Seray Kulcu; Guney, Elif; Sen, Orhan; Erel, Ozcan

2017-01-01

Introduction The role of oxidative stress in the pathogenesis of psoriasis has been investigated in previous studies with conflicting results. On the other hand, well-established treatments currently used in psoriasis exert their effects via a boost of oxidative stress. Recently, a strong positive association between psoriasis, metabolic syndrome and dyslipidemia has also been described showing the complex nature of the disease. Aim To examine thiol/disulphide homeostasis, a newly developed homeostasis assay in psoriasis and evaluate the possible association between thiol/disulphide homeostasis and dyslipidemia in psoriasis. Material and methods The study population included 92 psoriasis patients and 71 healthy subjects. Serum native thiol, total thiol and disulphide levels were investigated in patients with psoriasis and in healthy subjects. In addition, lipid profile (serum total cholesterol, triglyceride, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol) levels were investigated in both groups. The association between thiol-disulphide parameters and dyslipidemia was also evaluated. Results Serum total cholesterol and triglyceride levels were found to be higher in patients with psoriasis than in the healthy group. Lower plasma disulphide and higher native thiol levels were found in patients with psoriasis indicating an antioxidant status. Conclusions To our knowledge, this is the first study showing the shift of dynamic thiol/disulphide homeostasis towards the thiol form in psoriasis which indicate higher antioxidant status. PMID:29507562

EPA attenuates ultraviolet radiation-induced downregulation of aquaporin-3 in human keratinocytes.

PubMed

Jeon, Byoung-Kook; Kang, Moon-Kyung; Lee, Ghang-Tai; Lee, Kun-Kuk; Lee, Ho-Sub; Woo, Won-Hong; Mun, Yeun-Ja

2015-08-01

Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid (ω-3 PUFA) that protects against photodamage and photocarcinogenesis in mammals. Aquaporin-3 (AQP3) is a water/glycerol transport protein that is found in basal layer keratinocytes. In this study, we have investigated the protective effect of EPA against ultraviolet B (UVB)-induced AQP3 downregulation in human keratinocytes. EPA treatment was found to increase AQP3 gene and protein expression in human epidermal keratinocytes (HaCaT). Using a specific inhibitor, we observed that the effect of EPA on AQP3 expression was mediated by extracellular signal-regulated kinase (ERK) activation. UVB radiation induced AQP3 downregulation in HaCaT cells, and it was found that EPA treatment attenuated UVB-induced AQP3 reduction and the associated cell death. UVB-induced downregulation of AQP3 was blocked by EPA and p38 inhibitor SB203580. Collectively, the present results show that EPA increased AQP3 expression and that this led to a reduction UVB-induced photodamage.

Sleep disturbance in psoriasis - a case-controlled study.

PubMed

Jensen, P; Zachariae, C; Skov, L; Zachariae, R

2018-04-28

Sleep is essential for daytime functioning and health. Given the physical symptoms of psoriasis, a higher prevalence of sleep disorders could be expected. So far, the studies examining sleep disturbance in psoriasis have been of less-than-optimal methodological quality and with mixed results. We aimed to: 1) examine the prevalence of sleep disturbance in patients with plaque psoriasis compared to controls, 2) evaluate associations with health-related quality of life (HRQoL), and 3) examine possible disease-related predictors of disturbed sleep. We used a cross-sectional, case-controlled design. Participants included 179 consecutively recruited patients with plaque psoriasis and 105 controls. Measures included psoriasis severity (Psoriasis Area and Severity index [PASI]); HRQoL (Dermatology Life Quality Index [DLQI]); insomnia severity (Insomnia Severity Index [ISI]); sleep quality (Pittsburgh Sleep Quality Index [PSQI]); stress (Perceived Stress Scale [PSS]); Itch (Itch Severity Scale [ISS]); and depressive symptoms (Beck Depression Inventory [BDI]). Analyses included group comparisons and regression analyses to identify predictors of sleep disturbance. Twenty-five per cent of patients with psoriasis reported clinical insomnia (ISI > 15), compared with 10.5% of controls. In all, 53.9% of patients with psoriasis were poor sleepers (PSQI > 5), compared with 21.9% of controls. Itch was statistically significantly associated with all sleep-related outcomes. A higher proportion of patients with psoriasis suffer from poor sleep than controls from the general population. Itch was the main predictor of impaired sleep. Improved control of psoriasis with decreased itch may improve sleep disturbance in psoriasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Clinical efficacy and IL-17 targeting mechanism of Indigo naturalis as a topical agent in moderate psoriasis.

PubMed

Cheng, Hui-Man; Wu, Yang-Chang; Wang, Qingmin; Song, Michael; Wu, Jackson; Chen, Dion; Li, Katherine; Wadman, Eric; Kao, Shung-Te; Li, Tsai-Chung; Leon, Francisco; Hayden, Karen; Brodmerkel, Carrie; Chris Huang, C

2017-09-02

Indigo naturalis is a Traditional Chinese Medicine (TCM) ingredient long-recognized as a therapy for several inflammatory conditions, including psoriasis. However, its mechanism is unknown due to lack of knowledge about the responsible chemical entity. We took a different approach to this challenge by investigating the molecular profile of Indigo naturalis treatment and impacted pathways. A randomized, double-blind, placebo-controlled clinical study was conducted using Indigo naturalis as topical monotherapy to treat moderate plaque psoriasis in a Chinese cohort (n = 24). Patients were treated with Indigo naturalis ointment (n = 16) or matched placebo (n = 8) twice daily for 8 weeks, with 1 week of follow-up. At week 8, significant improvements in Psoriasis Area and Severity Index (PASI) scores from baseline were observed in Indigo naturalis-treated patients (56.3% had 75% improvement [PASI 75] response) compared with placebo (0.0%). A gene expression signature of moderate psoriasis was established from baseline skin biopsies, which included the up-regulation of the interleukin (IL)-17 pathway as a key component; Indigo naturalis treatment resulted in most of these signature genes returning toward normal, including down-regulation of the IL-17 pathway. Using an in vitro keratinocyte assay, an IL-17-inhibitory effect was observed for tryptanthrin, a component of Indigo naturalis. This study demonstrated the clinical efficacy of Indigo naturalis in moderate psoriasis, and exemplified a novel experimental medicine approach to understand TCM targeting mechanisms. NCT01901705 .

Critical role of environmental factors in the pathogenesis of psoriasis.

PubMed

Zeng, Jinrong; Luo, Shuaihantian; Huang, Yumeng; Lu, Qianjin

2017-08-01

Psoriasis is a common cutaneous disease with multifactorial etiology including genetic and non-genetic factors, such as drugs, smoking, drinking, diet, infection and mental stress. Now, the role of the interaction between environmental factors and genetics are considered to be a main factor in the pathogenesis of psoriasis. However, it is a challenge to explore the mechanisms how the environmental factors break the body balance to affect the onset and development of psoriasis. In this article, we review the pathogenesis of psoriasis and summarize numerous clinical data to reveal the association between environmental factors and psoriasis. In addition, we focus on the mechanisms of environmental risk factors impact on psoriasis and provide a series of potential treatments against environmental risk factors. © 2017 Japanese Dermatological Association.

Low-concentration vemurafenib induces the proliferation and invasion of human HaCaT keratinocytes through mitogen-activated protein kinase pathway activation.

PubMed

Roh, Mi Ryung; Kim, Jung Min; Lee, Sang Hee; Jang, Hong Sun; Park, Kyu Hyun; Chung, Kee Yang; Rha, Sun Young

2015-09-01

Cutaneous squamous cell carcinomas and keratoacanthomas commonly occur in patients treated with BRAF inhibitors. We investigated the effect of the BRAF inhibitor vemurafenib on normal immortalized human HaCaT keratinocytes to explore the mechanism of hyperproliferative cutaneous neoplasia associated with the use of BRAF inhibitors. Vemurafenib induced an increase in viable cell number in BRAF wild-type cell lines (SK-MEL-2 and HaCaT) but not in BRAF mutant cell lines (SK-MEL-24 and G361). In HaCaT keratinocytes, a low concentration (2 μmol/L) of vemurafenib increased cell proliferation and activated mitogen-activated protein kinase kinase/extracellular signal-regulated kinase in a CRAF-dependent manner. Invasiveness of HaCaT cells in a Matrigel assay significantly increased upon cultivation of cells with 2 μmol/L vemurafenib for 24 h. Gelatin zymography, reverse transcription polymerase chain reaction and western blot results revealed that 2 μmol/L vemurafenib treatment increased matrix metalloproteinase (MMP)-2 and MMP-9 expressions and activities in HaCaT cells. These results offer additional insight into the complex mechanism of paradoxical mitogen-activated protein kinase signaling involved in hyperproliferative cutaneous neoplasias that arise after BRAF inhibition and suggest a possible role for MMP in tumor progression and invasion. © 2015 Japanese Dermatological Association.

Metabolic syndrome and psoriasis severity in South-East Asian patients: An investigation of potential association using current and chronological assessments.

PubMed

Chularojanamontri, Leena; Wongpraparut, Chanisada; Silpa-Archa, Narumol; Chaweekulrat, Pichanee

2016-12-01

Although studies regarding prevalence of metabolic syndrome (MS) in Asian psoriatic patients are limited and show varying results, a previous report describes a significant increase in prevalence of MS in Thai psoriatic patients, as compared with rates in the general population. However, no significant association between MS and psoriasis severity using the Psoriasis Area and Severity Index (PASI) was found, which differs from the findings of Korean and Japanese studies. This study aimed at re-evaluating the association between MS and psoriasis severity in Thai patients using current assessment (PASI) and chronological assessment (historical course and interventions). A total of 273 psoriatic patients were recruited. After controlling for age and sex, 96 patients were assigned to the MS group and 96 patients to the non-MS group. Similar to the previous study, no significant differences were identified between metabolic and non-metabolic patients regarding PASI, age of onset, disease duration and family history of psoriasis. However, the numbers of hospitalizations (P = 0.018) and interventions (P = 0.028) were significantly higher in metabolic patients than in non-metabolic patients. Further, a greater number of metabolic components was significantly associated with a higher number of hospitalizations (P = 0.012), pustular or erythrodermic psoriasis episodes (P = 0.049), and interventions (P = 0.005). Body mass index of 23 kg/m 2 or more, abdominal obesity and high blood pressure were associated with an increased risk of treatment failure. Using chronological assessment, our study supported that MS negatively affects psoriasis severity and treatment outcomes. Screening for MS is highly recommended for psoriatic patients. © 2016 Japanese Dermatological Association.

Identification of a missense variant in LNPEP that confers psoriasis risk.

PubMed

Cheng, Hui; Li, Yang; Zuo, Xian-Bo; Tang, Hua-Yang; Tang, Xian-Fa; Gao, Jin-Ping; Sheng, Yu-Jun; Yin, Xian-Yong; Zhou, Fu-Sheng; Zhang, Chi; Chen, Gang; Zhu, Jun; Pan, Qian; Liang, Bo; Zheng, Xiao-Dong; Li, Pan; Ding, Yan-Tao; Cheng, Fang; Luo, Jing; Chang, Rui-Xue; Pan, Gong-Bu; Fan, Xing; Wang, Zai-Xing; Zhang, An-Ping; Liu, Jian-Jun; Yang, Sen; Sun, Liang-Dan; Zhang, Xue-Jun

2014-02-01

Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To further advance gene discovery, we extended our genome-wide association study data set of 1,139 cases and 2,234 controls and replicated two independent cohorts of 7,200 cases and 10,491 controls. We identified the missense variant rs2303138 (p.Ala763Thr) within the LNPEP gene associated with psoriasis (Pcombined=1.83 × 10(-13), odds ratio=1.16) and validated four previously reported genes: IL28RA, NFKBIA, TRAF3IP2, and CARD14 (9.74 × 10(-11)P9.37 × 10(-5)), which confirmed the involvement of the nuclear factor-κB signaling pathway in psoriasis pathogenesis. LNPEP, also named insulin-responsive aminopeptidase, was identified as an angiotensin IV receptor. Protein function prediction suggested that this missense variant of LNPEP was most likely deleterious. Expression analysis showed that LNPEP was significantly downregulated in psoriatic lesions compared with the control skin (P=1.44 × 10(-6)) and uninvolved patient skin (P=2.95 × 10(-4)). Pathway analysis indicated that LNPEP was involved in the renin-angiotensin system, which also has a key role in cardiovascular disease and diabetes. These results provided genetic evidence that psoriasis might share common mechanisms with hypertension and diabetes, which was consistent with clinical observations. Our study identified a genetic susceptibility factor and provided genetic evidence of insight into psoriasis pathogenesis with the involvement of the renin-angiotensin system pathway.

The proteinase-activated receptor-2 mediates phagocytosis in a Rho-dependent manner in human keratinocytes.

PubMed

Scott, Glynis; Leopardi, Sonya; Parker, Lorelle; Babiarz, Laura; Seiberg, Miri; Han, Rujiing

2003-09-01

Recent work shows that the G-protein-coupled receptor proteinase activated receptor-2 activates signals that stimulate melanosome uptake in keratinocytes in vivo and in vitro. The Rho family of GTP-binding proteins is involved in cytoskeletal remodeling during phagocytosis. We show that proteinase-activated receptor-2 mediated phagocytosis in human keratinocytes is Rho dependent and that proteinase-activated receptor-2 signals to activate Rho. In contrast, Rho activity did not affect either proteinase-activated receptor-2 activity or mRNA and protein levels. We explored the signaling mechanisms of proteinase-activated receptor-2 mediated Rho activation in human keratinocytes and show that activation of proteinase-activated receptor-2, either through specific proteinase-activated receptor-2 activating peptides or through trypsinization, elevates cAMP in keratinocytes. Proteinase-activated receptor-2 mediated Rho activation was pertussis toxin insensitive and independent of the protein kinase A signaling pathway. These data are the first to show that proteinase-activated receptor-2 mediated phagocytosis is Rho dependent and that proteinase-activated receptor-2 signals to Rho and cAMP in keratinocytes. Because phagocytosis of melanosomes is recognized as an important mechanism for melanosome transfer to keratinocytes, these results suggest that Rho is a critical signaling intermediate in melanosome uptake in keratinocytes.

Modulation of keratinocyte expression of antioxidants by 4-hydroxynonenal, a lipid peroxidation end product

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Ruijin; Heck, Diane E.; Mishin, Vladimir

2014-03-01

4-Hydroxynonenal (4-HNE) is a lipid peroxidation end product generated in response to oxidative stress in the skin. Keratinocytes contain an array of antioxidant enzymes which protect against oxidative stress. In these studies, we characterized 4-HNE-induced changes in antioxidant expression in mouse keratinocytes. Treatment of primary mouse keratinocytes and PAM 212 keratinocytes with 4-HNE increased mRNA expression for heme oxygenase-1 (HO-1), catalase, NADPH:quinone oxidoreductase (NQO1) and glutathione S-transferase (GST) A1-2, GSTA3 and GSTA4. In both cell types, HO-1 was the most sensitive, increasing 86–98 fold within 6 h. Further characterization of the effects of 4-HNE on HO-1 demonstrated concentration- and time-dependentmore » increases in mRNA and protein expression which were maximum after 6 h with 30 μM. 4-HNE stimulated keratinocyte Erk1/2, JNK and p38 MAP kinases, as well as PI3 kinase. Inhibition of these enzymes suppressed 4-HNE-induced HO-1 mRNA and protein expression. 4-HNE also activated Nrf2 by inducing its translocation to the nucleus. 4-HNE was markedly less effective in inducing HO-1 mRNA and protein in keratinocytes from Nrf2 −/− mice, when compared to wild type mice, indicating that Nrf2 also regulates 4-HNE-induced signaling. Western blot analysis of caveolar membrane fractions isolated by sucrose density centrifugation demonstrated that 4-HNE-induced HO-1 is localized in keratinocyte caveolae. Treatment of the cells with methyl-β-cyclodextrin, which disrupts caveolar structure, suppressed 4-HNE-induced HO-1. These findings indicate that 4-HNE modulates expression of antioxidant enzymes in keratinocytes, and that this can occur by different mechanisms. Changes in expression of keratinocyte antioxidants may be important in protecting the skin from oxidative stress. - Highlights: • Lipid peroxidation generates 4-hydroxynonenal, a reactive aldehyde. • 4-HNE induces antioxidant proteins in mouse keratinocytes. • Induction of

Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry.

PubMed

Fiorentino, David; Ho, Vincent; Lebwohl, Mark G; Leite, Luiz; Hopkins, Lori; Galindo, Claudia; Goyal, Kavitha; Langholff, Wayne; Fakharzadeh, Steven; Srivastava, Bhaskar; Langley, Richard G

2017-11-01

The effect of systemic therapy on malignancy risk among patients with psoriasis is not fully understood. Evaluate the impact of systemic treatment on malignancy risk among patients with psoriasis in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). Nested case-control analyses were performed among patients with no history of malignancy. Cases were defined as first malignancy (other than nonmelanoma skin cancer) in the Psoriasis Longitudinal Assessment and Registry, and controls were matched by age, sex, geographic region, and time on registry. Study therapies included methotrexate, ustekinumab, and tumor necrosis factor-α (TNF-α) inhibitors. Exposure was defined as 1 or more doses of study therapy within 12 months of malignancy onset and further stratified by duration of therapy. Multivariate conditional logistic regression, adjusted for potential confounders, was used to estimate odds ratios of malignancies associated with therapy. Among 12,090 patients, 252 malignancy cases were identified and 1008 controls were matched. Treatment with methotrexate or ustekinumab for more than 0 months to less than 3 months, 3 months to less than 12 months, or 12 months or longer was not associated with increased malignancy risk versus no exposure. Longer-term (≥12 months) (odds ratio, 1.54; 95% confidence interval, 1.10-2.15; P = .01), but not shorter-term treatment, with a TNF-α inhibitor was associated with increased malignancy risk. Cases and controls could belong to 1 or more therapy categories. Long-term (≥12 months) treatment with a TNF-α inhibitor, but not methotrexate and ustekinumab, may increase risk for malignancy in patients with psoriasis. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Cutaneous blood flow in psoriasis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Klemp, P.; Staberg, B.

1983-12-01

The disappearance rate of /sup 133/Xe was studied in 20 patients with psoriasis vulgaris, using an epicutaneous labeling technique in involved skin lesions or normal-appearing skin of the proximal extensor site of the forearm. Control experiments were performed in 10 normal subjects. Calculations of the cutaneous blood flow (CBF) in psoriatic skin lesions were performed using a tissue-to-blood partition coefficient for /sup 133/Xe, lambda c,pso, of 1.2 ml/100 g/min. lambda c,pso was estimated after the relative content of water, lipids, and proteins had been analyzed in psoriatic skin biopsies of 6 patients with untreated psoriasis. The mean relative content ofmore » water was markedly reduced to 23.5 +/- 1.5% (SEM), and lipids and proteins were markedly increased to 2.5 +/- 0.7% and 74.0 +/- 2.2, respectively, compared to previously published data for normal skin (water 72.5%, lipids 1%, proteins 26.5%). Mean CBF in untreated psoriatic skin was 63.5 +/- 9.0 ml/100 g/min. This was significantly higher than the mean CBF in 10 normal subjects, 6.3 +/- 0.5 ml/100 g/min (p much less than 0.0001). Mean CBF in normal-appearing skin in patients with psoriasis was 11.0 +/- 1.3 ml/100 g/min. This was significantly higher than CBF in normal subjects (p less than 0.0002).« less

Oxidative damage in keratinocytes exposed to cigarette smoke and aldehydes.

PubMed

Avezov, Katia; Reznick, Abraham Z; Aizenbud, Dror

2014-06-01

Cigarette smoke (CS) is a significant environmental source of human exposure to chemically active saturated (acetaldehyde) and α,β-unsaturated aldehydes (acrolein) inducing protein carbonylation and dysfunction. The exposure of oral tissues to environmental hazards is immense, especially in smokers. The objectives of the current study were to examine the effect of aldehydes originating from CS on intracellular proteins of oral keratinocytes and to observe the antioxidant response in these cells. Intracellular protein carbonyl modification under CS, acrolein and acetaldehyde exposure in the HaCaT keratinocyte cell line, representing oral keratinocytes was examined by Western blot. Possible intracellular enzymatic dysfunction under the above conditions was examined by lactate dehydrogenase (LDH) activity assay. Oxidative stress response was investigated, by DCF (2,7-dichlorodihydrofluorescein) assay and GSH (glutathione) oxidation. Intracellular protein carbonyls increased 5.2 times after CS exposure and 2.7 times after exposure to 1 μmol of acrolein. DCF assay revealed an increase of fluorescence intensity 3.2 and 3.1 times after CS and acrolein exposure, respectively. CS caused a 72.5% decrease in intracellular GSH levels compared to controls. Activity of intracellular LDH was preserved. α,β-Unsaturated aldehydes from CS are capable of intracellular protein carbonylation and have a role in intracellular oxidative stress elevation in keratinocytes, probably due to the reduction in GSH levels. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pediatric psoriasis: Should we be concerned with comorbidity? Cross-sectional study.

PubMed

Kelati, Awatef; Baybay, Hanane; Najdi, Adil; Zinoune, Safae; Mernissi, Fatima Z

2017-08-01

Similarly to psoriasis in adults, recent research has linked psoriasis to several comorbidities in children. The aim of this study was therefore to describe comorbidities associated with pediatric psoriasis, to investigate their relationship with psoriasis characteristics and severity, and to perform a review of the literature. A cross-sectional study was performed on a sample of Moroccan children with psoriasis, in 2014-2016. A total of 64 pediatric psoriasis patients had metabolic comorbidities in association with psoriasis; 20 children had non-metabolic comorbidities; and 76 children had no comorbidity. The metabolic comorbidities were as follows: abdominal obesity, 40% (n = 64); overweight, 12.5% (n = 20); metabolic syndrome, 3.7% (n = 6); and dyslipidemia, 3.1% (n = 5); the non-metabolic comorbidities were atopy, 4.3% (n = 7); epilepsy, 3.1% (n = 5); celiac disease, 1.8% (n = 3); vitiligo, 1.8% (n = 3); alopecia ariata, 0.6% (n = 1); and valvular cardiopathy, 0.6% (n = 1). No cases of diabetes mellitus, obesity, or high blood pressure were recorded. Significant factors associated with metabolic comorbidity were extended psoriasis vulgaris >10% (P = 0.01; OR, 2.19), severe psoriasis especially pustular and erythroderma (P = 0.018; OR, 2), nail involvement (P = 0.016; OR, 1.5), face involvement (P = 0.01; OR, 1,59), resistance to topical treatment (P = 0.003; OR, 2.5) and alteration of quality of life (P = 0.02; OR, 1,7). There was no significant risk factor associated with non-metabolic comorbidity. Given the frequent association of pediatric psoriasis with many disorders, these comorbidities should be investigated and identified so that they can be taken into account in the management of psoriasis in order to avoid treatment failure. Regular follow up should be carried out in patients at risk of metabolic comorbidity. © 2017 Japan Pediatric Society.

Candida albicans-induced inflammatory response in human keratinocytes.

PubMed

Wollina, U; Künkel, W; Bulling, L; Fünfstück, C; Knöll, B; Vennewald, I; Hipler, U-C

2004-06-01

Candida albicans strains 3153a, ATCC 48867, CBS 2730, DSM 70014, and Vir 13 were cultivated and sterile C. albicans filtrates were produced. The interaction of soluble Candida factors of these infiltrates with human HaCaT keratinocytes was assayed in vitro. The following parameters were analyzed: cell proliferation, protein synthesis, nuclear matrix protein (NMP) 41 release, cytokine release (IL-1beta, soluble IL-2 receptor, IL-6, and IL-8), and reactive oxygen species (ROS). Cell counts at 1, 12, and 24 h were significantly lower for C. albicans strains CBS 2730 and VIR 13 (P < 0.05). There was no significant change for the remaining strains. Neither the protein synthesis nor the NMP-41 release was significantly affected. IL-6 and IL-8 were stimulated by C. albicans filtrates to different amounts with higher levels in strains of low virulence. There was no effect on the other cytokines. The production of ROS by HaCaT keratinocytes was suppressed. The induction of an inflammatory keratinocyte response by soluble C. albicans factors may play a role among the host-yeast interactions.

Andrographolide alleviates imiquimod-induced psoriasis in mice via inducing autophagic proteolysis of MyD88.

PubMed

Shao, Fenli; Tan, Tao; Tan, Yang; Sun, Yang; Wu, Xingxin; Xu, Qiang

2016-09-01

Psoriasis is a chronic inflammatory skin disease with excessive activation of toll-like receptors (TLRs), which play important roles in developing psoriasis. Targeting TLR signaling remains a challenge for treating psoriasis. Here, we found that andrographolide (Andro), a small-molecule natural product, alleviated imiquimod- but not interleukin 23 (IL-23)-induced psoriasis in mice with reducing expressions of IL-23 and IL-1β in the skin. The improvement in imiquimod-induced psoriasis by Andro was not observed in microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) knockout mice. Furthermore, Andro inhibited mRNA expressions of IL-23, IL-6 and IL-1β but not CD80 and CD86 in bone-marrow derived dendritic cells (BMDCs) treated with lipopolysaccharide (LPS) in a MAP1LC3B-dependent manner. In addition, Andro inhibited imiquimod-induced mRNA expressions of IL-23, IL-6, IL-1β, CD80 and CD86 in BMDCs from mice. Interestingly, Andro induced a degradation of myeloid differentiation factor 88 (MyD88) and blocked the recruitment of TNF receptor-associated factor 6 (TRAF6) to MyD88 upon LPS stimulation in BMDCs from mice. Blockade of autophagic proteolysis using NH4Cl or MAP1LC3B(-/-) BMDCs abolished the Andro-induced MyD88 degradation. In conclusion, Andro controls activation of MyD88-dependent cytokines and alleviates psoriasis in mice via inducing autophagic proteolysis of MyD88, which could be a novel strategy to treat psoriasis. Copyright © 2016 Elsevier Inc. All rights reserved.

Psoriasis in Children: A Review.

PubMed

Balato, Anna; Scalvenzi, Massimiliano; Cirillo, Teresa; Gallo, Lucia; Ayala, Fabio; Balato, Nicola

2015-01-01

Psoriasis is a chronic, immune-mediated, inflammatory systemic disease which targets primarily the skin. It presents a genetic basis, affecting 1 to 3% of the white population. Nevertheless, the existence of two psoriasis incidence peaks has been suggested (one in adolescence before 20 years of age and another in adulthood) onset may occur at any age, including childhood and adolescence, in which its prevalence ranges between 0.7% and 1.2%. As for adult psoriasis, pediatric psoriasis has recently been associated with obesity, metabolic syndrome, increased waist circumference percentiles, and metabolic laboratory abnormalities, warranting early monitoring and lifestyle modifications. In addition, due to psoriasis chronic nature and frequently occurring relapses, psoriatic patients tend to have an impaired quality of life, often requiring long-term treatment. Therefore, education of both pediatric patients and their parents is essential to successful and safe disease management. However, systemic treatment of children is challenging as the absence of standardized guidelines and the fact that evidence-based data form randomized controlled trials are very limited. This review shows an overview of the current understanding of the pathogenesis, comorbidities, differential diagnosis, treatment and prevention of pediatric psoriasis, also presenting with an emphasis on the necessity of an integrated treatment approach involving different specialists such as dermatologist, pediatricians, rheumatologists, etc.

Imiquimod induced ApoE-deficient mice might be a composite animal model for the study of psoriasis and dyslipideamia comorbidity.

PubMed

Xie, Xinran; Zhang, Lei; Lin, Yan; Wang, Yan; Liu, Weihong; Li, Xue; Li, Ping

2017-10-01

Psoriasis patients are at increased risk of developing lipid metabolism disturbances. Both psoriasis and dyslipideamia not only closely interact in disease development, but occur as mutual side effects in some medicine treatment. The interactive mechanism of the two diseases is complicated and still unclear. Here, we proposed applying imiquimod on the dorsal skin of ApoE -/- mice to establish a composite animal model which formed psoriasiform skin lesions under hyperlipidemic condition. By comparison with corresponding wild-type(C57BL/6) mice, the composite mice model was evaluated by skin pathological features, lipid levels, immune inflammatory factors in order to clarify the diseases interplay mechanism. In addition, IL-17 mAb treatment was applied to observe the effect of IL-17 antibody on the composite animal model. The results verified that imiquimod-induced ApoE -/- mice model presented keratinocyte hyperplasia, parakeratosis, inflammatory cells infiltration and elevated serum lipid levels, and also reflected the complex interaction between inflammation and lipid metabolism. IL-17 mAb could inhibit psoriasis skin lesions with lipid accumulation via STAT3 pathway, but no influence on elevated serum cholesterol. Imiquimod-induced ApoE -/- mice model presented the pathological features of psoriasis and dyslipideamia, which could be an ideal composite animal model for the study of pathogenesis and pharmacotherapeutics of psoriasis and dyslipideamia comorbidity. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Efficacy of Iralfaris shampoo in the treatment of scalp psoriasis: a videodermoscopy evaluation prospective study in 70 patients.

PubMed

Rossi, A; Pranteda, G; Iorio, A; Mari, E; Milani, M

2012-12-01

This work has the aim to test the sensibility of VSCAPSI method in the evaluation of effectiveness of a medicated shampoo for the treatment of scalp psoriasis. Psoriasis is a chronic inflammatory skin disease histologically characterized by proliferation and loss of differentiation of keratinocytes, angiogenesis with vasodilatation and increased permeability, and inflammation. Scalp involvement is a common clinical feature of psoriasis, that is present in the 25% of patients who suffer of it. Videodermoscopy (VD) permits a magnified view of the surface components of the epidermis and papillary dermis, which are not visible to the naked eye, together with the ability to capture digitally the viewed images and to store them for later use. Moreover videodermoscopy is a non-invasive technique, used to analyze cutaneous peripheral microcirculation. Therefore VD could be an useful tool in evaluating the efficacy of treatments for scalp psoriasis. The clinical benefit of currently available medicated shampoos for the treatment of scalp psoriasis is restricted, due to their limited efficacy, low cosmetic appeal and safety and tolerability problems. Therefore effective and safe products are needed especially for the long term management of scalp psoriasis. A specific shampoo designed for the scalp hygiene in psoriatic patients has been recently developed. This shampoo contains urea, glycolic acid, salicylic acid, icthyol pale and laureth 9 (polidocanol). Aim of the study was to evaluate in a 12-week prospective monocenter, open-study the efficacy and tolerability of an emollient, keratolytic shampoo (Iralfaris shampoo ISDIN, Barcelona; Ir-S) applied three times a week in patients with scalp psoriasis. The efficacy of the shampoo has been valuated with VSCAPSI. Seventy subjects with mild to moderate/severe scalp psoriasis were enrolled in the trial, after their informed consent. Efficacy was assessed using a specific and validated videodermoscopy scalp psoriasis severity

A case of psoriasis with secondary amyloidosis, associated symbrachydactyly of the hand and a transverse deficiency of the foot.

PubMed

Balzani, A; Pagnotta, A; Montesi, G; Gravante, G; Nicoli, F; Cervelli, V

2012-07-01

Secondary amyloidosis is associated with a variety of chronic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, familial Mediterranean fever, osteomyelitis, inflammatory bowel diseases and infective or neoplastic conditions. Few cases of secondary amyloidosis complicating psoriasis have been reported. We describe a 58-year-old patient with secondary amyloidosis, psoriasis, an associated symbrachydactyly of the hand and a transverse deficiency of the foot. To the best of our knowledge, no case of this association has been previously reported.

Single Low-Dose Radiation Induced Regulation of Keratinocyte Differentiation in Calcium-Induced HaCaT Cells.

PubMed

Hahn, Hyung Jin; Youn, Hae Jeong; Cha, Hwa Jun; Kim, Karam; An, Sungkwan; Ahn, Kyu Joong

2016-08-01

We are continually exposed to low-dose radiation (LDR) in the range 0.1 Gy from natural sources, medical devices, nuclear energy plants, and other industrial sources of ionizing radiation. There are three models for the biological mechanism of LDR: the linear no-threshold model, the hormetic model, and the threshold model. We used keratinocytes as a model system to investigate the molecular genetic effects of LDR on epidermal cell differentiation. To identify keratinocyte differentiation, we performed western blots using a specific antibody for involucrin, which is a precursor protein of the keratinocyte cornified envelope and a marker for keratinocyte terminal differentiation. We also performed quantitative polymerase chain reaction. We examined whether LDR induces changes in involucrin messenger RNA (mRNA) and protein levels in calcium-induced keratinocyte differentiation. Exposure of HaCaT cells to LDR (0.1 Gy) induced p21 expression. p21 is a key regulator that induces growth arrest and represses stemness, which accelerates keratinocyte differentiation. We correlated involucrin expression with keratinocyte differentiation, and examined the effects of LDR on involucrin levels and keratinocyte development. LDR significantly increased involucrin mRNA and protein levels during calcium-induced keratinocyte differentiation. These studies provide new evidence for the biological role of LDR, and identify the potential to utilize LDR to regulate or induce keratinocyte differentiation.

Single Low-Dose Radiation Induced Regulation of Keratinocyte Differentiation in Calcium-Induced HaCaT Cells

PubMed Central

Hahn, Hyung Jin; Youn, Hae Jeong; Cha, Hwa Jun; Kim, Karam; An, Sungkwan

2016-01-01

Background We are continually exposed to low-dose radiation (LDR) in the range 0.1 Gy from natural sources, medical devices, nuclear energy plants, and other industrial sources of ionizing radiation. There are three models for the biological mechanism of LDR: the linear no-threshold model, the hormetic model, and the threshold model. Objective We used keratinocytes as a model system to investigate the molecular genetic effects of LDR on epidermal cell differentiation. Methods To identify keratinocyte differentiation, we performed western blots using a specific antibody for involucrin, which is a precursor protein of the keratinocyte cornified envelope and a marker for keratinocyte terminal differentiation. We also performed quantitative polymerase chain reaction. We examined whether LDR induces changes in involucrin messenger RNA (mRNA) and protein levels in calcium-induced keratinocyte differentiation. Results Exposure of HaCaT cells to LDR (0.1 Gy) induced p21 expression. p21 is a key regulator that induces growth arrest and represses stemness, which accelerates keratinocyte differentiation. We correlated involucrin expression with keratinocyte differentiation, and examined the effects of LDR on involucrin levels and keratinocyte development. LDR significantly increased involucrin mRNA and protein levels during calcium-induced keratinocyte differentiation. Conclusion These studies provide new evidence for the biological role of LDR, and identify the potential to utilize LDR to regulate or induce keratinocyte differentiation. PMID:27489424

Pediatric Psoriasis Comorbidity Screening Guidelines.

PubMed

Osier, Emily; Wang, Audrey S; Tollefson, Megha M; Cordoro, Kelly M; Daniels, Stephen R; Eichenfield, Andrew; Gelfand, Joel M; Gottlieb, Alice B; Kimball, Alexa B; Lebwohl, Mark; Mehta, Nehal N; Paller, Amy S; Schwimmer, Jeffrey B; Styne, Dennis M; Van Voorhees, Abby S; Tom, Wynnis L; Eichenfield, Lawrence F

2017-07-01

Psoriasis is a complex inflammatory skin condition associated with serious medical comorbidities in adults, including obesity, hypertension, dyslipidemia, type 2 diabetes mellitus, psoriatic arthritis, nonalcoholic fatty liver disease, depression, anxiety, and decreased quality of life. Because psoriasis begins in childhood in almost one-third of patients, early identification of risk may be critical to minimizing effects on future health. To develop the first set of guidelines for comorbidity screening for patients with pediatric psoriasis based on current evidence. A literature review was performed using PubMed from January 1999 through December 2015. Limiting the search to human studies published in English and removing reviews and editorials produced 153 relevant manuscripts. An expert panel in psoriasis, pediatric dermatology, pediatric rheumatology, pediatric gastroenterology, pediatric endocrinology, and adult and pediatric cardiology used the patient-centered Strength of Recommendation Taxonomy (SORT) method to evaluate and grade the quality of evidence. Because of the limited number of pediatric studies published on these topics, the strength of the panel's recommendations is classified as SORT level C expert consensus recommendations. The majority of recommendations coincide with those endorsed by the American Academy of Pediatrics for the general pediatric patient but with added attention to signs and symptoms of arthritis, depression, and anxiety. The panel also identified key areas for further investigation. Patients with pediatric psoriasis should receive routine screening and identification of risk factors for associated comorbidities. These guidelines are relevant for all health care providers caring for patients with pediatric psoriasis, including primary care clinicians, dermatologists, and pediatric specialists. Because these are the first pediatric guidelines, re-review and refinement will be necessary as studies further detail, and possibly

Ski protein levels increase during in vitro progression of HPV16-immortalized human keratinocytes and in cervical cancer

PubMed Central

Chen, Yi; Pirisi, Lucia; Creek, Kim E.

2013-01-01

We compared the levels of the Ski oncoprotein, an inhibitor of transforming growth factor-beta (TGF-β) signaling, in normal human keratinocytes (HKc), HPV16 immortalized HKc (HKc/HPV16), and differentiation resistant HKc/HPV16 (HKc/DR) in the absence and presence of TGF-β. Steady-state Ski protein levels increased in HKc/HPV16 and even further in HKc/DR, compared to HKc. TGF-β treatment of HKc, HKc/HPV16, and HKc/DR dramatically decreased Ski. TGF-β-induced Ski degradation was delayed in HKc/DR. Ski and phospho-Ski protein levels are cell cycle dependent with maximal Ski expression and localization to centrosomes and mitotic spindles during G2/M. ShRNA knock down of Ski in HKc/DR inhibited cell proliferation. More intense nuclear and cytoplasmic Ski staining and altered Ski localization were found in cervical cancer samples compared to adjacent normal tissue in a cervical cancer tissue array. Overall, these studies demonstrate altered Ski protein levels, degradation and localization in HPV16-transformed human keratinocytes and in cervical cancer. PMID:23809940

Very low-calorie ketogenic diet may allow restoring response to systemic therapy in relapsing plaque psoriasis.

PubMed

Castaldo, Giuseppe; Galdo, Giovanna; Rotondi Aufiero, Felice; Cereda, Emanuele

2016-01-01

Psoriasis is a chronic disease associated with overweight/obesity and related cardiometabolic complications. The link between these diseases is likely the inflammatory background associated with adipose tissue, particularly the visceral one. Accordingly, previous studies have demonstrated that in the long-term weight loss may improve the response to systemic therapies. We report a case report of a woman in her 40s suffering from relapsing moderate-to-severe plaque psoriasis and obesity-related metabolic syndrome, in whom adequate response to ongoing treatment with biological therapy (adalimumab) was restored after only 4 weeks of very low-calorie, carbohydrate-free (ketogenic), protein-based diet. Accordingly, through rapid and consistent weight loss, very low calorie ketogenic diet may allow restoring a quick response to systemic therapy in a patient suffering from relapsing psoriasis. This intervention should be considered in overweight/obese patients before the rearrangement of systemic therapy. Nonetheless, studies are required to evaluate whether very low calorie ketogenic diets should be preferred to common low-calorie diets to improve the response to systemic therapy at least in patients with moderate-to-severe psoriasis. Copyright © 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Keratinocyte-derived Laminin-332 Protein Promotes Melanin Synthesis via Regulation of Tyrosine Uptake*

PubMed Central

Chung, Heesung; Jung, Hyejung; Lee, Jung-hyun; Oh, Hye Yun; Kim, Ok Bin; Han, Inn-Oc; Oh, Eok-Soo

2014-01-01

Melanocytes, which produce the pigment melanin, are known to be closely regulated by neighboring keratinocytes. However, how keratinocytes regulate melanin production is unclear. Here we report that melanin production in melanoma cells (B16F10 and MNT-1) was increased markedly on a keratinocyte-derived extracellular matrix compared with a melanoma cell-derived extracellular matrix. siRNA-mediated reduction of keratinocyte-derived laminin-332 expression decreased melanin synthesis in melanoma cells, and laminin-332, but not fibronectin, enhanced melanin content and α-melanocyte-stimulating hormone-regulated melanin production in melanoma cells. Similar effects were observed in human melanocytes. Interestingly, however, laminin-332 did not affect the expression or activity of tyrosinase. Instead, laminin-332 promoted the uptake of extracellular tyrosine and, subsequently, increased intracellular levels of tyrosine in both melanocytes and melanoma cells. Taken together, these data strongly suggest that keratinocyte-derived laminin-332 contributes to melanin production by regulating tyrosine uptake. PMID:24951591

Keratinocyte-derived laminin-332 protein promotes melanin synthesis via regulation of tyrosine uptake.

PubMed

Chung, Heesung; Jung, Hyejung; Lee, Jung-Hyun; Oh, Hye Yun; Kim, Ok Bin; Han, Inn-Oc; Oh, Eok-Soo

2014-08-01

Melanocytes, which produce the pigment melanin, are known to be closely regulated by neighboring keratinocytes. However, how keratinocytes regulate melanin production is unclear. Here we report that melanin production in melanoma cells (B16F10 and MNT-1) was increased markedly on a keratinocyte-derived extracellular matrix compared with a melanoma cell-derived extracellular matrix. siRNA-mediated reduction of keratinocyte-derived laminin-332 expression decreased melanin synthesis in melanoma cells, and laminin-332, but not fibronectin, enhanced melanin content and α-melanocyte-stimulating hormone-regulated melanin production in melanoma cells. Similar effects were observed in human melanocytes. Interestingly, however, laminin-332 did not affect the expression or activity of tyrosinase. Instead, laminin-332 promoted the uptake of extracellular tyrosine and, subsequently, increased intracellular levels of tyrosine in both melanocytes and melanoma cells. Taken together, these data strongly suggest that keratinocyte-derived laminin-332 contributes to melanin production by regulating tyrosine uptake. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Psoriasis and Nonalcoholic Fatty Liver Disease.

PubMed

Carrascosa, J M; Bonanad, C; Dauden, E; Botella, R; Olveira-Martín, A

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver condition in the West. The prevalence and severity of NAFLD is higher and the prognosis worse in patients with psoriasis. The pathogenic link between psoriasis and NAFLD is chronic inflammation and peripheral insulin resistance, a common finding in diseases associated with psoriasis. NAFLD should therefore be ruled out during the initial evaluation of patients with psoriasis, in particular if they show signs of metabolic syndrome and require systemic treatment. Concomitant psoriasis and NAFLD and the likelihood of synergy between them place limitations on general recommendations and treatment for these patients given the potential for liver toxicity. As hepatotoxic risk is associated with some of the conventional drugs used in this setting (e.g., acitretin, methotrexate, and ciclosporin), patients prescribed these treatments should be monitored as appropriate. Anti-tumor necrosis factor agents hold the promise of potential benefits based on their effects on the inflammatory process and improving peripheral insulin resistance. However, cases of liver toxicity have also been reported in relation to these biologics. No evidence has emerged to suggest that anti-p40 or anti-interleukin 17 agents provide benefits or have adverse effects. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Skin-infiltrating, interleukin-22-producing T cells differentiate pediatric psoriasis from adult psoriasis.

PubMed

Cordoro, Kelly M; Hitraya-Low, Maria; Taravati, Keyon; Sandoval, Priscila Munoz; Kim, Esther; Sugarman, Jeffrey; Pauli, Mariela L; Liao, Wilson; Rosenblum, Michael D

2017-09-01

Evidence from adult psoriasis studies implicates an imbalance between regulatory and effector T cells, particularly T H -17-producing T cells, in the pathogenesis of psoriasis. Little is known about the immunopathology of psoriasis in children. We sought to functionally characterize the inflammatory cell profiles of psoriatic plaques from pediatric patients and compare them with healthy, age-matched controls and adult psoriasis patients. Skin samples from pediatric psoriasis patients and healthy controls were analyzed by multiparameter flow cytometry to determine the dominant immune cell subsets present and cytokines produced. Lesional tissue from pediatric psoriasis patients had significantly increased interleukin (IL) 22 derived from CD4 + and CD8 + cells compared with the tissues from healthy pediatric controls and adult psoriasis patients. Tissue from pediatric psoriasis patients had significantly less elevation of IL-17 derived from CD4 + and CD8 + cells compared with the tissue from adult psoriasis patients. In contrast with the lesions from adult patients, lesional skin in pediatric patients with psoriasis did not have increases in regulatory T cells. This is a pilot study, thus the sample size is small. Significant differences in IL-17 and IL-22 expression were observed in the pediatric psoriasis patients compared with pediatric healthy controls and adult psoriasis patients. IL-22 might be relevant in the pathogenesis of pediatric psoriasis and represents a potential treatment target unique to pediatric psoriasis. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

EFFECT OF ARSENICALS ON THE EXPRESSION OF CELL CYCLE PROTEINS AND EARLY SIGNALING EVENTS IN PRIMARY HUMAN KERATINOCYTES.

EPA Science Inventory

Effect of Arsenicals on the Expression of Cell Cycle Proteins and Early Signaling Events in Primary Human Keratinocytes.

Mudipalli, A, Owen R. D. and R. J. Preston, Environmental Carcinogenesis Division, USEPA, RTP, NC 27711.

Environmental exposure to arsenic is a m...

S100A8 and S100A9 are messengers in the crosstalk between epidermis and dermis modulating a psoriatic milieu in human skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Young; Jang, Sunhyae; Min, Jeong-Ki

2012-07-13

Highlights: Black-Right-Pointing-Pointer Upregulated S100A8 and/or S100A9 in psoriasis epidermis induce cytokine production. Black-Right-Pointing-Pointer Upregulated S100A8 and/or S100A9 in psoriasis epidermis induce migration of immune cells. Black-Right-Pointing-Pointer Upregulated S100A8 and/or S100A9 in psoriasis epidermis induce angiogenesis. Black-Right-Pointing-Pointer S100A8 and/or S100A9 may play a role in the crosstalk between epidermis and dermis in psoriasis. -- Abstract: S100A8 and S100A9 are members of the S100A8 protein family that exist as homodimers and heterodimers in neutrophils, monocytes, and macrophages. Recent studies have shown the pivotal roles of S100A8 and S100A9 in the propagation of inflammation and keratinocyte proliferation in psoriasis. We found significant up-regulationmore » of S100A8 and S100A9 secretion from keratinocytes in psoriatic lesions. To mimic the in vivo secretory conditions of S100A8 and S100A9 from psoriatic epidermal keratinocytes, we used the culture medium (CM) of S100A8 and S100A8/A9 adenovirus-transduced keratinocytes to investigate the functions of S100A8 and S100A9. We detected increased levels of various pro-inflammatory cytokines in the CM, including IL-8 and TNF-{alpha}, which are involved in aggravating psoriatic skin lesions, and IL-6 and members of the CXCL family of pro-angiogenic cytokines. The CM increased immune cell migration and increased angiogenesis in human umbilical vein endothelial cells. In conclusion, we found that the upregulated production of S100A8 and S100A9 by psoriatic epidermal keratinocytes activated adjacent keratinocytes to produce several cytokines. Moreover, S100A8 and S100A9 themselves function as pro-angiogenic and chemotactic factors, generating a psoriatic milieu in skin.« less

Association Between Statin Use and Risk for Keratinocyte Carcinoma in the Veterans Affairs Topical Tretinoin Chemoprevention Trial

PubMed Central

Dore, David D.; Lapane, Kate L.; Trivedi, Amal N.; Mor, Vincent; Weinstock, Martin A.

2013-01-01

Background Recent evidence suggests that statins may prevent cancer. Objective To quantify the association between statin use and the occurrence of keratinocyte carcinoma in high-risk veterans. Design Cohort study. Setting 6 Veterans Affairs medical centers. Participants 1037 participants of the Veterans Affairs Topical Tretinoin Chemoprevention Trial, a randomized, multicenter, double-blind, vehicle-controlled trial of topical tretinoin, 0.1%, for prevention of keratinocyte carcinoma conducted from November 1998 to November 2004. Measurements Time to first occurrence of keratinocyte carcinoma on the face or ears. Participants using a statin at randomization, according to the Veterans Affairs Pharmacy Benefits Management database, were considered exposed. Study dermatologists conducted physical examinations at baseline and every 6 months during follow-up. The association between statin use at randomization and the outcome was evaluated by using propensity score matching (n = 608) and Cox proportional hazards regression (n = 1037). Results Among the 1037 participants, 37% used a statin at randomization (n = 397) for a median duration of at least 900 days over a median follow-up of 3.5 years. In the propensity score-matched analysis, statin use at randomization was not associated with keratinocyte carcinoma (rate ratio, 0.92 [95% CI, 0.73 to 1.16]), a finding that was consistent with the estimates derived from the Cox proportional hazards regression (rate ratio, 0.84 [CI, 0.70 to 1.02]). Limitations The extent of residual confounding is unknown, and the confidence bounds around the measures of association were wide. These data may not be generalizable to lower-risk populations. Conclusion These data show no conclusive or consistent relationship between long-term statin use and risk for keratinocyte carcinoma. Funding Department of Veterans Affairs, Agency for Healthcare Research and Quality, American Cancer Society, and National Institutes of Health. PMID:19124815

Drug induced psoriasis.

PubMed

Milavec-Puretić, Višnja; Mance, Marko; Ceović, Romana; Lipozenčić, Jasna

2011-01-01

Psoriasis is a chronic inflammatory skin disorder clinically characterized by erythematous, sharply demarcated papules and rounded plaques covered by silvery micaceous scale. While the exact causes of psoriasis have yet to be discovered, the immune system and genetics are known to play major roles in its development. Many external factors including infections, stress and medications may exacerbate psoriasis. Some of the most common medications know to trigger or worsen existing psoriasis include lithium, gold salts, beta blockers and antimalarials. Exacerbation of psoriasis due to the following medications has also been observed: adrenergic antagonists, interferon, gemfibrozil, iodine, digoxin and chlonidine. Having reviewed a variety of cases, we observed a relationship between certain medications and documented their involvement in exacerbating or inducing psoriasis.

Rotation is the primary motion of paired human epidermal keratinocytes.

PubMed

Tate, Sota; Imai, Matome; Matsushita, Natsuki; Nishimura, Emi K; Higashiyama, Shigeki; Nanba, Daisuke

2015-09-01

Collective motion of keratinocytes is involved in morphogenesis, homeostasis, and wound healing of the epidermis. Yet how the collective motion of keratinocytes emerges from the behavior of individual cells is still largely unknown. The aim of this study was to find the cellular behavior that links single and collective motion of keratinocytes. We investigated the behavior of two-cell colonies of HaCaT keratinocytes by a combination of time-lapse imaging and image processing. The two-cell colonies of HaCaT cells were formed as a contacted pair of keratinocyte clones. Image analysis and cell culture experiments revealed that the rotational speed of two-cell colonies was positively associated with their proliferative capacity. α6 integrin was required for the rotational motion of two-cell keratinocyte colonies. We also confirmed that two-cell colonies of keratinocytes predominantly exhibited the rotational, but not translational, motion, two modes of motion in a contact pair of rotating objects. The rotational motion is the primary motion of two-cell keratinocyte colonies and its speed is positively associated with their proliferative capacity. This study suggests that the assembly of rotating keratinocytes generates the collective motion of proliferative keratinocytes during morphogenesis and wound healing of the epidermis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

p53-Regulated Apoptosis Is Differentiation Dependent in Ultraviolet B-Irradiated Mouse Keratinocytes

PubMed Central

Tron, Victor A.; Trotter, Martin J.; Tang, Liren; Krajewska, Maryla; Reed, John C.; Ho, Vincent C.; Li, Gang

1998-01-01

Previous studies from our laboratory, using p53 transgenic mice, have suggested that ultraviolet (UV) light-induced keratinocyte apoptosis in the skin is not affected by overexpression of mutant p53 protein. To further elucidate a possible role for p53 in UV-induced keratinocyte cell death, we now examine apoptosis in skin and isolated keratinocytes from p53 null (−/−) mice and assess the influence of cell differentiation on this process. In vivo, using this knockout model, epidermal keratinocytes in p53−/− mice exhibited only a 5.2-fold increase in apoptosis after 2000 J/m2 UVB irradiation compared with a 26.3-fold increase in normal control animals. If this p53-dependent apoptosis is important in elimination of precancerous, UV-damaged keratinocytes, then it should be active in the undifferentiated cells of the epidermal basal layer. To test this hypothesis, we examined the effect of differentiation on UV-induced apoptosis in primary cultures of murine and human keratinocytes. Apoptosis was p53-independent in undifferentiated murine keratinocytes, which exhibited relative resistance to UVB-induced killing with only a 1.5-fold increase in apoptosis in p53+/+ cells and a 1.4-fold increase in p53−/− cells. Differentiated keratinocytes, in contrast, showed a 9.4-fold UVB induction of apoptosis in p53+/+ cells, almost three times the induction observed in p53−/− cells. This UV-induced difference in apoptosis was observed when keratinocytes were cultured on type IV collagen substrate, but not on plastic alone. Western blotting of UV-irradiated, differentiated keratinocytes did not support a role for either Bax or Bcl-2 in this process. In support of these findings in mice, cell death in human cultured keratinocytes also occurred in a differentiation-associated fashion. We conclude that p53-induced apoptosis eliminates damaged keratinocytes in the differentiated cell compartment, but this mechanism is not active in the basal, undifferentiated cells and

Rab11b mediates melanin transfer between donor melanocytes and acceptor keratinocytes via coupled exo/endocytosis.

PubMed

Tarafder, Abul K; Bolasco, Giulia; Correia, Maria S; Pereira, Francisco J C; Iannone, Lucio; Hume, Alistair N; Kirkpatrick, Niall; Picardo, Mauro; Torrisi, Maria R; Rodrigues, Inês P; Ramalho, José S; Futter, Clare E; Barral, Duarte C; Seabra, Miguel C

2014-04-01

The transfer of melanin from melanocytes to keratinocytes is a crucial process underlying maintenance of skin pigmentation and photoprotection against UV damage. Here, we present evidence supporting coupled exocytosis of the melanin core, or melanocore, by melanocytes and subsequent endocytosis by keratinocytes as a predominant mechanism of melanin transfer. Electron microscopy analysis of human skin samples revealed three lines of evidence supporting this: (1) the presence of melanocores in the extracellular space; (2) within keratinocytes, melanin was surrounded by a single membrane; and (3) this membrane lacked the melanosomal membrane protein tyrosinase-related protein 1 (TYRP1). Moreover, co-culture of melanocytes and keratinocytes suggests that melanin exocytosis is specifically induced by keratinocytes. Furthermore, depletion of Rab11b, but not Rab27a, caused a marked decrease in both keratinocyte-stimulated melanin exocytosis and transfer to keratinocytes. Thus, we propose that the predominant mechanism of melanin transfer is keratinocyte-induced exocytosis, mediated by Rab11b through remodeling of the melanosome membrane, followed by subsequent endocytosis by keratinocytes.

Modulation of LXR-α and the effector genes by Ascorbic acid and Statins in psoriatic keratinocytes.

PubMed

Soodgupta, Deepti; Kaul, Deepak; Kanwar, A J; Parsad, Davinder

2014-12-01

Recent studies have revealed critical roles that nuclear receptors like LXR-α (Liver X Receptor- alpha) plays as a class of post-transcriptional gene regulator in skin development and diseases. Keeping in view the fact that LXR-α plays crucial role in keratinocyte proliferation and differentiation, it becomes imperative to dissect the pathways and role of LXR-α genomics in the pathogenesis of psoriasis with ultimate aim to explore novel preventive/therapeutic strategies as treatment options. To explore the effects of agonists and activators of LXR-α on its own gene expression and the putative targets in psoriatic keratinocytes. Identification of promoter sequences for (vitamin D receptor) VDR and Catalase were done using in silico analysis followed by β-galactosidase (β-gal) reporter plasmid assay in keratinocytes from clinically heathy subjects. Determination of relative levels of LXR-α,VDR and catalase in control versus treated cells upon activation of LXR-α with Atorvastatin + 22R hydroxycholestrol and Ascorbic acid + 22R hydroxycholestrol was done by PCR and Cell Proliferation Assay. The cells transfected with the reporter plasmid element for VDR and catalase showed more than 5 and 4 fold increase respectively in the β-gal activity compared to the control. An increase of 55% in LXR-α gene expression at RNA level was observed in Atorvastatin + 22-R hydroxycholestrol compared to 24% in Ascorbic acid + 22-ROH cholesterol. The expression of the VDR and Catalase was significantly increased in both treated keratinocytes compared to its normal counterpart.

Trends in Type of Original Psoriasis Publications by Decade, 1960 to 2010.

PubMed

Sako, Eric; Famenini, Shannon; Wu, Jashin J

2016-01-01

Research investigating psoriasis has spanned decades, and as our understanding of the disease has evolved, the focus of publications has changed. We sought to characterize the trends in original psoriasis-related research from 1960 to 2010 chronologically by decade. A literature review was performed using the keyword psoriasis in the MEDLINE database. All original psoriasis-related articles published at the beginning of each decade were searched and categorized by study type and topic. Number of articles per topic. A total of 869 original psoriasis-related articles were found. The number of publications increased 18 fold over 5 decades. The immunology and pathogenesis of psoriasis was the most frequently researched topic (36%), and retrospective studies were the most common study type (37%). Recent highly published topics included biologic therapy, genetics, and psoriasis-associated cardiovascular disease. Original psoriasis-related publications have grown substantially since 1960. Basic science research into the immunology and pathogenesis has been and continues to be the mainstay of psoriasis research. Recent research trends suggest the focus has expanded to topics such as psoriasis-associated cardiovascular disease, genetics, and biologic therapy.

Ca2+-dependent localization of integrin-linked kinase to cell junctions in differentiating keratinocytes.

PubMed

Vespa, Alisa; Darmon, Alison J; Turner, Christopher E; D'Souza, Sudhir J A; Dagnino, Lina

2003-03-28

Integrin complexes are necessary for proper proliferation and differentiation of epidermal keratinocytes. Differentiation of these cells is accompanied by down-regulation of integrins and focal adhesions as well as formation of intercellular adherens junctions through E-cadherin homodimerization. A central component of integrin adhesion complexes is integrin-linked kinase (ILK), which can induce loss of E-cadherin expression and epithelial-mesenchymal transformation when ectopically expressed in intestinal and mammary epithelia. In cultured primary mouse keratinocytes, we find that ILK protein levels are independent of integrin expression and signaling, since they remain constant during Ca(2+)-induced differentiation. In contrast, keratinocyte differentiation is accompanied by marked reduction in kinase activity in ILK immunoprecipitates and altered ILK subcellular distribution. Specifically, ILK distributes in close apposition to actin fibers along intercellular junctions in differentiated but not in undifferentiated keratinocytes. ILK localization to cell-cell borders occurs independently of integrin signaling and requires Ca(2+) as well as an intact actin cytoskeleton. Further, and in contrast to what is observed in other epithelial cells, ILK overexpression in differentiated keratinocytes does not promote E-cadherin down-regulation and epithelial-mesenchymal transition. Thus, novel tissue-specific mechanisms control the formation of ILK complexes associated with cell-cell junctions in differentiating murine epidermal keratinocytes.

Psoriasis in those planning a family, pregnant or breast-feeding. The Australasian Psoriasis Collaboration.

PubMed

Rademaker, Marius; Agnew, Karen; Andrews, Megan; Armour, Katherine; Baker, Chris; Foley, Peter; Frew, John; Gebauer, Kurt; Gupta, Monisha; Kennedy, Debra; Marshman, Gillian; Sullivan, John

2017-05-23

The Australasian Psoriasis Collaboration has reviewed the evidence for managing moderate to severe psoriasis in those who are pregnant or are breast-feeding, or planning a family. The severity of the psoriasis, associated comorbidities and specific anti-psoriasis treatment, along with other exposures, can have a deleterious effect on pregnancy outcomes. Psoriasis itself increases the risk of preterm and low birthweight babies, along with spontaneous and induced abortions, but no specific birth defects have been otherwise demonstrated. The baseline risk for a live born baby to have a major birth defect is 3%, and significant neuro-developmental problem is 5%. In Australia, pregnant women with psoriasis are more likely to be overweight or obese, depressed, or smoke in their first trimester, and are also less likely to take prenatal vitamins or supplements. Preconception counselling to improve maternal, pregnancy and baby health is therefore strongly encouraged. The topical and systemic therapies commonly used in psoriasis are each discussed separately, with regards to pregnancy exposure, breast-feeding and effects on male fertility and mutagenicity. The systemic therapies included are acitretin, adalimumab, apremilast, certolizumab, ciclosporin, etanercept, infliximab, ixekizumab, methotrexate, NBUVB, prednisone, PUVA, secukinumab and ustekinumab. The topical therapies include dithranol (anthralin), calcipotriol, coal tar, corticosteroids (weak, potent and super-potent), moisturisers, salicylic acid, tacrolimus, and tazarotene. As a general recommendation, effective drugs that have been widely used for years are preferable to newer alternatives with less foetal safety data. It is equally important to evaluate the risks of not treating, as severe untreated disease may negatively impact both mother and the foetus. © 2017 The Australasian College of Dermatologists.

Internalized stigma in psoriasis: A multicenter study.

PubMed

Alpsoy, Erkan; Polat, Mualla; FettahlıoGlu-Karaman, Bilge; Karadag, Ayse Serap; Kartal-Durmazlar, Pelin; YalCın, Basak; Emre, Selma; Didar-Balcı, Didem; Bilgic-Temel, Asli; Arca, Ercan; Koca, Rafet; Gunduz, Kamer; Borlu, Murat; Ergun, Tulin; Dogruk-Kacar, Seval; Cordan-Yazici, Ayca; Dursun, Pınar; BilgiC, Ozlem; Gunes-Bilgili, Serap; Sendur, Neslihan; Baysal, Ozge; Halil-Yavuz, Ibrahim; Yagcioglu, Gizem; Yilmaz, Ertan; Kavuzlu, Ufuk; Senol, Yesim

2017-08-01

Internalized stigma is the adoption of negative attitudes and stereotypes of the society regarding a person's illness. It causes decreased self-esteem and life-satisfaction, increased depression and suicidality, and difficulty in coping with the illness. The primary aim of this study was to investigate the internalized stigma state of psoriatic patients and to identify the factors influencing internalized stigma. The secondary aim was to identify the correlation of internalized stigma with quality of life and perceived health status. This multicentre, cross-sectional study comprised 1485 patients. There was a significant positive correlation between mean values of Psoriasis Internalized Stigma Scale (PISS) and Psoriasis Area and Severity Index, Body Surface Area, Dermatological Life Quality Index and General Health Questionnaire-12 (P < 0.001 in all). Lower percieved health score (P = 0.001), early onset psoriasis (P = 0.016), family history of psoriasis (P = 0.0034), being illiterate (P < 0.001) and lower income level (P < 0.001) were determinants of high PISS scores. Mean PISS values were higher in erythrodermic and generalized pustular psoriasis. Involvement of scalp, face, hand, genitalia and finger nails as well as arthropathic and inverse psoriasis were also related to significantly higher PISS scores (P = 0.001). Our findings imply that psoriatic patients experience high levels of internalized stigma which are associated with psoriasis severity, involvement of visible body parts, genital area, folds or joints, poorer quality of life, negative perceptions of general health and psychological illnesses. Therefore, internalized stigma may be one of the major factors responsible from psychosocial burden of the disease. © 2017 Japanese Dermatological Association.

Cutaneous lupus erythematosus, morphea profunda and psoriasis: A case report.

PubMed

García-Arpa, Mónica; Flores-Terry, Miguel A; Ramos-Rodríguez, Claudia; Franco-Muñoz, Monserrat; González-Ruiz, Lucía; Ramírez-Huaranga, Marco Aurelio

2018-04-03

Psoriasis is a common inflammatory dermatosis that may be associated with a number of diseases. Recent studies provide evidence that there is a greater frequency of autoimmune diseases, but association with autoimmune connective tissue diseases is uncommon. The coexistence of psoriasis and lupus erythematosus is rare. Besides, the occurrence of morphea has rarely been reported in patients with lupus or psoriasis. We report a woman with cutaneous lupus and morphea profunda associated with psoriasis, with an excellent response to methotrexate, and review the literature. Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Deciphering metabonomics biomarkers-targets interactions for psoriasis vulgaris by network pharmacology.

PubMed

Gu, Jiangyong; Li, Li; Wang, Dongmei; Zhu, Wei; Han, Ling; Zhao, Ruizhi; Xu, Xiaojie; Lu, Chuanjian

2018-06-01

Psoriasis vulgaris is a chronic inflammatory and immune-mediated skin disease. 44 metabonomics biomarkers were identified by high-throughput liquid chromatography coupled to mass spectrometry in our previous work, but the roles of metabonomics biomarkers in the pathogenesis of psoriasis is unclear. The metabonomics biomarker-enzyme network was constructed. The key metabonomics biomarkers and enzymes were screened out by network analysis. The binding affinity between each metabonomics biomarker and target was calculated by molecular docking. A binding energy-weighted polypharmacological index was introduced to evaluate the importance of target-related pathways. Long-chain fatty acids, phospholipids, Estradiol and NADH were the most important metabonomics biomarkers. Most key enzymes belonged hydrolase, thioesterase and acyltransferase. Six proteins (TNF-alpha, MAPK3, iNOS, eNOS, COX2 and mTOR) were extensively involved in inflammatory reaction, immune response and cell proliferation, and might be drug targets for psoriasis. PI3K-Akt signaling pathway and five other pathways had close correlation with the pathogenesis of psoriasis and could deserve further research. The inflammatory reaction, immune response and cell proliferation are mainly involved in psoriasis. Network pharmacology provide a new insight into the relationships between metabonomics biomarkers and the pathogenesis of psoriasis. KEY MESSAGES   • Network pharmacology was adopted to identify key metabonomics biomarkers and enzymes.   • Six proteins were screened out as important drug targets for psoriasis.   • A binding energy-weighted polypharmacological index was introduced to evaluate the importance of target-related pathways.

Deciphering the Mechanism of Action of Wrightia tinctoria for Psoriasis Based on Systems Pharmacology Approach.

PubMed

Sundarrajan, Sudharsana; Lulu, Sajitha; Arumugam, Mohanapriya

2017-11-01

Psoriasis is a chronic immune-mediated disorder of the skin. The disease manifests itself with red or silvery scaly plaques distributing over the lower back, scalp, and extensor aspects of limbs. Several medications are available for the treatment of psoriasis; however, high rates of remission and side-effects still persist as a major concern. Siddha, one of the traditional systems of Indian medicine offers cure to many dermatological conditions, including psoriasis. The oil prepared from the leaves of Wrightia tinctoria is prescribed by many healers for the treatment of psoriasis. This work aims to decipher the mechanism of action of the W. tinctoria in curing psoriasis and its associated comorbidities. The work integrates various pharmacology approaches such as drug-likeness evaluation, oral bioavailability predictions, and network pharmacology approaches to understand the roles of various bioactive components of the herb. This work identified 67 compounds of W. tinctoria interacting with 238 protein targets. The compounds were found to act through synergistic mechanism in reviving the disrupted process in the diseased state. The results of this work not only shed light on the pharmacological action of the herb but also validate the usage of safe herbal drugs.

Biomarkers in psoriasis and psoriatic arthritis.

PubMed

Villanova, Federica; Di Meglio, Paola; Nestle, Frank O

2013-04-01

Psoriasis is a common immune-mediated disease of the skin, which associates in 20-30% of patients with psoriatic arthritis (PsA). The immunopathogenesis of both conditions is not fully understood as it is the result of a complex interaction between genetic, environmental and immunological factors. At present there is no cure for psoriasis and there are no specific markers that can accurately predict disease progression and therapeutic response. Therefore, biomarkers for disease prognosis and response to treatment are urgently needed to help clinicians with objective indications to improve patient management and outcomes. Although many efforts have been made to identify psoriasis/PsA biomarkers none of them has yet been translated into routine clinical practice. In this review we summarise the different classes of possible biomarkers explored in psoriasis and PsA so far and discuss novel strategies for biomarker discovery.

Medical nutrition therapy as a potential complementary treatment for psoriasis--five case reports.

PubMed

Brown, Amy C; Hairfield, Michelle; Richards, Douglas G; McMillin, David L; Mein, Eric A; Nelson, Carl D

2004-09-01

This research evaluated five case studies of patients with psoriasis following a dietary regimen. There is no cure for psoriasis and the multiple treatments currently available only attempt to reduce the severity of symptoms. Treatments range from topical applications, systemic therapies, and phototherapy; while some are effective, many are associated with significant adverse effects. There is a need for effective, affordable therapies with fewer side effects that address the causes of the disorder. Evaluation consisted of a study group of five patients diagnosed with chronic plaque psoriasis (two men and three women, average age 52 years; range 40-68 years) attending a 10-day, live-in program during which a physician assessed psoriasis symptoms and bowel permeability. Subjects were then instructed on continuing the therapy protocol at home for six months. The dietary protocol, based on Edgar Cayce readings, included a diet of fresh fruits and vegetables, small amounts of protein from fish and fowl, fiber supplements, olive oil, and avoidance of red meat, processed foods, and refined carbohydrates. Saffron tea and slippery elm bark water were consumed daily. The five psoriasis cases, ranging from mild to severe at the study onset, improved on all measured outcomes over a six-month period when measured by the Psoriasis Area and Severity Index (PASI) (average pre- and post-test scores were 18.2 and 8.7, respectively), the Psoriasis Severity Scale (PSS) (average pre- and post-test scores were 14.6 and 5.4, respectively), and the lactulose/mannitol test of intestinal permeability (average pre- and post-test scores were 0.066 to 0.026, respectively). These results suggest a dietary regimen based on Edgar Cayce's readings may be an effective medical nutrition therapy for the complementary treatment of psoriasis; however, further research is warranted to confirm these results.

Modulation of mitochondrial activity in HaCaT keratinocytes by the cell penetrating peptide Z-Gly-RGD(DPhe)-mitoparan.

PubMed

Richardson, Adam; Muir, Lewis; Mousdell, Sasha; Sexton, Darren; Jones, Sarah; Howl, John; Ross, Kehinde

2018-01-30

Biologically active cell penetrating peptides (CPPs) are an emerging class of therapeutic agent. The wasp venom peptide mastoparan is an established CPP that modulates mitochondrial activity and triggers caspase-dependent apoptosis in cancer cells, as does the mastoparan analogue mitoparan (mitP). Mitochondrial depolarisation and activation of the caspase cascade also underpins the action of dithranol, a topical agent for treatment of psoriasis. The effects of a potent mitP analogue on mitochondrial activity were therefore examined to assess its potential as a novel approach for targeting mitochondria for the treatment of psoriasis. In HaCaT keratinocytes treated with the mitP analogue Z-Gly-RGD(DPhe)-mitP for 24 h, a dose-dependent loss of mitochondrial activity was observed using the methyl-thiazolyl-tetrazolium (MTT) assay. At 10 μmol L -1 , MTT activity was less than 30% that observed in untreated cells. Staining with the cationic dye JC-1 suggested that Z-Gly-RGD(DPhe)-mitP also dissipated the mitochondrial membrane potential, with a threefold increase in mitochondrial depolarisation levels. However, caspase activity appeared to be reduced by 24 h exposure to Z-Gly-RGD(DPhe)-mitP treatment. Furthermore, Z-Gly-RGD(DPhe)-mitP treatment had little effect on overall cell viability. Our findings suggest Z-Gly-RGD(DPhe)-mitP promotes the loss of mitochondrial activity but does not appear to evoke apoptosis in HaCaT keratinocytes.

Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture.

PubMed

Stuart, Philip E; Nair, Rajan P; Tsoi, Lam C; Tejasvi, Trilokraj; Das, Sayantan; Kang, Hyun Min; Ellinghaus, Eva; Chandran, Vinod; Callis-Duffin, Kristina; Ike, Robert; Li, Yanming; Wen, Xiaoquan; Enerbäck, Charlotta; Gudjonsson, Johann E; Kõks, Sulev; Kingo, Külli; Esko, Tõnu; Mrowietz, Ulrich; Reis, Andre; Wichmann, H Erich; Gieger, Christian; Hoffmann, Per; Nöthen, Markus M; Winkelmann, Juliane; Kunz, Manfred; Moreta, Elvia G; Mease, Philip J; Ritchlin, Christopher T; Bowcock, Anne M; Krueger, Gerald G; Lim, Henry W; Weidinger, Stephan; Weichenthal, Michael; Voorhees, John J; Rahman, Proton; Gregersen, Peter K; Franke, Andre; Gladman, Dafna D; Abecasis, Gonçalo R; Elder, James T

2015-12-03

Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 × 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Systematic Identification and Characterization of Novel Human Skin-Associated Genes Encoding Membrane and Secreted Proteins

PubMed Central

Buhren, Bettina Alexandra; Martinez, Cynthia; Schrumpf, Holger; Gasis, Marcia; Grether-Beck, Susanne; Krutmann, Jean

2013-01-01

Through bioinformatics analyses of a human gene expression database representing 105 different tissues and cell types, we identified 687 skin-associated genes that are selectively and highly expressed in human skin. Over 50 of these represent uncharacterized genes not previously associated with skin and include a subset that encode novel secreted and plasma membrane proteins. The high levels of skin-associated expression for eight of these novel therapeutic target genes were confirmed by semi-quantitative real time PCR, western blot and immunohistochemical analyses of normal skin and skin-derived cell lines. Four of these are expressed specifically by epidermal keratinocytes; two that encode G-protein-coupled receptors (GPR87 and GPR115), and two that encode secreted proteins (WFDC5 and SERPINB7). Further analyses using cytokine-activated and terminally differentiated human primary keratinocytes or a panel of common inflammatory, autoimmune or malignant skin diseases revealed distinct patterns of regulation as well as disease associations that point to important roles in cutaneous homeostasis and disease. Some of these novel uncharacterized skin genes may represent potential biomarkers or drug targets for the development of future diagnostics or therapeutics. PMID:23840300

Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: Results from a 52-week, open-label, phase 3 study (UNCOVER-J).

PubMed

Saeki, Hidehisa; Nakagawa, Hidemi; Nakajo, Ko; Ishii, Taeko; Morisaki, Yoji; Aoki, Takehiro; Cameron, Gregory S; Osuntokun, Olawale O

2017-04-01

Psoriasis, a chronic, immune-mediated skin disease characterized by red, scaly plaques, affects approximately 0.3% of the population in Japan. The aim of this open-label study was to evaluate the long-term efficacy and safety of ixekizumab, a humanized, anti-interleukin-17A monoclonal antibody, in Japanese patients with plaque psoriasis (n = 78, including 11 psoriatic arthritis), erythrodermic psoriasis (n = 8) and generalized pustular psoriasis (n = 5). Ixekizumab was administrated s.c. at baseline (week 0, 160 mg), from weeks 2 to 12 (80 mg every 2 weeks), and from weeks 16 to 52 (80 mg every 4 weeks). At week 52, 92.3% of patients with plaque psoriasis achieved Psoriasis Area and Severity Index (PASI) 75, 80.8% achieved PASI 90, 48.7% achieved PASI 100, and 52.6% had remission of plaques (by static Physician Global Assessment, sPGA [0]). Difficult to treat areas of psoriasis (nail or scalp) also responded to ixekizumab. All patients with psoriatic arthritis who were assessed (5/5) achieved an American College of Rheumatology 20 response. Most patients with erythrodermic psoriasis or generalized pustular psoriasis responded to ixekizumab and the clinical outcome was maintained over 52 weeks (75% and 60% of patients achieved sPGA [0, 1] at week 52, respectively). Mostly mild or moderate treatment-emergent adverse events were reported by 79 of 91 patients; the most common were nasopharyngitis, eczema, seborrheic dermatitis, urticaria and injection site reactions. In conclusion, 52-week ixekizumab treatment was efficacious and well tolerated in Japanese patients with plaque psoriasis. Efficacy was also observed in patients with erythrodermic psoriasis, generalized pustular psoriasis and psoriatic arthritis. © 2016 Eli Lilly Japan K.K. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.

Generalised fibrotic gingival enlargement in a psoriatic patient: an association or a coincidence?

PubMed

Thada, Smitha Rani; Vineetha, Ravindranath; Pai, Keerthilatha M

2015-09-21

Gingival fibromatosis is a rare, benign, slow progressive fibrous overgrowth of gingiva, with great genetic and clinical heterogeneity. It can be inherited as an isolated trait (hereditary/idiopathic gingival fibromatosis), and/or as a component of a syndrome. We report a case of a young girl suffering from psoriasis who also presented with an unusual generalised idiopathic gingival fibromatosis. Psoriasis, a chronic inflammatory skin disease, of multifactorial origin, is characterised by keratinocyte hyperproliferation, dedifferentiation, neoangiogenesis and inflammation. T cell-mediated immunity is considered to be the key element in the disease process. The existence of oral mucosal alterations in patients with psoriasis is a controversial topic, as histopathological correlations are not clearly evident, and oral and cutaneous lesions do not follow a parallel course. However, this article highlights a possible association of T-lymphocyte stimulation inducing fibroblasts to undergo epidermal hyperproliferation and increased collagen production in the gingiva, which in turn may be responsible for inducing gingival hyperplasia. 2015 BMJ Publishing Group Ltd.

Oxidative stress drives CD8+ T-cell skin trafficking in patients with vitiligo through CXCL16 upregulation by activating the unfolded protein response in keratinocytes.

PubMed

Li, Shuli; Zhu, Guannan; Yang, Yuqi; Jian, Zhe; Guo, Sen; Dai, Wei; Shi, Qiong; Ge, Rui; Ma, Jingjing; Liu, Ling; Li, Kai; Luan, Qi; Wang, Gang; Gao, Tianwen; Li, Chunying

2017-07-01

In patients with vitiligo, an increased reactive oxygen species (ROS) level has been proved to be a key player during disease initiation and progression in melanocytes. Nevertheless, little is known about the effects of ROS on other cells involved in the aberrant microenvironment, such as keratinocytes and the following immune events. CXCL16 is constitutively expressed in keratinocytes and was recently found to mediate homing of CD8 + T cells in human skin. We sought to explicate the effect of oxidative stress on human keratinocytes and its capacity to drive CD8 + T-cell trafficking through CXCL16 regulation. We first detected putative T-cell skin-homing chemokines and ROS in serum and lesions of patients with vitiligo. The production of candidate chemokines was detected by using quantitative real-time PCR and ELISA in keratinocytes exposed to H 2 O 2 . Furthermore, the involved mediators were analyzed by using quantitative real-time PCR, Western blotting, ELISA, and immunofluorescence. Next, we tested the chemotactic migration of CD8 + T cells from patients with vitiligo mediated by the CXCL16-CXCR6 pair using the transwell assay. CXCL16 expression increased and showed a positive correlation with oxidative stress levels in serum and lesions of patients with vitiligo. The H 2 O 2 -induced CXCL16 expression was due to the activation of 2 unfolded protein response pathways: kinase RNA (PKR)-like ER kinase-eukaryotic initiation factor 2α and inositol-requiring enzyme 1α-X-box binding protein 1. CXCL16 produced by stressed keratinocytes induced migration of CXCR6 + CD8 + T cells derived from patients with vitiligo. CXCR6 + CD8 + T-cell skin infiltration is accompanied by melanocyte loss in lesions of patients with vitiligo. Our study demonstrated that CXCL16-CXCR6 mediates CD8 + T-cell skin trafficking under oxidative stress in patients with vitiligo. The CXCL16 expression in human keratinocytes induced by ROS is, at least in part, caused by unfolded protein response

Patient perspectives in the management of psoriasis: results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey.

PubMed

Lebwohl, Mark G; Bachelez, Hervé; Barker, Jonathan; Girolomoni, Giampiero; Kavanaugh, Arthur; Langley, Richard G; Paul, Carle F; Puig, Lluís; Reich, Kristian; van de Kerkhof, Peter C M

2014-05-01

Available psoriasis surveys offer valuable information about psoriasis and psoriatic arthritis (PsA), but are limited by methodology or enrollment requirements. To further the understanding of the unmet needs of psoriasis and PsA patients. This was a large, multinational, population-based survey of psoriasis and/or PsA patients in North America and Europe. Patients were selected by list-assisted random digit dialing and did not have to currently be under the care of a health care provider, a patient organization member, or receiving treatment; 139,948 households were screened and 3426 patients completed the survey. The prevalence of psoriasis/PsA ranged from 1.4% to 3.3%; 79% had psoriasis alone and 21% had PsA. When rating disease severity at its worst, 27% (psoriasis) and 53% (PsA ± psoriasis) of patients rated it as severe. Psoriasis patients indicated that their most bothersome signs or symptoms were itching (43%), scales (23%), and flaking (20%). Of psoriasis patients, 45% had not seen a physician in a year; >80% of psoriasis patients with ≥ 4 palms body surface area and 59% of PsA patients were receiving no treatment or topical treatment only. Of patients who had received oral or biologic therapy, 57% and 45%, respectively, discontinued therapy, most often for safety/tolerability reasons and a lack/loss of efficacy. The survey lacked a control group, did not account for ethnic and health care system differences across countries, and was limited by factors associated with any patient survey, including accurate recall and interpretation of questions. Several identified unmet needs warrant additional attention and action, including improved severity assessment, PsA screening, patient awareness, and treatment options. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Dietary Recommendations for Adults With Psoriasis or Psoriatic Arthritis From the Medical Board of the National Psoriasis Foundation: A Systematic Review.

PubMed

Ford, Adam R; Siegel, Michael; Bagel, Jerry; Cordoro, Kelly M; Garg, Amit; Gottlieb, Alice; Green, Lawrence J; Gudjonsson, Johann E; Koo, John; Lebwohl, Mark; Liao, Wilson; Mandelin, Arthur M; Markenson, Joseph A; Mehta, Nehal; Merola, Joseph F; Prussick, Ronald; Ryan, Caitriona; Schwartzman, Sergio; Siegel, Evan L; Van Voorhees, Abby S; Wu, Jashin J; Armstrong, April W

2018-06-20

Psoriasis is a chronic, inflammatory skin disease and has significant associated morbidity and effect on quality of life. It is important to determine whether dietary interventions help reduce disease severity in patients with psoriatic diseases. To make evidence-based dietary recommendations for adults with psoriasis and/or psoriatic arthritis from the Medical Board of the National Psoriasis Foundation. We used literature from prior systematic reviews as well as additional primary literature from the MEDLINE database from January 1, 2014, to August 31, 2017, that evaluated the impact of diet on psoriasis. We included observational and interventional studies of patients with psoriasis or psoriatic arthritis. The quality of included studies was assessed using the Newcastle-Ottawa scale for observational studies and the Cochrane Risk of Bias Tool for interventional studies. We made evidence-based dietary recommendations, which were voted on by the National Psoriasis Foundation Medical Board. We identified 55 studies meeting the inclusion criteria for this review. These studies represent 77 557 unique participants of which 4534 have psoriasis. Based on the literature, we strongly recommend dietary weight reduction with a hypocaloric diet in overweight and obese patients with psoriasis. We weakly recommend a gluten-free diet only in patients who test positive for serologic markers of gluten sensitivity. Based on low-quality data, select foods, nutrients, and dietary patterns may affect psoriasis. For patients with psoriatic arthritis, we weakly recommend vitamin D supplementation and dietary weight reduction with a hypocaloric diet in overweight and obese patients. Dietary interventions should always be used in conjunction with standard medical therapies for psoriasis and psoriatic arthritis. Adults with psoriasis and/or psoriatic arthritis can supplement their standard medical therapies with dietary interventions to reduce disease severity. These dietary

Increased psoriasis frequency in patients with familial Mediterranean fever

PubMed Central

Batu, Ezgi Deniz; Seyhoğlu, Emrah; Sari, Alper; Sönmez, Hafize Emine; Armagan, Berkan; Demir, Selcan; Kilic, Levent; Karadag, Omer; Akdogan, Ali; Bilginer, Yelda; Ertenli, Ihsan; Kiraz, Sedat; Apras Bilgen, Sule; Kalyoncu, Umut

2018-01-01

Objective Familial Mediterranean fever (FMF) is a periodic fever syndrome caused by MEFV mutations. FMF may be associated with psoriasis in some cases. The prevalence of psoriasis in the normal Turkish population is 0.42%. We aimed to investigate the prevalence of psoriasis among FMF patients and their relatives. Methods FMF patients followed at Hacettepe University Adult and Pediatric Rheumatology Departments between January and August 2016 were included. FMF patients/their relatives were accepted to have psoriasis if the diagnosis was made by a dermatologist. Results A total of 351 FMF patients (177 adults; 174 children) were included. The median (min–max) age of adult and pediatric patients was 35 (19–63) and 10 (2–18) years, respectively. Thirteen (3.7%) FMF patients (11 adults, 2 children) had psoriasis. Psoriasis was more common in adult than pediatric patients (p = 0.02). Psoriasis was present in 22 (12.4%) of adult and 9 (5.2%) of pediatric patients’ relatives (p = 0.023). The frequency of psoriasis in ≥1 relatives of FMF patients was found to be 8.8%. Abdominal pain and fever were significantly higher, and arthralgia, arthritis, pleural chest pain, and pericarditis were significantly less frequent in the pediatric group than in adults (p < 0.05). Conclusion Psoriasis was more common in FMF patients than in the normal population. Thus, FMF patients should be questioned and carefully examined for psoriasis lesions and psoriasis family history. Prospective multicenter studies may be important to find the incidence of psoriasis in FMF. PMID:29363386

Increased psoriasis frequency in patients with familial Mediterranean fever.

PubMed

Erden, Abdulsamet; Batu, Ezgi Deniz; Seyhoğlu, Emrah; Sari, Alper; Sönmez, Hafize Emine; Armagan, Berkan; Demir, Selcan; Bilgin, Emre; Kilic, Levent; Karadag, Omer; Akdogan, Ali; Bilginer, Yelda; Ertenli, Ihsan; Kiraz, Sedat; Apras Bilgen, Sule; Kalyoncu, Umut

2018-03-01

Familial Mediterranean fever (FMF) is a periodic fever syndrome caused by MEFV mutations. FMF may be associated with psoriasis in some cases. The prevalence of psoriasis in the normal Turkish population is 0.42%. We aimed to investigate the prevalence of psoriasis among FMF patients and their relatives. FMF patients followed at Hacettepe University Adult and Pediatric Rheumatology Departments between January and August 2016 were included. FMF patients/their relatives were accepted to have psoriasis if the diagnosis was made by a dermatologist. A total of 351 FMF patients (177 adults; 174 children) were included. The median (min-max) age of adult and pediatric patients was 35 (19-63) and 10 (2-18) years, respectively. Thirteen (3.7%) FMF patients (11 adults, 2 children) had psoriasis. Psoriasis was more common in adult than pediatric patients (p = 0.02). Psoriasis was present in 22 (12.4%) of adult and 9 (5.2%) of pediatric patients' relatives (p = 0.023). The frequency of psoriasis in ≥1 relatives of FMF patients was found to be 8.8%. Abdominal pain and fever were significantly higher, and arthralgia, arthritis, pleural chest pain, and pericarditis were significantly less frequent in the pediatric group than in adults (p < 0.05). Psoriasis was more common in FMF patients than in the normal population. Thus, FMF patients should be questioned and carefully examined for psoriasis lesions and psoriasis family history. Prospective multicenter studies may be important to find the incidence of psoriasis in FMF.

Metabolic syndrome in patients with psoriasis: A comparative study.

PubMed

Lakshmi, Sristi; Nath, Amiya Kumar; Udayashankar, Carounanidy

2014-04-01

Psoriasis patients are at increased risk of developing the metabolic syndrome (MS). Proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6 that are increased in the psoriatic plaques are known to contribute to features of MS such as hypertension, dyslipidemia and insulin resistance. (1) To establish the frequency of MS in patients with psoriasis. (2) To study the risk factors associated with MS in psoriasis. A hospital based comparative study was conducted involving 40 adult patients with psoriasis and 40 age- and sex-matched controls. All participants were evaluated for components of MS. Both groups included 31 males and 9 females. The mean age of the cases and controls were 49.95 years and 49.35 years, respectively. Psoriasis patients with MS had a statistically significant higher mean age (56.31 ± 11.36 years) compared with those without MS (46.89 ± 11.51 years). MS was present in 13 out of 40 (32.5%) patients with psoriasis and 12 out of 40 (30%) controls; this difference was not statistically significant. Higher age and female gender correlated with the presence of MS in psoriasis patients. The presence of MS in psoriasis patients was statistically independent of psoriasis area severity index score, body surface area involvement or psoriatic arthropathy. Our results suggest that there is no close correlation between psoriasis and MS in South Indian patients.

Topical Therapies in Psoriasis

PubMed Central

Torsekar, R.; Gautam, Manjyot M.

2017-01-01

Topical therapy as monotherapy is useful in psoriasis patients with mild disease. Topical agents are also used as adjuvant for moderate-to-severe disease who are being concurrently treated with either ultraviolet light or systemic medications. Emollients are useful adjuncts to the treatment of psoriasis. Use of older topical agents such as anthralin and coal tar has declined over the years. However, they are cheaper and can still be used for the treatment of difficult psoriasis refractory to conventional treatment. Salicylic acid can be used in combination with other topical therapies such as topical corticosteroids (TCS) and calcineurin inhibitors for the treatment of thick limited plaques to increase the absorption of the latter into the psoriatic plaques. Low- to mid-potent TCS are used in facial/flexural psoriasis and high potent over palmoplantar/thick psoriasis lesions. The addition of noncorticosteroid treatment can also facilitate the avoidance of long-term daily TCS. Tacrolimus and pimecrolimus can be used for the treatment of facial and intertriginous psoriasis. Tazarotene is indicated for stable plaque psoriasis usually in combination with other therapies such as TCS. Vitamin D analogs alone in combination with TCS are useful in stable plaques over limbs and palmoplantar psoriasis. Topical therapies for scalp psoriasis include TCS, Vitamin D analogs, salicylic acid, coal tar, and anthralin in various formulations such as solutions, foams, and shampoos. TCS, vitamin D analogs, and tazarotene can be used in the treatment of nail psoriasis. PMID:28761838

Highlighting Interleukin-36 Signalling in Plaque Psoriasis and Pustular Psoriasis.

PubMed

Furue, Kazuhisa; Yamamura, Kazuhiko; Tsuji, Gaku; Mitoma, Chikage; Uchi, Hiroshi; Nakahara, Takeshi; Kido-Nakahara, Makiko; Kadono, Takafumi; Furue, Masutaka

2018-01-12

Plaque psoriasis and pustular psoriasis are overlapping, but distinct, disorders. The therapeutic response to biologics supports the pivotal role of the tumour necrosis alpha (TNF-?)/ interleukin (IL)-23/IL-17/IL-22 axis in the pathogenesis of these disorders. Recently, functional activation of the IL-36 receptor (IL-36R) was discovered to be another driving force in the pathogenesis of psoriasis. This was first highlighted by the discovery that a loss-of-function mutation of the IL-36R antagonist (IL-36Ra) causes pustular psoriasis. Although the TNF-?/IL-23/IL-17/IL-22 axis and the functional activation of IL-36R are fundamentally involved in plaque psoriasis and pustular psoriasis, respectively, the 2 pathways are closely related and mutually reinforced, resulting in full-blown clinical manifestations. This review summarizes current topics on how IL-36 agonists (IL-36?, IL-36?, IL-36?) signal IL-36R, the pathological expression of IL-36 agonists and IL-36Ra in plaque and pustular psoriatic lesions, and the cross-talk between the TNF-?/IL-23/IL-17/IL-22 axis and the functional activation of IL-36R in the epidermal milieu.

Microorganisms and psoriasis.

PubMed Central

Rosenberg, E. W.; Noah, P. W.; Skinner, R. B.

1994-01-01

It has been suggested previously that psoriasis is best explained as a distinctive inflammatory response to a variety of microbial stimuli, all acting primarily through activation of the alternative complement pathway. For the past several years we have conducted a "Problem Psoriasis Clinic" based on that premise. Patients are questioned, examined, and subjected to microbiologic laboratory investigations in an attempt to identify possibly relevant microorganisms, and then are treated with antibiotics. This article lists the most commonly found microorganisms in psoriasis patients and describes the usual treatment for each. Results obtained with this approach compare favorably with those achieved with more usual anti-psoriasis treatments. We recommend that a microbiologic investigation and a trial of antimicrobial treatment should precede any plan to treat psoriasis patients with anything more than the simplest topical agents. PMID:8040907

The extracellular adherence protein (Eap) of Staphylococcus aureus acts as a proliferation and migration repressing factor that alters the cell morphology of keratinocytes.

PubMed

Eisenbeis, Janina; Peisker, Henrik; Backes, Christian S; Bur, Stephanie; Hölters, Sebastian; Thewes, Nicolas; Greiner, Markus; Junker, Christian; Schwarz, Eva C; Hoth, Markus; Junker, Kerstin; Preissner, Klaus T; Jacobs, Karin; Herrmann, Mathias; Bischoff, Markus

2017-02-01

Staphyloccocus aureus is a major human pathogen and a common cause for superficial and deep seated wound infections. The pathogen is equipped with a large arsenal of virulence factors, which facilitate attachment to various eukaryotic cell structures and modulate the host immune response. One of these factors is the extracellular adherence protein Eap, a member of the "secretable expanded repertoire adhesive molecules" (SERAM) protein family that possesses adhesive and immune modulatory properties. The secreted protein was previously shown to impair wound healing by interfering with host defense and neovascularization. However, its impact on keratinocyte proliferation and migration, two major steps in the re-epithelialization process of wounds, is not known. Here, we report that Eap affects the proliferation and migration capacities of keratinocytes by altering their morphology and adhesive properties. In particular, treatment of non-confluent HaCaT cell cultures with Eap resulted in cell morphology changes as well as a significant reduction in cell proliferation and migration. Eap-treated HaCaT cells changed their appearance from an oblong via a trapezoid to an astral-like shape, accompanied by decreases in cell volume and cell stiffness, and exhibited significantly increased cell adhesion. Eap had a similar influence on endothelial and cancer cells, indicative for a general effect of Eap on eukaryotic cell morphology and functions. Specifically, Eap was found to interfere with growth factor-stimulated activation of the mitogen-activated protein kinase (MAPK) pathway that is known to be responsible for cell shape modulation, induction of proliferation and migration of epithelial cells. Western blot analyses revealed that Eap blocked the phosphorylation of extracellular signal-regulated kinase 1 and 2 (Erk1/2) in keratinocyte growth factor (KGF)-stimulated HaCaT cells. Together, these data add another antagonistic mechanism of Eap in wound healing, whereby the

Upregulation of adhesion complex proteins and fibronectin by human keratinocytes treated with an aqueous extract from the leaves of Chromolaena odorata (Eupolin).

PubMed

Phan, T T; Allen, J; Hughes, M A; Cherry, G; Wojnarowska, F

2000-01-01

The fresh leaves and extract of the plant Chromolaena odorata are a traditional herbal treatment in developing countries for burns, soft tissue wounds and skin infections. We have previously shown that the extract had an effect on the growth and proliferation of keratinocytes and fibroblasts in culture. This study has demonstrated that Eupolin extract increased expression of several components of the adhesion complex and fibronectin by human keratinocytes. Using indirect immunofluorescence we found increased expression (dose-dependent) of laminin 5, laminin 1, collagen IV, and fibronectin. The expression of the b1 and b4 integrins was upregulated by the extract at low concentrations (0.1 and 1 microg/ml), but the expression was decreased at higher doses of Eupolin (10 microg-150 microg/ml). A number of clinical studies carried out by Vietnamese and international medical investigators have demonstrated the efficacy of this extract on the wound healing process. In this study we have shown that Eupolin stimulated the expression of many proteins of the adhesion complex and fibronectin by human keratinocytes. The adhesion complex proteins are essential to stabilise epithelium and this effect could contribute to the clinical efficacy of Eupolin in healing.

Cardiovascular comorbidities of pediatric psoriasis among hospitalized children in the United States.

PubMed

Kwa, Lauren; Kwa, Michael C; Silverberg, Jonathan I

2017-12-01

Psoriasis has been shown to be associated with cardiovascular disease in adults. Little is known about cardiovascular risk in pediatric psoriasis. To determine if there is an association between pediatric psoriasis and cardiovascular comorbidities. Data were analyzed from the 2002-2012 Nationwide Inpatient Sample, which included 4,884,448 hospitalized children aged 0-17 years. Bivariate and multivariate survey logistic regression models were created to calculate the odds of psoriasis on cardiovascular comorbidities. In multivariate survey logistic regression models adjusting for age, sex, and race/ethnicity, pediatric psoriasis was significantly associated with 5 of 10 cardiovascular comorbidities (adjusted odds ratio [95% confidence interval]), including obesity (3.15 [2.46-4.05]), hypertension (2.63 [1.93-3.59]), diabetes (2.90 [1.90-4.42]), arrhythmia (1.39 [1.02-1.88]), and valvular heart disease (1.90 [1.07-3.37]). The highest odds of cardiovascular risk factors occurred in blacks and Hispanics and children ages 0-9 years, but there were no sex differences. The study was limited to hospitalized children. We were unable to assess the impact of psoriasis treatment or family history on cardiovascular risk. Pediatric psoriasis is associated with higher odds of multiple cardiovascular comorbidities among hospitalized patients. Strategies for mitigating excess cardiovascular risk in pediatric psoriasis need to be determined. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

In silico database screening of potential targets and pathways of compounds contained in plants used for psoriasis vulgaris.

PubMed

May, Brian H; Deng, Shiqiang; Zhang, Anthony L; Lu, Chuanjian; Xue, Charlie C L

2015-09-01

Reviews and meta-analyses of clinical trials identified plants used as traditional medicines (TMs) that show promise for psoriasis. These include Rehmannia glutinosa, Camptotheca acuminata, Indigo naturalis and Salvia miltiorrhiza. Compounds contained in these TMs have shown activities of relevance to psoriasis in experimental models. To further investigate the likely mechanisms of action of the multiple compounds in these TMs, we undertook a computer-based in silico investigation of the proteins known to be regulated by these compounds and their associated biological pathways. The proteins reportedly regulated by compounds in these four TMs were identified using the HIT (Herbal Ingredients' Targets) database. The resultant data were entered into the PANTHER (Protein ANnotation THrough Evolutionary Relationship) database to identify the pathways in which the proteins could be involved. The study identified 237 compounds in the TMs and these retrieved 287 proteins from HIT. These proteins identified 59 pathways in PANTHER with most proteins being located in the Apoptosis, Angiogenesis, Inflammation mediated by chemokine and cytokine, Gonadotropin releasing hormone receptor, and/or Interleukin signaling pathways. All four TMs contained compounds that had regulating effects on Apoptosis regulator BAX, Apoptosis regulator Bcl-2, Caspase-3, Tumor necrosis factor (TNF) or Prostaglandin G/H synthase 2 (COX2). The main proteins and pathways are primarily related to inflammation, proliferation and angiogenesis which are all processes involved in psoriasis. Experimental studies have reported that certain compounds from these TMs can regulate the expression of proteins involved in each of these pathways.

SOCS3 inhibits the pathological effects of IL-22 in non-melanoma skin tumor-derived keratinocytes

PubMed Central

Madonna, Stefania; Scarponi, Claudia; Morelli, Martina; Sestito, Rosanna; Scognamiglio, Pasqualina Liana; Marasco, Daniela; Albanesi, Cristina

2017-01-01

Basal cell carcinomas (BCC) and squamous-cell carcinomas (SCC) are common malignancies in humans, caused by neoplastic transformation of keratinocytes of the basal or suprabasal layers of epidermis, respectively. Tumor-infiltrating lymphocytes (TILs) are frequently found in BCC and SCC, and functionally promote epithelial carcinogenesis. TILs secreting IL-22, in particular, participate to BCC and SCC growth by inducing keratinocyte proliferation and migration, as well as the expression of inflammatory, anti-apoptotic and pro-angiogenic genes. In this study, we identified SOCS3 as a valid candidate to be manipulated for suppressing tumorigenic functions in BCC and SCC. We found that SOCS3 and SOCS1 expression was reduced in vivo, in tumor lesions of BCC and SCC, as compared to other skin inflammatory conditions such as psoriasis, despite the high number of IL-22-secreting TILs. Moreover, IL-22 was not able to induce in vitro the transcriptional expression of SOCS3 in BCC-or SCC-derived keratinocytes, contrarily to healthy cells. Aimed at rescuing SOCS3 activity in these tumor contexts, a SOCS3-derived peptide, named KIR-ESS, was synthesized, and its ability in suppressing IL-22-induced responses was evaluated in healthy and transformed keratinocytes. We found that KIR-ESS peptide efficiently suppressed the IL-22 molecular signaling in keratinocytes, by acting on STAT3 and Erk1/2 cascade, as well as on the expression of STAT3-dependent downstream genes. Interestingly, after treatment with peptide, both healthy and transformed keratinocytes could no longer aberrantly proliferate and migrate in response to IL-22. Finally, treatment of athymic nude mice bearing SCC xenografts with KIR-ESS peptide concomitantly reduced tumor growth and activated STAT3 levels. As a whole, these data provides the rationale for the use in BCC and SCC skin tumors of SOCS3 mimetics, being able to inhibit the deleterious effects of IL-22 in these contexts. PMID:28445952

SOCS3 inhibits the pathological effects of IL-22 in non-melanoma skin tumor-derived keratinocytes.

PubMed

Madonna, Stefania; Scarponi, Claudia; Morelli, Martina; Sestito, Rosanna; Scognamiglio, Pasqualina Liana; Marasco, Daniela; Albanesi, Cristina

2017-04-11

Basal cell carcinomas (BCC) and squamous-cell carcinomas (SCC) are common malignancies in humans, caused by neoplastic transformation of keratinocytes of the basal or suprabasal layers of epidermis, respectively. Tumor-infiltrating lymphocytes (TILs) are frequently found in BCC and SCC, and functionally promote epithelial carcinogenesis. TILs secreting IL-22, in particular, participate to BCC and SCC growth by inducing keratinocyte proliferation and migration, as well as the expression of inflammatory, anti-apoptotic and pro-angiogenic genes.In this study, we identified SOCS3 as a valid candidate to be manipulated for suppressing tumorigenic functions in BCC and SCC. We found that SOCS3 and SOCS1 expression was reduced in vivo, in tumor lesions of BCC and SCC, as compared to other skin inflammatory conditions such as psoriasis, despite the high number of IL-22-secreting TILs. Moreover, IL-22 was not able to induce in vitro the transcriptional expression of SOCS3 in BCC-or SCC-derived keratinocytes, contrarily to healthy cells. Aimed at rescuing SOCS3 activity in these tumor contexts, a SOCS3-derived peptide, named KIR-ESS, was synthesized, and its ability in suppressing IL-22-induced responses was evaluated in healthy and transformed keratinocytes. We found that KIR-ESS peptide efficiently suppressed the IL-22 molecular signaling in keratinocytes, by acting on STAT3 and Erk1/2 cascade, as well as on the expression of STAT3-dependent downstream genes. Interestingly, after treatment with peptide, both healthy and transformed keratinocytes could no longer aberrantly proliferate and migrate in response to IL-22. Finally, treatment of athymic nude mice bearing SCC xenografts with KIR-ESS peptide concomitantly reduced tumor growth and activated STAT3 levels. As a whole, these data provides the rationale for the use in BCC and SCC skin tumors of SOCS3 mimetics, being able to inhibit the deleterious effects of IL-22 in these contexts.

Keratin pattern of acanthosis nigricans in syndromelike association with polythelia, polycystic kidneys, and syndactyly.

PubMed

Bonnekoh, B; Wevers, A; Spangenberger, H; Mahrle, G; Krieg, T

1993-09-01

Acanthosis nigricans (AN) comprises a broad spectrum of etiologic subtypes. The underlying pathomechanisms have not yet been completely clarified. We present a patient affected with a syndromelike AN subtype including disturbed epidermopoiesis as evidenced by immunohistologic findings and in situ hybridization. A 54-year-old white man contracted AN during childhood. There were connate malformations consisting of webbed toes II/III on the right side and a supernumerary left mammilla. As an adult he developed psoriasis vulgaris, obesity, and latent diabetes mellitus, polycystic kidney and liver disease. With regard to keratin 6 mRNA, and the protein expression of keratin 6/16, KI-67, and proliferating cell nuclear antigen, the AN lesion showed moderate hyperproliferation. A much higher degree of hyperproliferation was evident in psoriatic areas of the patient's skin. In contrast to psoriatic tissue, basal keratinocytes of the AN showed an unusually high expression of keratin 18 and 19 protein. The observation thus deals with a unique, syndromelike constellation of AN characterized by a particular epidermal pattern of moderate hyperproliferation. A further dysregulation of protein expression in the epidermis is indicated by the demonstration of the rare keratins 18 and 19 in basal keratinocytes of the AN lesion.

Subjective Health Complaints in Individuals with Psoriasis and Psoriatic Arthritis: Associations with the Severity of the Skin Condition and Illness Perceptions - A Cross-Sectional Study.

PubMed

Nordbø, Emma Charlott Andersson; Aamodt, Geir; Ihlebæk, Camilla Martha

2017-06-01

High comorbidity has been reported among persons with psoriasis and psoriatic arthritis (PsA), but the occurrence of subjective health complaints (SHCs) in these patient groups is poorly understood. The study aimed to describe the prevalence of SHCs among individuals with psoriasis and PsA in Norway, and investigate whether the severity of their skin condition and their illness perceptions were associated with the number and severity of health complaints. Participants were recruited through the Psoriasis and Eczema Association of Norway (PEF) (n = 942). The participants answered a self-administered questionnaire covering subjective health complaints, the severity of their skin condition, and their illness perceptions measured with the Brief Illness Perception Questionnaire (BIPQ-R). The prevalence and severity of SHCs were high. Participants with PsA reported more complaints and higher severity of complaints compared with participants with psoriasis. In both groups, the severity of the skin condition was associated with the number and severity of SHCs. Cognitive illness perceptions (consequences) and emotional illness perceptions (emotional affect) were associated with SHCs in participants with psoriasis, whereas only cognitive illness perceptions (consequences and identity) were associated with SHCs in participants with PsA. The high prevalence and severity of SHCs among individuals with psoriasis and PsA were associated with the severity of the skin condition and illness perceptions. Somatic and cognitive sensitizations are proposed as possible mechanisms. The findings suggest that holistic approaches are essential when managing these patient groups in health care institutions and clinical practice.

Exogenous hydrogen sulfide promotes cell proliferation and differentiation by modulating autophagy in human keratinocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xie, Xin; Dai, Hui; Zhuang, Binyu

The effects and the underlying mechanisms of hydrogen sulfide (H{sub 2}S) on keratinocyte proliferation and differentiation are still less known. In the current study, we investigated the effects and the underlying mechanisms of exogenous H{sub 2}S on keratinocyte proliferation and differentiation. Human keratinocytes (HaCaT cells) were treated with various concentrations (0.05, 0.25, 0.5 and 1 mM) of sodium hydrosulfide (NaHS, a donor of H{sub 2}S) for 24 h. A CCK-8 assay was used to assess cell viability. Western blot analysis was performed to determine the expression levels of proteins associated with differentiation and autophagy. Transmission electron microscopy was performed to observe autophagicmore » vacuoles, and flow cytometry was applied to evaluate apoptosis. NaHS promoted the viability, induced the differentiation, and enhanced autophagic activity in a dose-dependent manner in HaCaT cells but had no effect on cell apoptosis. Blockage of autophagy by ATG5 siRNA inhibited NaHS-induced cell proliferation and differentiation. The current study demonstrated that autophagy in response to exogenous H{sub 2}S treatment promoted keratinocyte proliferation and differentiation. Our results provide additional insights into the potential role of autophagy in keratinocyte proliferation and differentiation. - Highlights: • Exogenous H{sub 2}S promotes keratinocyte proliferation and differentiation. • The effects of H{sub 2}S on proliferation and differentiation is modulated by autophagy. • Exogenous H{sub 2}S has no effect on keratinocyte apoptosis.« less

Antimycotics suppress the Malassezia extract-induced production of CXC chemokine ligand 10 in human keratinocytes.

PubMed

Hau, Carren S; Kanda, Naoko; Makimura, Koichi; Watanabe, Shinichi

2014-02-01

Malassezia, a lipophilic yeast, exacerbates atopic dermatitis. Malassezia products can penetrate the disintegrated stratum corneum and encounter subcorneal keratinocytes in the skin of atopic dermatitis patients. Type 1 helper T (Th1) cells infiltrate chronic lesions with atopic dermatitis, and antimycotic agents improve its symptoms. We aimed to identify Malassezia-induced chemokines in keratinocytes and examine whether antimycotics suppressed this induction. Normal human keratinocytes were incubated with a Malassezia restricta extract and antimycotics. Chemokine expression was analyzed by enzyme-linked immunosorbent assays and real-time polymerase chain reaction. Signal transducer and activator of transcription (STAT)1 activity was examined by luciferase assays. The tyrosine-phosphorylation of STAT1 was analyzed by western blotting. The M. restricta extract increased the mRNA and protein expression of Th1-attracting CXC chemokine ligand (CXCL)10 and STAT1 activity and phosphorylation in keratinocytes, which was suppressed by a Janus kinase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine suppressed M. restricta extract-induced CXCL10 mRNA and protein expression and STAT1 activity and phosphorylation. These effects were similarly induced by 15-deoxy-Δ-(12,14) -prostaglandin J2 (15d-PGJ2 ), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes. The antimycotic-induced suppression of CXCL10 production and STAT1 activity was counteracted by a lipocalin-type prostaglandin D synthase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine may suppress the M. restricta-induced production of CXCL10 by inhibiting STAT1 through an increase in 15d-PGJ2 production in keratinocytes. These antimycotics may block the Th1-mediated inflammation triggered by Malassezia in the chronic phase of atopic dermatitis. © 2014

p16 immunostaining in keratinocytic neoplasia in organ transplant recipients: Bowen's disease shows a characteristic pattern.

PubMed

Genders, Roel E; Beck, Samuel; Bouwes Bavinck, Jan Nico; van den Munckhof, Henk A M; Kouwenhoven, Stijn T P; de Koning, Maurits N C; de Gruijl, Frank R; Jenkins, David; Willemze, Rein; Quint, Koen D

2017-01-01

For selecting therapy, it is important to distinguish different types of keratinocytic neoplasia. It is sometimes difficult to make histopathologic diagnosis, especially in organ transplant recipients (OTR) who develop numerous lesions. To investigate p16 immunostaining in different types of keratinocytic neoplasia in OTR, we studied 59 actinic keratoses (AK), 51 Bowen' s disease (BD), 63 squamous cell carcinomas (SCC), 16 benign keratotic lesions (BKL) from 31 OTR patients and 25 controls (eczema and psoriasis). Tissue sections were stained for H&E and p16. We scored intensity, proportion and distribution of p16 positive lesional cells. In 19% of AK, 92% of BD, 35% of SCC and 12% of BKL more than 15% of lesional cells were p16-positive. In 16% of AK, 80% of BD, 18% of SCC and 13% of BKL strong p16 staining was observed. BKL, AK and SCC showed focal and patchy staining, BD showed diffuse pattern with strong staining of all atypical cells. Sparing of the basal layer was predominantly seen in BD. No control specimen showed p16-overexpression. p16 immunostaining shows a characteristic pattern in BD, but not in AK, SCC and BKL. It appears useful in recognizing BD, but not in differentiating between other keratinocytic neoplasia. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Osteomalacia associated with cutaneous psoriasis as the presenting feature of coeliac disease: a case report.

PubMed

Frikha, Faten; Snoussi, Mouna; Bahloul, Zouhir

2012-01-01

Celiac disease (CD) is a chronic digestive disease that results in hypersensitivity to the gliadin fraction of Gluten. Malabsorption syndrome may be responsible for weight loss, diarrhea, osteomalacia, and vitamins deficiency. Herein we report a patient with coeliac disease (CD) who presented with osteomalacia and psoriasis without classical symptoms of CD. A 25-year-old North African Tunisian white woman was admitted to the hospital because of a 1-year history of bone pain, weight loss and weakness. She had cutaneous psoriasis on dermatologic examination. She had also anemia, hypocalcemia and pathological fracture. She was diagnosed to have osteomalacia on the basis of clinical, biological and radiological findings. Further investigations revealed the presence of antiglutaminase antibodies, and histopathologic findings of the duodenal biopsy were consistent with celiac disease. The patient showed a fast response to gluten-free diet, and full recovery with calcium and vitamin D replacement. Coeliac disease is frequently misdiagnosed leading to major complications such as osteolamacia. In the other hand, osteomalacia can still be the presenting feature of undiagnosed celiac disease. Association between osteomalacia and cutaneous psoriasis is rarely reported.

Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation

PubMed Central

Johnston, Andrew; Fritz, Yi; Dawes, Sean M.; Diaconu, Doina; Al-Attar, Paul M.; Guzman, Andrew M.; Chen, Cynthia S.; Fu, Wen; Gudjonsson, Johann E.; McCormick, Thomas S.; Ward, Nicole L.

2013-01-01

IL-17C is a functionally distinct member of the IL-17 family that binds IL-17RE/A to promote innate defense in epithelial cells and regulate Th17 cell differentiation. We demonstrate that IL-17C (not IL-17A) is the most abundant IL-17 isoform in lesional psoriasis skin (1058pg/ml vs. 8pg/ml; p<0.006) and localizes to keratinocytes (KCs), endothelial cells (ECs) and leukocytes. ECs stimulated with IL-17C produce increased TNFα and KCs stimulated with IL-17C/TNFα produce similar inflammatory gene response patterns as those elicited by IL-17A/TNFα, including increases in IL-17C, TNFα, IL-8, IL-1α/β, IL-1F5, IL-1F9, IL-6, IL-19, CCL20, S100A7/A8/A9, DEFB4, LCN2 and PI3 (p<0.05); indicating a positive pro-inflammatory feedback loop between the epidermis and ECs. Psoriasis patients treated with etanercept rapidly decrease cutaneous IL-17C levels, suggesting IL-17C/TNFα-mediated inflammatory signaling is critical for psoriasis pathogenesis. Mice genetically engineered to overexpress IL-17C in KCs develop well-demarcated areas of erythematous, flakey “involved” skin adjacent to areas of normal appearing “uninvolved” skin despite increased IL-17C expression in both areas (p<0.05). Uninvolved skin displays increased angiogenesis and elevated S100A8/A9expression (p<0.05) but no epidermal hyperplasia; whereas involved skin exhibits robust epidermal hyperplasia, increased angiogenesis and leukocyte infiltration and upregulated TNFα, IL-1α/β, IL-17A/F, IL-23p19, VEGF, IL-6 and CCL20 (p<0.05) suggesting that IL-17C, when coupled with other pro-inflammatory signals, initiates the development of psoriasiform dermatitis. This skin phenotype was significantly improved following 8 weeks of TNFα inhibition. These findings identify a role for IL-17C in skin inflammation and suggest a pathogenic function for the elevated IL-17C observed in lesional psoriasis skin. PMID:23359500

Partial clinical response to anakinra in severe palmoplantar pustular psoriasis.

PubMed

Tauber, M; Viguier, M; Alimova, E; Petit, A; Lioté, F; Smahi, A; Bachelez, H

2014-09-01

Palmoplantar pustular psoriasis is a clinical psoriasis variant characterised by a high impact on quality of life and poor response to biologics approved for plaque type psoriasis.The recombinant interleukin-1 (IL-1) receptor antagonist anakinra has been recently used for the treatment of isolated refractory cases of generalised pustular psoriasis with contrasted results. To report the clinical response in two patients treated with anakinra as salvage therapy in two patients with severe palmoplantar pustular psoriasis refractory to currently available antipsoriatic systemic therapies. Anakinra was given subcutaneously at the daily dose of 100 mg, and clinical response was evaluated using the palmoplantar psoriasis area and severity index (PPPASI). Only partial and transient responses were observed in both patients, who had to stop anakinra due to lack of efficacy and to side effects. Anakinra appears to provide only partial clinical improvement in refractory palmoplantar pustular psoriasis. Prospective clinical studies on larger populations are warranted to investigate more accurately both efficacy and safety of IL-1-inhibiting strategies in pustular psoriasis. © 2014 British Association of Dermatologists.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Zheng Jun; Shin, Jung-Min; Choi, Dae-Kyoung

Psoriasis is a common skin disease, of which pathogenesis involves the increase of inflammatory reaction in epidermal cells. In an attempt to find therapeutics for psoriasis, we found that cucurbitacin B has an inhibitory potential on imiquimod-induced inflammation of keratinocytes. Cucurbitacin B significantly inhibited imiquimod-induced expression of crucial psoriatic cytokines, such as IL-8 and CCL20, via down-regulation of NF-κB and STAT3 signaling pathway in human keratinocytes. In addition, keratinocyte proliferation was markedly inhibited by cucurbitacin B. The potential beneficial effect of cucurbitacin B on psoriasis was further validated in imiquimod-induced psoriasiform dermatitis of experimental animal. Topical application of cucurbitacin Bmore » resulted in significant reduction of epidermal hyperplasia and inflammatory cytokines production, and ameliorated the psoriatic symptom. Taken together, these results suggest that cucurbitacin B may be a potential candidate for the treatment of psoriasis. - Highlights: • Cucurbitacin B has a potential for inhibiting the growth of keratinocytes. • Cucurbitacin B inhibits imiquimod-induced inflammatory reaction in keratinocytes. • Cucurbitacin B inhibits imiquimod-induced psoriasiform dermatitis in experimental animal.« less

A novel molecular disease classifier for psoriasis and eczema.

PubMed

Garzorz-Stark, Natalie; Krause, Linda; Lauffer, Felix; Atenhan, Anne; Thomas, Jenny; Stark, Sebastian P; Franz, Regina; Weidinger, Stephan; Balato, Anna; Mueller, Nikola S; Theis, Fabian J; Ring, Johannes; Schmidt-Weber, Carsten B; Biedermann, Tilo; Eyerich, Stefanie; Eyerich, Kilian

2016-10-01

Novel specific therapies for psoriasis and eczema have been developed, and they mark a new era in the treatment of these complex inflammatory skin diseases. However, within their broad clinical spectrum, psoriasis and eczema phenotypes overlap making an accurate diagnosis impossible in special cases, not to speak about predicting the clinical outcome of an individual patient. Here, we present a novel robust molecular classifier (MC) consisting of NOS2 and CCL27 gene that diagnosed psoriasis and eczema with a sensitivity and specificity of >95% in a cohort of 129 patients suffering from (i) classical forms; (ii) subtypes; and (iii) clinically and histologically indistinct variants of psoriasis and eczema. NOS2 and CCL27 correlated with clinical and histological hallmarks of psoriasis and eczema in a mutually antagonistic way, thus highlighting their biological relevance. In line with this, the MC could be transferred to the level of immunofluorescence stainings for iNOS and CCL27 protein on paraffin-embedded sections, where patients were diagnosed with sensitivity and specificity >88%. Our MC proved superiority over current gold standard methods to distinguish psoriasis and eczema and may therefore build the basis for molecular diagnosis of chronic inflammatory skin diseases required to establish personalized medicine in the field. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Epidemiology and Comorbidity in Children with Psoriasis and Atopic Eczema.

PubMed

Augustin, Matthias; Radtke, Marc A; Glaeske, Gerd; Reich, Kristian; Christophers, Enno; Schaefer, Ines; Jacobi, Arnd

2015-01-01

First studies have shown that juvenile psoriasis is associated with an increased prevalence of comorbidity. We carried out a data analysis to characterise the profiles of comorbidity in children with psoriasis and atopic eczema. Prevalence data were derived from the database of a German statutory health insurance company according to ICD-10 codes L40 (psoriasis) and L20 (atopic eczema) of children up to 18 years insured in 2009. Data sets included 1.64 million persons and 293,181 children. 1,313 children = 0.45% (0.42-0.47) had a diagnosis of psoriasis and 30,354 = 10.35% (10.24-10.47) had a diagnosis of atopic eczema. Obesity, hyperlipidaemia, arterial hypertension and diabetes were more often diagnosed in children with psoriasis in comparison to all children without psoriasis and to those with atopic eczema. Children with psoriasis and atopic eczema show different and specific patterns of comorbidity which should be detected early and treated adequately. © 2015 S. Karger AG, Basel.

Childhood and adulthood traumatic experiences in patients with psoriasis.

PubMed

Simonić, Edita; Kaštelan, Marija; Peternel, Sandra; Pernar, Mirjana; Brajac, Ines; Rončević-Gržeta, Ika; Kardum, Igor

2010-09-01

It is well known that several psychiatric disorders may be related to childhood psychological trauma. Recent studies have associated childhood exposure to trauma to some skin diseases. Our study aimed at exploring whether psoriasis is related to the reported positive and negative traumatic life events in different age intervals beginning from early childhood to adulthood. Furthermore, we investigated differences between psoriatics with early and late onset according to traumatic experiences in different age intervals. Also, we investigated the possible correlation of traumatic experiences with the disease severity. One hundred patients with psoriasis and 101 controls (patients with skin conditions considered to be "non-psychosomatic") were enrolled in the study. All participants completed a specific questionnaire measuring traumatic life experiences (Traumatic Antecedents Questionnaire, TAQ). The TAQ assesses positive personal experiences (competence and safety) and negative personal experiences (neglect, separation, secrets, emotional, physical and sexual abuse, trauma witnessing, other traumas and exposure to alcohol/drugs) from early childhood to adulthood. The severity of psoriasis was estimated according to the Psoriasis Area and Severity Index (PASI), a standardized measuring instrument. The amount of positive experiences did not differ significantly among groups, except for safety scores that were higher in controls compared with both psoriatic groups (early and late onset). On the other side, negative traumatic experiences appeared more frequently in patients with psoriasis during all developmental periods. We found no correlation between severity of psoriasis and traumatic experiences. The present study demonstrates an increased history of childhood and adulthood negative traumatic experiences in patients with psoriasis compared to the control group. Our findings suggest a relationship between retrospectively reported negative traumatic experiences and

Coincident systemic lupus erythematosus and psoriasis vulgaris: a case report.

PubMed

Wang, Y; Da, G; Yu, Y; Han, J; Li, H

2015-12-01

Psoriasis vulgaris is an autoimmune chronic inflammatory skin disease, but its association with other typical autoimmune disease such as systemic lupus erythematosus has only occasionally been reported. We presented a 25-year-old female who developed systemic lupus erythematosus associated with psoriasis vulgaris. Her conditions were in good control after she got administration of prednisolone (5 mg/day) and Tripterygium Wilfordii Hook (20 mg/day). It is necessary to integrate past history and physical examination to diagnose coincident SLE and psoriasis, and combined treatment with prednisolone and Tripterygium Wilfordii Hook proves effective.

Identification of a novel proinflammatory human skin-homing Vγ9Vδ2 T cell subset with a potential role in psoriasis.

PubMed

Laggner, Ute; Di Meglio, Paola; Perera, Gayathri K; Hundhausen, Christian; Lacy, Katie E; Ali, Niwa; Smith, Catherine H; Hayday, Adrian C; Nickoloff, Brian J; Nestle, Frank O

2011-09-01

γδ T cells mediate rapid tissue responses in murine skin and participate in cutaneous immune regulation including protection against cancer. The role of human γδ cells in cutaneous homeostasis and pathology is characterized poorly. In this study, we show in vivo evidence that human blood contains a distinct subset of proinflammatory cutaneous lymphocyte Ag and CCR6-positive Vγ9Vδ2 T cells, which is rapidly recruited into perturbed human skin. Vγ9Vδ2 T cells produced an array of proinflammatory mediators including IL-17A and activated keratinocytes in a TNF-α- and IFN-γ-dependent manner. Examination of the common inflammatory skin disease psoriasis revealed a striking reduction of circulating Vγ9Vδ2 T cells in psoriasis patients compared with healthy controls and atopic dermatitis patients. Decreased numbers of circulating Vγ9Vδ2 T cells normalized after successful treatment with psoriasis-targeted therapy. Taken together with the increased presence of Vγ9Vδ2 T cells in psoriatic skin, these data indicate redistribution of Vγ9Vδ2 T cells from the blood to the skin compartment in psoriasis. In summary, we report a novel human proinflammatory γδ T cell involved in skin immune surveillance with immediate response characteristics and with potential clinical relevance in inflammatory skin disease.

The herpes simplex virus-induced demise of keratinocytes is associated with a dysregulated pattern of p63 expression.

PubMed

Megyeri, Klára; Orosz, László; Kormos, Bernadett; Pásztor, Katalin; Seprényi, György; Ocsovszki, Imre; Mándi, Yvette; Bata-Csörgo, Zsuzsanna; Kemény, Lajos

2009-01-01

p63 plays a pivotal role in the development and maintenance of stratified epithelial tissues. In an effort to gain insight into the pathogenic mechanisms of skin infections caused by HSV-1 and HSV-2, we determined the patterns of p63 expression in primary keratinocytes and in the HaCaT cell line. The levels of DeltaNp63alpha and a 50kDa p73 isoform were decreased, Bax-alpha remained unaffected, while the expressions of the Bax-beta, TAp63gamma and a 44.5kDa p73 isoform were highly increased in both HSV-1-infected HaCaT cells and primary keratinocytes. In contrast, in response to HSV-2 infection the levels of DeltaNp63alpha, a 50kDa p73 isoform and a 44.5kDa p73 protein were decreased, Bax-alpha and TAp63gamma remained unaffected, while the expression of Bax-beta was slightly increased. The knockdown of TAp63 expression enhanced the viability of HSV-1-infected cells. Thus, HSV-1 and HSV-2 modulate the patterns of p63 and Bax expression in a serotype-specific manner. The dysregulated pattern of p63 expression observed in HSV-infected keratinocytes may comprise part of a mechanism by which these viruses perturb the functions of keratinocytes and lead to their demise.

Psoriasis: in between the skin and the fat.

PubMed

Ståhle, Mona

2015-03-01

Substantial epidemiological evidence indicates that psoriasis associates with a predisposition to develop metabolic dysregulation leading to obesity and insulin resistance. However, the nature of this association and the potential underlying mechanisms remain unclear. In a recent report, Gerdes et al. explored the hypothesis that wingless-type MMTV integration site, Wnt5a, which has been linked to aberrant fat cell metabolism, may be driving this process. In this study, the authors compare circulating serum levels of Wnt5a in individuals with psoriasis and compare with healthy controls matched for age, gender and BMI. The bottom-line results show higher levels of Wnt5a in psoriasis patients irrespective of BMI compared to the matched non-psoriatic controls, indicating that psoriasis per se may result in increased secretion of Wnt5a into the circulation. In addition, there was a significant difference among patients with higher levels of Wnt5a in the obese psoriasis population. The study, even though being purely descriptive, may serve to inspire a more mechanistic approach exploring not only Wnt5a, but other inflammatory pathways in between the skin and the fat. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Paradoxical, Cupping-Induced Localized Psoriasis: A Koebner Phenomenon.

PubMed

Vender, Reid; Vender, Ronald

2015-01-01

Cupping therapy is a traditional Chinese medicine used to heal psoriasis. The Koebner phenomenon is the occurrence of psoriatic lesions at the site of cutaneous injury. To describe the first case of biopsy-proven cupping-induced localized psoriasis, an example of the Koebner phenomenon. The histopathology of the lesions is described. A brief review of the literature regarding cupping therapy and its efficacy are discussed. A 45-year-old Asian male presented himself to the dermatology clinic for further treatment of his psoriasis. Four unusually circular plaques on the lower back were discovered. Pathologic diagnosis revealed an early lesion of psoriasis. on further inquiry, the patient admitted to undergoing a recent "cupping" procedure in an attempt to cure his condition. The efficacy of cupping therapy is controversial, and psoriatic patients may develop localized psoriasis through koebnerization as a result of cupping therapy rather than achieve desirable therapeutic benefits. © 2014 Canadian Dermatology Association.

The efficacy and safety of topically applied indigo naturalis ointment in patients with plaque-type psoriasis.

PubMed

Lin, Yin-Ku; Wong, Wen-Rou; Chang, Ya-Ching; Chang, Chee-Jen; Tsay, Pei-Kwei; Chang, Shu-Chen; Pang, Jong-Hwei Su

2007-01-01

It has been reported in the Chinese literature that indigo naturalis exhibits potential antipsoriatic effects in systemic therapy. To evaluate the efficacy and safety of topically applied indigo naturalis on treating plaque-type psoriasis and to analyze the histological change in skin tissues. Fourteen patients with chronic plaque psoriasis were enrolled. The patients were topically applied with either indigo naturalis ointment or vehicle ointment on contralateral skin lesions daily for 8 weeks. Efficacy was evaluated on the basis of the clinical scores, including induration, scaling, erythema and clearing percentage. At the end of treatment, skin punch biopsies were taken and prepared for the immunohistochemical analysis. A significant reduction in clinical scores was achieved with topically applied indigo naturalis ointment. Analysis of biopsies showed a marked improvement of skin histology. The expressions of proliferating marker Ki-67 and inflammatory marker CD3 were decreased, but the differentiation marker such as filaggrin was increased in the epidermis after indigo naturalis ointment treatment. The results suggest that topical application of indigo naturalis ointment may be a novel, safe and effective therapy for psoriasis that is mediated, at least in part, by modulating the proliferation and differentiation of keratinocytes in epidermis, as well as by inhibiting the infiltration of T lymphocytes and therefore the subsequent inflammatory reactions in psoriatic lesions. Copyright 2007 S. Karger AG, Basel.

The concept of psoriasis as a systemic inflammation: implications for disease management.

PubMed

Reich, K

2012-03-01

Psoriasis is a systemic, immune-mediated disorder, characterized by inflammatory skin and joint manifestations. A range of co-morbidities is associated with psoriasis, including metabolic diseases, such as diabetes, and psychological disorders. Although the systemic nature of psoriasis often remains unrecognized, the inflammatory processes involved may be associated with the development of co-morbidities, which, themselves, have a significant impact on the patient's health and quality of life. The relative risks of myocardial infarction (MI) and stroke are increased in patients with psoriasis compared with the general population. These are especially seen in younger patients with more severe disease, and are believed to contribute to the 3- to 4-year reduction in life expectancy among patients with severe psoriasis. The recent results of large studies indicate that the increased cardiovascular (CV) risk is at least partially attributable to psoriasis and independent of the presence of metabolic co-morbidities. The possible interplay between psoriasis and CV disease is complex. Metabolic diseases such as obesity and diabetes have overlapping genetic predispositions with psoriasis. Both conditions are likely to also interact at a functional level because obesity and the up-regulation of pro-inflammatory mediators in psoriasis appear to influence adipocyte homoeostasis, inducing non-professional immune functions. This may perpetuate psoriatic inflammation, displaying similarities to the immunopathogenesis of atherosclerosis. Finally, the disturbed adipokine profile and inflammation associated with psoriasis enhances insulin resistance, causing subsequent endothelial dysfunction, atherosclerosis and eventual coronary events. The differential contribution of psoriasis and uncontrolled classical CV risk factors to the increased CV risk seen in psoriasis patients is not clear. Successful treatment with methotrexate appears to lower the rates of MI in patients with

Prevalence and comorbidities in adults with psoriasis compared to atopic eczema.

PubMed

Radtke, M A; Schäfer, I; Glaeske, G; Jacobi, A; Augustin, M

2017-01-01

Most data suggesting an association between psoriasis and cardiovascular disease (CVD) have come from specialized populations at either low or high risk of CVD. Atopic dermatitis (AD) has been associated with a number of modifiable risk factors, particularly obesity. There has been a recent controversy on the suggestion that associations with comorbidities in psoriasis may be due to overreporting or biased by disease severity and therefore not necessarily representative of the general psoriasis population. To evaluate the prevalence of AD and psoriasis and to compare the prevalence rates of comorbidities based on a large sample of health insurance data. Data were collected from a database of non-selected individuals from a German statutory health insurance organization that covers all geographic regions. Individuals identified by International Classification of Diseases (ICD)-10 codes applied to all outpatient and inpatient visits in the year 2009. Comorbidities were evaluated by ICD-10 diagnoses. The database consisted of 1 642 852 members of a German statutory health insurance. Of 1 349 671 data sets analyzed, 37 456 patients ≥18 years were diagnosed with psoriasis (prevalence 2.78%), and 48 140 patients ≥18 years of age were diagnosed with AD, equivalent to a prevalence of 3.67%. Patients with psoriasis showed increased rates of comorbidities in all age groups. Comorbidities related to the metabolic syndrome including arterial hypertension [prevalence ratio (PR), 1.94; 95% confidence interval (CI), 1.90-1.98], hyperlipidaemia (PR, 1.77; 95% CI, 1.73-1.81), obesity (PR, 1.74; 95% CI, 1.69-1.79) and diabetes mellitus (PR, 1.88; 95% CI, 1.83-1.94) were significantly more common among patients with psoriasis compared to AD. Diseases forming part of the metabolic syndrome showed significant lower prevalence rates in patients with AD than in patients with psoriasis. Within the limitations of secondary healthcare data, our study disproves the suggestion that

BMAL1 and CLOCK proteins in regulating UVB-induced apoptosis and DNA damage responses in human keratinocytes.

PubMed

Sun, Yang; Wang, Peiling; Li, Hongyu; Dai, Jun

2018-06-26

A diverse array of biological processes are under circadian controls. In mouse skin, ultraviolet ray (UVR)-induced apoptosis and DNA damage responses are time-of-day dependent, which are controlled by core clock proteins. This study investigates the roles of clock proteins in regulating UVB responses in human keratinocytes (HKCs). We found that the messenger RNA expression of brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) genes is altered by low doses (5 mJ/cm 2 ) of UVB in the immortalized HaCat HKCs cell line. Although depletion of BMAL1 or CLOCK has no effect on the activation of Rad3-related protein kinases-checkpoint kinase 1-p53 mediated DNA damage checkpoints, it leads to suppression of UVB-stimulated apoptotic responses, and downregulation of UVB-elevated expression of DNA damage marker γ-H2AX and cell cycle inhibitor p21. Diminished apoptotic responses are also observed in primary HKCs depleted of BMAL1 or CLOCK after UVB irradiation. While CLOCK depletion shows a suppressive effect on UVB-induced p53 protein accumulation, depletion of either clock gene triggers early keratinocyte differentiation of HKCs at their steady state. These results suggest that UVB-induced apoptosis and DNA damage responses are controlled by clock proteins, but via different mechanisms in the immortalized human adult low calcium temperature and primary HKCs. Given the implication of UVB in photoaging and photocarcinogenesis, mechanistic elucidation of circadian controls on UVB effects in human skin will be critical and beneficial for prevention and treatment of skin cancers and other skin-related diseases. © 2018 Wiley Periodicals, Inc.

Guttate Psoriasis Following Streptococcal Vulvovaginitis in a Five-year-old Girl.

PubMed

Hernandez, Melia; Simms-Cendan, Judith; Zendell, Kathleen

2015-10-01

Guttate psoriasis is frequently associated with a preceding pharyngeal or perianal streptococcal infection in children. Despite Group A beta-hemolytic streptococci (GABHS) being the most common cause of specific bacterial vulvovaginitis in prepubertal girls, there are no reports of streptococcal vulvovaginitis triggering guttate psoriasis. A five-year-old girl presented with guttate psoriasis following an episode of Streptococcal pyogenes vulvovaginitis. Following antibiotic treatment and bacterial eradication she developed vulvar psoriasis that resolved with high potency topical steroids. Identification of an antecedent streptoccocal infection can help predict the long term prognosis in children with guttate psoriasis. The vulvovaginal area should be considered as a source of GABHS infection in young girls with guttate psoriasis, and cultures should be considered if symptoms are present. Published by Elsevier Inc.

Reliability of the MDi Psoriasis® Application to Aid Therapeutic Decision-Making in Psoriasis.

PubMed

Moreno-Ramírez, D; Herrerías-Esteban, J M; Ojeda-Vila, T; Carrascosa, J M; Carretero, G; de la Cueva, P; Ferrándiz, C; Galán, M; Rivera, R; Rodríguez-Fernández, L; Ruiz-Villaverde, R; Ferrándiz, L

2017-09-01

Therapeutic decisions in psoriasis are influenced by disease factors (e.g., severity or location), comorbidity, and demographic and clinical features. We aimed to assess the reliability of a mobile telephone application (MDi-Psoriasis) designed to help the dermatologist make decisions on how to treat patients with moderate to severe psoriasis. We analyzed interobserver agreement between the advice given by an expert panel and the recommendations of the MDi-Psoriasis application in 10 complex cases of moderate to severe psoriasis. The experts were asked their opinion on which treatments were most appropriate, possible, or inappropriate. Data from the same 10 cases were entered into the MDi-Psoriasis application. Agreement was analyzed in 3 ways: paired interobserver concordance (Cohen's κ), multiple interobserver concordance (Fleiss's κ), and percent agreement between recommendations. The mean percent agreement between the total of 1210 observations was 51.3% (95% CI, 48.5-54.1%). Cohen's κ statistic was 0.29 and Fleiss's κ was 0.28. Mean agreement between pairs of human observers only, excluding the MDi-Psoriasis recommendations, was 50.5% (95% CI, 47.6-53.5%). Paired agreement between the recommendations of the MDi-Psoriasis tool and the majority opinion of the expert panel (Cohen's κ) was 0.44 (68.2% agreement). The MDi-Psoriasis tool can generate recommendations that are comparable to those of experts in psoriasis. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Cardiovascular and Metabolic Diseases Comorbid with Psoriasis: Beyond the Skin

PubMed Central

Furue, Masutaka; Tsuji, Gaku; Chiba, Takahito; Kadono, Takafumi

2017-01-01

A close association of systemic inflammation with cardiovascular diseases and metabolic syndrome is recently a popular topic in medicine. Psoriasis is a chronic inflammatory skin disease with a prevalence of approximately 0.1-0.5% in Asians. It is characterized by widespread scaly erythematous macules that cause significant physical and psychological burdens for the affected individuals. The accelerated inflammation driven by the TNF-α/IL-23/IL-17A axis is now known to be the major mechanism in the development of psoriasis. Psoriasis is not a mere skin disease; it is significantly associated with cardiovascular diseases and metabolic syndrome, which suggests that the chronic skin inflammation extends the systemic inflammation beyond the skin. In this article, we review the epidemiological and pathological aspects of psoriasis and its comorbidities. PMID:28674347

Stem cells in psoriasis.

PubMed

Hou, Ruixia; Li, Junqin; Niu, Xuping; Liu, Ruifeng; Chang, Wenjuan; Zhao, Xincheng; Wang, Qiang; Li, Xinhua; Yin, Guohua; Zhang, Kaiming

2017-06-01

Psoriasis is a complex chronic relapsing inflammatory disease. Although the exact mechanism remains unknown, it is commonly accepted that the development of psoriasis is a result of multi-system interactions among the epidermis, dermis, blood vessels, immune system, neuroendocrine system, metabolic system, and hematopoietic system. Many cell types have been confirmed to participate in the pathogenesis of psoriasis. Here, we review the stem cell abnormalities related to psoriasis that have been investigated recently. Copyright © 2016. Published by Elsevier B.V.

The relationship between duration of psoriasis, vascular inflammation, and cardiovascular events.

PubMed

Egeberg, Alexander; Skov, Lone; Joshi, Aditya A; Mallbris, Lotus; Gislason, Gunnar H; Wu, Jashin J; Rodante, Justin; Lerman, Joseph B; Ahlman, Mark A; Gelfand, Joel M; Mehta, Nehal N

2017-10-01

Psoriasis is associated with risk of cardiovascular (CV) disease (CVD) and a major adverse CV event (MACE). Whether psoriasis duration affects risk of vascular inflammation and MACEs has not been well characterized. We utilized two resources to understand the effect of psoriasis duration on vascular disease and CV events: (1) a human imaging study and (2) a population-based study of CVD events. First, patients with psoriasis (N = 190) underwent fludeoxyglucose F 18 positron emission tomography/computed tomography (duration effect reported as a β-coefficient). Second, MACE risk was examined by using nationwide registries (adjusted hazard ratios in patients with psoriasis (n = 87,161) versus the general population (n = 4,234,793). In the human imaging study, patients were young, of low CV risk by traditional risk scores, and had a high prevalence of cardiometabolic diseases. Vascular inflammation by fludeoxyglucose F 18 positron emission tomography/computed tomography was significantly associated with disease duration (β = 0.171, P = .002). In the population-based study, psoriasis duration had strong relationship with MACE risk (1.0% per additional year of psoriasis duration [hazard ratio, 1.010; 95% confidence interval, 1.007-1.013]). These studies utilized observational data. We found detrimental effects of psoriasis duration on vascular inflammation and MACE, suggesting that cumulative duration of exposure to low-grade chronic inflammation may accelerate vascular disease development and MACEs. Providers should consider inquiring about duration of disease to counsel for heightened CVD risk in psoriasis. Copyright © 2017 American Academy of Dermatology, Inc. All rights reserved.

Identification of a novel pro-inflammatory human skin-homing Vγ9Vδ2 T cell subset with a potential role in psoriasis

PubMed Central

LAGGNER, Ute; DI MEGLIO, Paola; PERERA, Gayathri K.; HUNDHAUSEN, Christian; LACY, Katie E.; ALI, Niwa; SMITH, Catherine H.; HAYDAY, Adrian C.; NICKOLOFF, Brian J.; NESTLE, Frank O.

2011-01-01

γδ T cells mediate rapid tissue responses in murine skin and participate in cutaneous immune regulation including protection against cancer. The role of human γδ cells in cutaneous homeostasis and pathology is poorly characterized. In this study we show in vivo evidence that human blood contains a distinct subset of pro-inflammatory cutaneous lymphocyte antigen (CLA) and C-C chemokine receptor (CCR) 6 positive Vγ9Vδ2 T cells, which is rapidly recruited into perturbed human skin. Vγ9Vδ2 T cells produced an array of pro-inflammatory mediators including IL-17A and activated keratinocytes in a TNF-α and IFN-γ dependent manner. Examination of the common inflammatory skin disease psoriasis revealed a striking reduction of circulating Vγ9Vδ2 T cells in psoriasis patients compared to healthy controls and atopic dermatitis patients. Decreased numbers of circulating Vγ9Vδ2 T cells normalized after successful treatment with psoriasis-targeted therapy. Together with the increased presence of Vγ9Vδ2 T cells in psoriatic skin, this data indicates redistribution of Vγ9Vδ2 T cells from the blood to the skin compartment in psoriasis. In summary, we report a novel human pro-inflammatory γδ T cell involved in skin immune surveillance with immediate response characteristics and with potential clinical relevance in inflammatory skin disease. PMID:21813772

One device, one equation: the simplest way to objectively evaluate psoriasis severity.

PubMed

Choi, Jae Woo; Kim, Bo Ri; Choi, Chong Won; Youn, Sang Woong

2015-02-01

The erythema, scale and thickness of psoriasis lesions could be converted to bioengineering parameters. An objective psoriasis severity assessment is advantageous in terms of accuracy and reproducibility over conventional severity assessment. We aimed to formulate an objective psoriasis severity index with a single bioengineering device that can possibly substitute the conventional subjective Psoriasis Severity Index. A linear regression analysis was performed to derive the formula with the subjective Psoriasis Severity Index as the dependent variable and various bioengineering parameters determined from 157 psoriasis lesions as independent variables. The construct validity of the objective Psoriasis Severity Index was evaluated with an additional 30 psoriasis lesions through a Pearson correlation analysis. The formula is composed of hue and brightness, which are sufficiently obtainable with a Colorimeter alone. A very strong positive correlation was found between the objective and subjective psoriasis severity indexes. The objective Psoriasis Severity Index is a novel, practical and valid assessment method that can substitute the conventional one. Combined with subjective area assessment, it could further replace the Psoriasis Area and Severity Index which is currently most popular. © 2014 Japanese Dermatological Association.

AKT delays the early-activated apoptotic pathway in UVB-irradiated keratinocytes via BAD translocation.

PubMed

Claerhout, Sofie; Decraene, David; Van Laethem, An; Van Kelst, Sofie; Agostinis, Patrizia; Garmyn, Marjan

2007-02-01

Upon irradiation with a high dose of UVB, keratinocytes undergo apoptosis as a protective mechanism. In previous work, we demonstrated the existence of an early-activated UVB-induced apoptotic pathway in growth factor-depleted human keratinocytes, which can be substantially delayed by the exclusive supplementation of IGF-1. We now show that in human keratinocytes, IGF-1 inhibits the onset of UVB-triggered apoptosis through a transcriptional independent, AKT-mediated mechanism, involving BAD serine 136 phosphorylation. Our results show that the early UVB-induced apoptosis in growth factor-depleted human keratinocytes is exclusively triggered through the mitochondrial pathway. It is accompanied by BAX translocation, cytochrome c release, and procaspase-9 cleavage, but not by procaspase-8 or BID cleavage. In human keratinocytes, IGF-1 supplementation inhibits these events in a transcription-independent manner. Both IGF-1 supplementation and the transduction of a membrane-targeted form of AKT result in a shift of the BH3-only protein BAD from the mitochondria to the cytoplasm, paralleled by an increase of AKT-specific Ser136 phospho-BAD bound to 14-3-3zeta protein. These data indicate that AKT-induced BAD phosphorylation and its subsequent cytoplasmic sequestration by 14-3-3zeta is a major mechanism responsible for the postponement of UVB-induced apoptosis in human keratinocytes.

Influence of psoriasis on work.

PubMed

Mattila, Kalle; Leino, Mauri; Mustonen, Anssi; Koulu, Leena; Tuominen, Risto

2013-04-01

Previous research indicates that psoriasis has an impact on early retirement, sick leave days and reduced work performance. To evaluate the disadvantages at work caused by psoriasis. The sample was based on patients visiting the dermatology outpatient clinic in Turku University Hospital. 262 returned a mailed questionnaire. The subjects were asked how many hours they were on a sick leave (absenteeism) and working while sick (presenteeism) due to psoriasis and other health reasons. Of the retired, 17.0% felt they were retired due to psoriasis. Those in the active work force reported on average 4.5 hours absenteeism and 8.3 hours of presenteeism due to psoriasis during the last 4 weeks. Psoriasis caused 27.0% of the total absenteeism and 39.0% of presenteeism. More than a quarter (28.9%) had been forced to modify their work due to psoriasis, most frequently to make the work less irritating for the skin. Psoriasis has a negative effect on patients' work in many ways, causing early retirement from work, sick leave days, change of occupation and work modifications.

Evaluation of abdominal fat index by ultrasonography and its relationship with psoriasis and metabolic syndrome.

PubMed

Gönül, Müzeyyen; Tatar, İdil; Canpolat, Filiz; Işıl Kurmus, Gökçe; Ergin, Can; Hekimoğlu, Baki

2017-10-01

Accumulating evidence indicates that psoriasis is associated with obesity and metabolic syndrome. Psoriasis and obesity share similar inflammatory mediators, and obesity may potentiate some inflammatory cytokines seen in psoriasis. Body fat distribution, particularly visceral adipose tissue (VAT), is an important factor in metabolic syndrome and atherosclerotic diseases. An association has been demonstrated between psoriasis and abdominal VAT measured by computed tomography (CT). To measure abdominal VAT noninvasively by ultrasonography (USG) in patients with psoriasis and investigated its relation to psoriasis and metabolic syndrome. The study population consisted of 41 psoriasis patients and 41 control subjects matched for age, sex, and body mass index. The maximal preperitoneal fat thickness (Pmax) at the anterior surface of the liver and the minimal subcutaneous fat thickness (Smin) of the abdomen were measured by USG. The abdominal fat index (AFI = Pmax/Smin ratio) was calculated and the results were compared between groups. The rate of metabolic syndrome was significantly higher in psoriasis patients ( p = 0.0018). The mean AFI was similar in both groups. AFI was not associated with psoriasis in subjects with metabolic syndrome ( p = 0.495) or with Psoriasis Area and Severity Index ( r = 0.123, p = 0.443). This is the first study to evaluate abdominal VAT by USG. Computed tomography may be more reliable than USG, but its high cost and radiation exposure are major disadvantages. Further studies are required to determine the relationships between psoriasis and VAT.

Osteomalacia associated with cutaneous psoriasis as the presenting feature of coeliac disease: a case report

PubMed Central

Frikha, Faten; Snoussi, Mouna; Bahloul, Zouhir

2012-01-01

Celiac disease (CD) is a chronic digestive disease that results in hypersensitivity to the gliadin fraction of Gluten. Malabsorption syndrome may be responsible for weight loss, diarrhea, osteomalacia, and vitamins deficiency. Herein we report a patient with coeliac disease (CD) who presented with osteomalacia and psoriasis without classical symptoms of CD. A 25-year-old North African Tunisian white woman was admitted to the hospital because of a 1-year history of bone pain, weight loss and weakness. She had cutaneous psoriasis on dermatologic examination. She had also anemia, hypocalcemia and pathological fracture. She was diagnosed to have osteomalacia on the basis of clinical, biological and radiological findings. Further investigations revealed the presence of antiglutaminase antibodies, and histopathologic findings of the duodenal biopsy were consistent with celiac disease. The patient showed a fast response to gluten-free diet, and full recovery with calcium and vitamin D replacement. Coeliac disease is frequently misdiagnosed leading to major complications such as osteolamacia. In the other hand, osteomalacia can still be the presenting feature of undiagnosed celiac disease. Association between osteomalacia and cutaneous psoriasis is rarely reported. PMID:22593794

Human papillomavirus types detected in skin warts and cancer differ in their transforming properties but commonly counteract UVB induced protective responses in human keratinocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shterzer, Naama; Heyman, Dariya; Shapiro, Beny

In the present study, E6E7 and E6 proteins of human papillomaviruses (HPVs) associated with skin warts and cancer were compared for their transforming and carcinogenic abilities in primary human keratinocytes (PHKs). We show that E6E7 of cancer associated beta HPV types, notably 49 and 24, were able to extend the life span and enhance the clonogenic efficiency of PHKs when maintained in serum free/low calcium medium. Activities of the beta HPV E6E7 were lower than those of HPV16 E6E7. In contrast, E6 proteins from HPV types detected in skin warts or cancer, notably 10, 49 and 38, attenuated UVB inducedmore » protective responses in PHKs including cell death, proliferation arrest and accumulation of the proapoptotic proteins, p53, bax or bak. Together, this investigation revealed functional differences and commonalities between HPVs associated with skin warts and cancer, and allowed the identification of specific properties of beta HPVs supporting their involvement in skin carcinogenesis. - Highlights: • Primary keratinocytes were used to evaluate transforming and carcinogenic abilities of cutaneous HPVs. • E6E7 of cancer associated β HPV types transform primary human keratinocytes. • E6 proteins of cancer and wart associated HPVs inhibit UVB induced cell death. • E6s of cancer and wart associated HPVs attenuate UVB induced proliferation arrest. • E6s of cancer and wart associated HPVs attenuate UVB induced apoptosis signaling.« less

Levels of physical activity in patients with severe psoriasis: a cross-sectional questionnaire study.

PubMed

Torres, Tiago; Alexandre, José Manuel; Mendonça, Denisa; Vasconcelos, Carlos; Silva, Berta Martins; Selores, Manuela

2014-04-01

Psoriasis is a chronic inflammatory disease associated with increased cardiovascular mortality, secondary to the increased prevalence of cardiovascular risk factors and premature atherosclerosis. Physical activity is a vital component in prevention and management of cardiovascular disease. Few studies have examined the level of physical activity in psoriasis patients, using validated questionnaires or other objective assessment tools. The aim of this study was to analyze and compare physical activity undertaken by patients with severe psoriasis and healthy controls, using the International Physical Activity Questionnaire-Short Form (IPAQ-S), a validated instrument for assessing physical activity. Ninety patients with severe plaque-type psoriasis and 160 healthy subjects were enrolled in the present study. Physical activity was evaluated using IPAQ-S. Psoriasis patients had reduced levels of physical activity compared with non-psoriasis patients, regardless of sex or whether the variable was continuous or categorical. The odds ratio for low-level physical activity for psoriasis patients, compared with controls, was 3.42 (95% CI 1.47-7.91), indicating that this severe psoriasis population did not undertake recommended levels of physical activity. Psoriasis patients exhibit decreased levels of physical activity, possibly for both psychological and physiological reasons. The lack of physical activity may contribute to the increased risk of cardiovascular disease in psoriasis patients, in addition to the intrinsic risks related to systemic inflammation and psoriasis-linked comorbidities. Regular physical activity should be encouraged in all psoriasis patients because of its beneficial effects on systemic inflammation and cardiometabolic comorbidities associated with psoriasis.

Kaposi's sarcoma concealed by stasis dermatitis in a patient with psoriasis.

PubMed

Erdoğan, Hilal Kaya; Bulur, Işıl; Saraçoğlu, Zeynep Nurhan; Karapınar, Tekden; Arık, Deniz

2017-09-01

Kaposi's sarcoma (KS) is a multifocal and angioproliferative neoplasm. KS may be accompanied by psoriasis; however, in most of these cases the main mechanism involves iatrogenic KS associated with the immunosuppressive drugs that are used in psoriasis treatment. In angioproliferative lesions as a result of venous insufficiency and stasis dermatitis, acroangiodermatitis (pseudo-KS) is initially considered. However, the concurrent occurrence of psoriasis, stasis dermatitis, and KS has not been previously reported. We report a case of classic-type KS in an 83-year-old man that was concealed by stasis dermatitis and accompanied by psoriasis.

IL-27 Regulates IL-18 binding protein in skin resident cells.

PubMed

Wittmann, Miriam; Doble, Rosella; Bachmann, Malte; Pfeilschifter, Josef; Werfel, Thomas; Mühl, Heiko

2012-01-01

IL-18 is an important mediator involved in chronic inflammatory conditions such as cutaneous lupus erythematosus, psoriasis and chronic eczema. An imbalance between IL-18 and its endogenous antagonist IL-18 binding protein (BP) may account for increased IL-18 activity. IL-27 is a cytokine with dual function displaying pro- and anti-inflammatory properties. Here we provide evidence for a yet not described anti-inflammatory mode of action on skin resident cells. Human keratinocytes and surprisingly also fibroblasts (which do not produce any IL-18) show a robust, dose-dependent and highly inducible mRNA expression and secretion of IL-18BP upon IL-27 stimulation. Other IL-12 family members failed to induce IL-18BP. The production of IL-18BP peaked between 48-72 h after stimulation and was sustained for up to 96 h. Investigation of the signalling pathway showed that IL-27 activates STAT1 in human keratinocytes and that a proximal GAS site at the IL-18BP promoter is of importance for the functional activity of IL-27. The data are in support of a significant anti-inflammatory effect of IL-27 on skin resident cells. An important novel property of IL-27 in skin pathobiology may be to counter-regulate IL-18 activities by acting on keratinocytes and importantly also on dermal fibroblasts.

Psoriasis (For Parents)

MedlinePlus

... accompanied by fever, chills, severe itching, and fatigue. Inverse psoriasis. This causes smooth, raw-looking patches of ... a healthy weight. This decreases the risk of inverse psoriasis. Remind your child to keep skin clean ...

Pemphigus foliaceus with pustular presentation in a patient with psoriasis*

PubMed Central

de Sousa, Vando Barbosa; Santana, Cândida Naira Lima e Lima; Pereira, Daniele do Nascimento; Gripp, Alexandre Carlos

2017-01-01

Pemphigus foliaceus is a chronic autoimmune disease of the skin, clinically characterized by scaly and crusty cutaneous erosions involving the seborrheic areas. The patient can eventually become erythrodermic. There are reports of atypical cases of pemphigus foliaceus with pustules and neutrophils, and clinical differentiation from generalized pustular psoriasis of von Zumbusch is difficult. We report the case of a 55-year-old man with a history of psoriasis vulgaris that has developed pemphigus foliaceus with pustules, triggered by withdrawal of systemic corticosteroids. This is the first report associating this atypical form of pemphigus with psoriasis, suggesting that an overlap with generalized pustular psoriasis can occur. PMID:29267466

Determinants of health-related quality of life in psoriasis patients in Malaysia.

PubMed

Nyunt, Wint Wint Thu; Low, Wah Yun; Ismail, Rokiah; Sockalingam, Sargunan; Min, Aung Ko Ko

2015-03-01

Psoriasis is a chronic dermatological disorder that has a negative impact on quality of life (QoL). This hospital-based cross-sectional study determined factors associated with health-related QoL (HRQoL) impairment in adult psoriasis patients. HRQoL was assessed using the Dermatology Life Quality Index (DLQI). Disease severity was assessed using the Psoriasis Area and Severity Index (PASI). A total of 223 patients, aged 18 to 83 years, were recruited. For 67 (30%) patients, psoriasis had very large to extremely large effect on their life (DLQI score = 11-30). The median DLQI score was 7 (interquartile range = 7). Factors significantly associated with severe impact on HRQoL (DLQI ≥ 10) were disease severity, single status, working status, sports activities, nail dystrophy, exposed area involvement, itch, disturbed sleep, stress, and infection. The factor predictive of severe impact of psoriasis on HRQoL was disease severity. A holistic approach in the management, including psychosocial issues, is absolutely crucial for the optimal care of psoriasis patients. © 2013 APJPH.

Risk of psoriasis in patients with childhood asthma: a Danish nationwide cohort study.

PubMed

Egeberg, A; Khalid, U; Gislason, G H; Mallbris, L; Skov, L; Hansen, P R

2015-07-01

Psoriasis and asthma are disorders driven by inflammation. Psoriasis may carry an increased risk of asthma, but the reverse relationship has not been investigated. To investigate the risk of psoriasis in subjects with childhood asthma in a nationwide Danish cohort. Data on all Danish individuals aged 6-14 years at study entry between 1 January 1997 and 31 December 2011 (n = 1,478,110) were linked at an individual level in nationwide registers. Incidence rates per 10,000 person-years were calculated, and incidence rate ratios (IRRs) adjusted for age, sex, concomitant medication and comorbidity were estimated by Poisson regression models. There were 21,725 cases of childhood asthma and 6586 incident cases of psoriasis. There were 5697 and 889 incident cases of mild and severe psoriasis, respectively. The incidence rates of overall, mild and severe psoriasis were 4.49, 3.88 and 0.61 for the reference population, and 5.95, 5.18 and 0.83 for subjects with childhood asthma, respectively. The IRRs for overall, mild and severe psoriasis were 3.94 [95% confidence interval (CI) 2.16-7.17], 5.03 (95% CI 2.48-10.21) and 2.27 (95% CI 0.61-8.42) for patients with childhood asthma. Childhood asthma was associated with a significantly increased risk of psoriasis. Further studies are warranted to determine the clinical significance and effects of therapeutic interventions on this association. © 2015 British Association of Dermatologists.

Photodynamic toxicity of hematoporphyrin derivatives to human keratinocytes in culture.

PubMed

Kappus, H; Reinhold, C; Artuc, M

Human keratinocytes in culture were able to take up hematoporphyrin derivatives (HPDs) used during photodynamic chemotherapy of tumors. In the absence of light, HPDs showed no cytotoxic effects to keratinocytes. However, after irradiation with visible light, HPDs induced immediate cytotoxicity as measured by the neutral red uptake assay. On the other hand, cell attachment as measured by protein estimation was not affected. When the cells treated with HPDs and irradiated with light were cultured for a further 72 h, they partially lost their ability to attach to the collagen surface. Most of the cells remaining attached after 72 h were no longer viable following treatment with HPDs and light. All parameters measured depended on the intracellular concentration of HPDs used (7-50 ng/10(5) cells) and the time of irradiation (0-30 min). These results suggest that human keratinocytes are a good model to study cytotoxic effects of photodynamically active drugs. Further, keratinocytes were unable to recover after damage caused by HPDs and light.

Psoriasis

PubMed Central

Di Meglio, Paola; Villanova, Federica; Nestle, Frank O.

2014-01-01

Psoriasis is a common chronic inflammatory skin disease with a spectrum of clinical phenotypes and results from the interplay of genetic, environmental, and immunological factors. Four decades of clinical and basic research on psoriasis have elucidated many of the pathogenic mechanisms underlying disease and paved the way to effective targeted therapies. Here, we review this progress and identify future directions of study that are supported by a more integrative research approach and aim at further improving the patients' life. PMID:25085957

Treatment of Nail Psoriasis: Common Concepts and New Trends

PubMed Central

Oram, Yasemin; Akkaya, A. Deniz

2013-01-01

The lifetime incidence of nail involvement in psoriatic patients is estimated to be 80–90%, and the nails can be affected in 10% to 55% of psoriatic patients. Psoriasis may also solely involve the nails, without any other skin findings, in which the treatment can be more challenging. Nail psoriasis may lead to considerable impairment in quality of life due to aesthetic concerns and more importantly limitations in daily activities resulting from the associated pain, which may be overlooked by the physicians. Several topical and systemic treatment modalities, as well as radiation and light systems, have been used in the treatment of nail psoriasis. In the last decade, the introduction of biologic agents and the utilization of laser systems have brought a new insight into the treatment of nail psoriasis. This paper focuses on the recent advances, as well as the conventional methods, in treating nail psoriasis in adults and children, in reference to an extensive literature search. PMID:23762032

Community differentiation of the cutaneous microbiota in psoriasis.

PubMed

Alekseyenko, Alexander V; Perez-Perez, Guillermo I; De Souza, Aieska; Strober, Bruce; Gao, Zhan; Bihan, Monika; Li, Kelvin; Methé, Barbara A; Blaser, Martin J

2013-12-23

Psoriasis is a common chronic inflammatory disease of the skin. We sought to characterize and compare the cutaneous microbiota of psoriatic lesions (lesion group), unaffected contralateral skin from psoriatic patients (unaffected group), and similar skin loci in matched healthy controls (control group) in order to discern patterns that govern skin colonization and their relationship to clinical diagnosis. Using high-throughput 16S rRNA gene sequencing, we assayed the cutaneous bacterial communities of 51 matched triplets and characterized these samples using community data analysis techniques. Intragroup Unifrac β diversity revealed increasing diversity from control to unaffected to lesion specimens. Likewise, principal coordinates analysis (PCoA) revealed separation of the lesion samples from unaffected and control along the first axis, suggesting that psoriasis is a major contributor to the observed diversity. The taxonomic richness and evenness decreased in both lesion and unaffected communities compared to control. These differences are explained by the combined increased abundance of the four major skin-associated genera (Corynebacterium, Propionibacterium, Staphylococcus, and Streptococcus), which present a potentially useful predictor for clinical skin type. Psoriasis samples also showed significant univariate decreases in relative abundances and strong classification performance of Cupriavidus, Flavisolibacter, Methylobacterium, and Schlegelella genera versus controls. The cutaneous microbiota separated into two distinct clusters, which we call cutaneotypes: (1) Proteobacteria-associated microbiota, and (2) Firmicutes-associated and Actinobacteria-associated microbiota. Cutaneotype 2 is enriched in lesion specimens compared to control (odds ratio 3.52 (95% CI 1.44 to 8.98), P <0.01). Our results indicate that psoriasis induces physiological changes both at the lesion site and at the systemic level, which select for specific differential microbiota among

Severity and management of psoriasis within primary care.

PubMed

Wade, Alan G; Crawford, Gordon M; Young, David; Leman, Joyce; Pumford, Neil

2016-10-14

Scottish Intercollegiate Guidelines Network and National Institute of Health and Care Excellence guidelines stress the importance of assessing patients with psoriasis for psoriatic arthritis, comorbidities associated with severe disease and quality of life (QoL). The purpose of the study was to evaluate the primary care management of psoriasis in relation to disease severity and QoL from a patient's perspective. A cross-sectional survey of adults (≥18 years) with psoriasis managed in primary care was conducted in Scotland over 1-year (2012-2013). Patients with psoriasis were identified and invited to participate in the online/telephone survey. The questionnaires included; Dermatology Life Quality Index (DLQI), Self-Administered Psoriasis Area and Severity Index (SAPASI), Psoriasis Epidemiology Screening Tool (PEST). The primary outcome measure was DLQI. Secondary outcomes included; demographics; comorbidities; involvement of different body sites; SAPASI and PEST scores. Relationships between measures were analysed using univariate analysis. The mean age of patients (n = 905) was 54.5 years (SD = 16.1), 436 (48.2 %) were men, and median DLQI and SAPASI scores were 4.0 and 6.0, respectively. Current psoriasis treatments were topical only (587, 64.9 %), oral medications or phototherapy (122, 13.5 %), biologics (26, 3 %) and none (156, 17.2 %). Despite SIGN recommendations, 256 of 391 patients (65.5 %) with a DLQI >5 (at least a moderate effect on QoL) had not seen a specialist during the past year. According to PEST scores, 259 patients (28.6 %) had symptoms suggestive of psoriatic arthritis requiring rheumatology referral. National recommendations are not being fully implemented in primary care in patients with psoriasis or psoriatic arthritis.

Prevalence of metabolic syndrome in Chinese psoriasis patients: A hospital-based cross-sectional study.

PubMed

Gui, Xin-Yu; Yu, Xiao-Ling; Jin, Hong-Zhong; Zuo, Ya-Gang; Wu, Chao

2018-01-01

Psoriasis, a chronic autoimmune skin disorder, is believed to contribute to cardiovascular diseases and metabolic syndrome. Psoriasis's association with the components of metabolic syndrome has been reported previously. However, large-scale cross-sectional studies about psoriasis and metabolic syndrome are rare in China. We assessed the prevalence of metabolic syndrome in Chinese psoriasis patients and controls. A total of 859 psoriasis patients and 1,718 controls were recruited in an age- and sex-matched cross-sectional study. Metabolic syndrome occurred in 14.3% of the psoriasis patients as opposed to 10.0% of the control participants (P = 0.001). Psoriasis patients had a higher prevalence of overweight/obesity, hyperglycemia and dyslipidemia when compared with controls. Meanwhile, psoriasis patients with metabolic syndrome were older, and had an older age of onset and a longer disease duration when compared with those without metabolic syndrome. The prevalence of metabolic syndrome is higher in the Chinese psoriatic population, which can favor cardiovascular events. The present study strengthens the value of treating psoriasis patients not only dealing with the skin lesions, and we suggest appropriate screening and relevant health education be carried out in the treatment of psoriasis patients. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Proteome-wide changes in primary skin keratinocytes exposed to diesel particulate extract-A role for antioxidants in skin health.

PubMed

Rajagopalan, Pavithra; Jain, Ankit P; Nanjappa, Vishalakshi; Patel, Krishna; Mangalaparthi, Kiran K; Babu, Niraj; Cavusoglu, Nükhet; Roy, Nita; Soeur, Jeremie; Breton, Lionel; Pandey, Akhilesh; Gowda, Harsha; Chatterjee, Aditi; Misra, Namita

2018-05-21

Skin acts as a protective barrier against direct contact with pollutants but inhalation and systemic exposure have indirect effect on keratinocytes. Exposure to diesel exhaust has been linked to increased oxidative stress. To investigate global proteomic alterations in diesel particulate extract (DPE)/its vapor exposed skin keratinocytes. We employed Tandem Mass Tag (TMT)-based proteomics to study effect of DPE/DPE vapor on primary skin keratinocytes. We observed an increased expression of oxidative stress response protein NRF2, upon chronic exposure of primary keratinocytes to DPE/its vapor which includes volatile components such as polycyclic aromatic hydrocarbons (PAHs). Mass spectrometry-based quantitative proteomics led to identification 4490 proteins of which 201 and 374 proteins were significantly dysregulated (≥1.5 fold, p ≤ 0.05) in each condition, respectively. Proteins involved in cellular processes such as cornification (cornifin A), wound healing (antileukoproteinase) and differentiation (suprabasin) were significantly downregulated in primary keratinocytes exposed to DPE/DPE vapor. These results were corroborated in 3D skin models chronically exposed to DPE/DPE vapor. Bioinformatics analyses indicate that DPE and its vapor affect distinct molecular processes in skin keratinocytes. Components of mitochondrial oxidative phosphorylation machinery were seen to be exclusively overexpressed upon chronic DPE vapor exposure. In addition, treatment with an antioxidant like vitamin E partially restores expression of proteins altered upon exposure to DPE/DPE vapor. Our study highlights distinct adverse effects of chronic exposure to DPE/DPE vapor on skin keratinocytes and the potential role of vitamin E in alleviating adverse effects of environmental pollution. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Periostin contributes to epidermal hyperplasia in psoriasis common to atopic dermatitis

PubMed Central

Arima, Kazuhiko; Ohta, Shoichiro; Takagi, Atsushi; Shiraishi, Hiroshi; Masuoka, Miho; Ontsuka, Kanako; Suto, Hajime; Suzuki, Shoichi; Yamamoto, Ken-ichi; Ogawa, Masahiro; Simmons, Olga; Yamaguchi, Yukie; Toda, Shuji; Aihara, Michiko; Conway, Simon J.; Ikeda, Shigaku; Izuhara, Kenji

2016-01-01

Background Epidermal hyperplasia is a histological hallmark observed in both atopic dermatitis (AD) and psoriasis, although the clinical features and the underlying immunological disorders of these diseases are different. We previously showed that periostin, a matricellular protein, plays a critical role in epidermal hyperplasia in AD, using a mouse model and a 3-dimensional organotypic coculture system. In this study, we explore the hypothesis that periostin is involved in epidermal hyperplasia in psoriasis. Methods To examine expression of periostin in psoriasis patients, we performed immunohistochemical analysis on skin biopsies from six such patients. To investigate periostin’s role in the pathogenesis of psoriasis, we evaluated periostin-deficient mice in a psoriasis mouse model induced by topical treatment with imiquimod (IMQ). Results Periostin was substantially expressed in the dermis of all investigated psoriasis patients. Epidermal hyperplasia induced by IMQ treatment was impaired in periostin-deficient mice, along with decreased skin swelling. However, upon treatment with IMQ, periostin deficiency did not alter infiltration of inflammatory cells such as neutrophils; production of IL-17, –22, or –23; or induction/expansion of IL-17– and IL-22–producing group 3 innate lymphoid cells. Conclusions Periostin plays an important role during epidermal hyperplasia in IMQ-induced skin inflammation, independently of the IL-23–IL-17/IL-22 axis. Periostin appears to be a mediator for epidermal hyperplasia that is common to AD and psoriasis. PMID:25572557

CDH1 regulates E2F1 degradation in response to differentiation signals in keratinocytes

PubMed Central

Singh, Randeep K.; Dagnino, Lina

2017-01-01

The E2F1 transcription factor plays key roles in skin homeostasis. In the epidermis, E2F1 expression is essential for normal proliferation of undifferentiated keratinocytes, regeneration after injury and DNA repair following UV radiation-induced photodamage. Abnormal E2F1 expression promotes nonmelanoma skin carcinoma. In addition, E2F1 must be downregulated for proper keratinocyte differentiation, but the relevant mechanisms involved remain poorly understood. We show that differentiation signals induce a series of post-translational modifications in E2F1 that are jointly required for its downregulation. Analysis of the structural determinants that govern these processes revealed a central role for S403 and T433. In particular, substitution of these two amino acid residues with non-phosphorylatable alanine (E2F1 ST/A) interferes with E2F1 nuclear export, K11- and K48-linked polyubiquitylation and degradation in differentiated keratinocytes. In contrast, replacement of S403 and T433 with phosphomimetic aspartic acid to generate a pseudophosphorylated E2F1 mutant protein (E2F1 ST/D) generates a protein that is regulated in a manner indistinguishable from that of wild type E2F1. Cdh1 is an activating cofactor that interacts with the anaphase-promoting complex/cyclosome (APC/C) ubiquitin E3 ligase, promoting proteasomal degradation of various substrates. We found that Cdh1 associates with E2F1 in keratinocytes. Inhibition or RNAi-mediated silencing of Cdh1 prevents E2F1 degradation in response to differentiation signals. Our results reveal novel regulatory mechanisms that jointly modulate post-translational modifications and downregulation of E2F1, which are necessary for proper epidermal keratinocyte differentiation. PMID:27903963

CDH1 regulates E2F1 degradation in response to differentiation signals in keratinocytes.

PubMed

Singh, Randeep K; Dagnino, Lina

2017-01-17

The E2F1 transcription factor plays key roles in skin homeostasis. In the epidermis, E2F1 expression is essential for normal proliferation of undifferentiated keratinocytes, regeneration after injury and DNA repair following UV radiation-induced photodamage. Abnormal E2F1 expression promotes nonmelanoma skin carcinoma. In addition, E2F1 must be downregulated for proper keratinocyte differentiation, but the relevant mechanisms involved remain poorly understood. We show that differentiation signals induce a series of post-translational modifications in E2F1 that are jointly required for its downregulation. Analysis of the structural determinants that govern these processes revealed a central role for S403 and T433. In particular, substitution of these two amino acid residues with non-phosphorylatable alanine (E2F1 ST/A) interferes with E2F1 nuclear export, K11- and K48-linked polyubiquitylation and degradation in differentiated keratinocytes. In contrast, replacement of S403 and T433 with phosphomimetic aspartic acid to generate a pseudophosphorylated E2F1 mutant protein (E2F1 ST/D) generates a protein that is regulated in a manner indistinguishable from that of wild type E2F1. Cdh1 is an activating cofactor that interacts with the anaphase-promoting complex/cyclosome (APC/C) ubiquitin E3 ligase, promoting proteasomal degradation of various substrates. We found that Cdh1 associates with E2F1 in keratinocytes. Inhibition or RNAi-mediated silencing of Cdh1 prevents E2F1 degradation in response to differentiation signals. Our results reveal novel regulatory mechanisms that jointly modulate post-translational modifications and downregulation of E2F1, which are necessary for proper epidermal keratinocyte differentiation.

Psoriasis and Cardiovascular Comorbidities: Focusing on Severe Vascular Events, Cardiovascular Risk Factors and Implications for Treatment

PubMed Central

Hu, Stephen Chu-Sung; Lan, Cheng-Che E.

2017-01-01

Psoriasis is a common and chronic inflammatory disease of the skin. It may impair the physical and psychosocial function of patients and lead to decreased quality of life. Traditionally, psoriasis has been regarded as a disease affecting only the skin and joints. More recently, studies have shown that psoriasis is a systemic inflammatory disorder which can be associated with various comorbidities. In particular, psoriasis is associated with an increased risk of developing severe vascular events such as myocardial infarction and stroke. In addition, the prevalence rates of cardiovascular risk factors are increased, including hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome. Consequently, mortality rates have been found to be increased and life expectancy decreased in patients with psoriasis, as compared to the general population. Various studies have also shown that systemic treatments for psoriasis, including methotrexate and tumor necrosis factor-α inhibitors, may significantly decrease cardiovascular risk. Mechanistically, the presence of common inflammatory pathways, secretion of adipokines, insulin resistance, angiogenesis, oxidative stress, microparticles, and hypercoagulability may explain the association between psoriasis and cardiometabolic disorders. In this article, we review the evidence regarding the association between psoriasis and cardiovascular comorbidities, focusing on severe vascular events, cardiovascular risk factors and implications for treatment. PMID:29065479

Differences in itch characteristics between psoriasis and atopic dermatitis patients: results of a web-based questionnaire.

PubMed

O'Neill, Jenna L; Chan, Yiong Huak; Rapp, Stephen R; Yosipovitch, Gil

2011-09-01

Differences in itch characteristics between different inflammatory dermatoses are not well described. The aim of this study was to assess differences in itch characteristics between patients with psoriasis and atopic dermatitis using a previously validated web-based questionnaire that was made available through the National Psoriasis Foundation and National Eczema Association for Science and Education websites. Participants rated frequency and intensity of itch, associated symptoms, itch descriptors, and effect of scratching. A total of 524 subjects with atopic dermatitis and 195 subjects with psoriasis completed the survey. Atopic dermatitis responders experienced more frequent and more intense itch. Associated sweating and heat sensation were also more common in atopic dermatitis. Scratching was considered pleasurable in both atopic dermatitis and psoriasis; pleasurability correlated weakly with itch intensity in atopic dermatitis. Psoriasis respondents reported higher embarrassment associated with itch. Itch sensation is experienced differently among patients with atopic dermatitis and psoriasis. Future therapeutic interventions may be developed to target these differences.

Cetuximab treatment in a patient with metastatic colorectal cancer and psoriasis

PubMed Central

Neyns, B.; Meert, V.; Vandenbroucke, F.

2008-01-01

Cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, has activity against colorectal cancer. Treatment is associated with skin toxicity, and the safety of cetuximab in patients with psoriasis is unknown. We report the case of a male patient with stage iv colorectal cancer (crc) and a life-long history of extensive psoriasis. This patient experienced a durable remission of his crc and major improvement of his psoriasis during single-agent treatment with cetuximab. We conclude that, despite its known skin toxicity, cetuximab treatment can be offered to colorectal patients suffering from psoriasis. PMID:18769609

Production and in vitro evaluation of soy protein-based biofilms as a support for human keratinocyte and fibroblast culture.

PubMed

Curt, Sèverine; Subirade, Muriel; Rouabhia, Mahmoud

2009-06-01

This study presents results on soy protein isolate (SPI) biofilm production and the corresponding effect on the stability and toxicity of the derived films. SPI biofilms were prepared from SPI chemically treated with formaldehyde at various concentrations (0%, 1%, 2%, and 3%) as cross-linking agents. In vitro SPI biofilm degradation was evaluated as a function of water absorption leading to weight and size modifications. SPI biofilm toxicity was determined as a function of human keratinocyte and fibroblast adhesion, viability, and proliferation. Cytokine gene expression supported this using reverse transcriptase polymerase chain reaction techniques. Our results confirm that SPI can be used to produce biofilms. The resulting SPI biofilms without formaldehyde swell significantly, which leads to their physical instability. Formaldehyde treatment enhanced the mechanical properties of these biofilms by covalently cross-linking polypeptide chains. The decreased water absorption was dependent on the amount of formaldehyde present. SPI biofilms with 2% and 3% formaldehyde were highly stable and easier to manipulate than those with 0% and 1% formaldehyde. Tissue culture analyses revealed that the SPI biofilms without formaldehyde were non-toxic to human cells (keratinocytes and fibroblasts). The presence of formaldehyde in biofilms did not have any effects on cell viability, adhesion, or proliferation. This was supported by the high level of messenger RNA expression of interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha by the keratinocytes and of IL-6 and IL-8 by the fibroblasts. Overall, we produced a stable, non-toxic soy protein support, which may be of potential interest in medical applications such as cell culture matrices and damaged tissue replacement.

Statin use and risk of first-time psoriasis diagnosis.

PubMed

Brauchli, Yolanda B; Jick, Susan S; Meier, Christoph R

2011-07-01

Statins have been suggested as a potential treatment for psoriasis because of their anti-inflammatory properties. However, evidence on the benefits of statins is scarce. We sought to study the association between use of statins or other lipid-lowering agents and the risk of developing psoriasis. We conducted a case-control analysis using the United Kingdom-based General Practice Research Database. We identified patients with an incident psoriasis diagnosis between 1994 and 2005 and matched one control subject to each patient on age, sex, general practice, calendar time, and years of history in the database. We estimated odds ratios (ORs) with 95% confidence intervals (CIs), stratified exposure by timing and duration, and adjusted the ORs for potential confounders. We identified 36,702 incident psoriasis cases and the same number of matched controls. Adjusted ORs for current use (last prescription <30 days before index date) of 1 to 4, 5 to 19, or greater than or equal to 20 prescriptions for statins, as compared with nonuse, were 0.60 (95% CI 0.45-0.80), 1.00 (95% CI 0.84-1.18), and 1.08 (95% CI 0.92-1.28), respectively. The ORs for recent and past use (last prescription 30-89 days and ≥90 days ago, respectively) were around 1, except for past use of 1 to 4 prescriptions (OR 1.39; 95% CI 1.09-1.78). Potential of residual confounding as a result of retrospective study design is a limitation. This large case-control study does not provide evidence for an altered risk of developing psoriasis in association with long-term use of statins. The reduced psoriasis risk for current short-term statin users is interesting, but whether the association is indeed causal needs further investigation. Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Intracrine sex steroid synthesis and signaling in human epidermal keratinocytes and dermal fibroblasts.

PubMed

Pomari, Elena; Dalla Valle, Luisa; Pertile, Paolo; Colombo, Lorenzo; Thornton, M Julie

2015-02-01

Peripheral intracrine sex steroid synthesis from adrenal precursors dehydroepiandrosterone (DHEA) and DHEA-sulfate has evolved in humans. We sought to establish if there are differences in intracrine, paracrine, and endocrine regulation of sex steroids by primary cultures of human skin epidermal keratinocytes and dermal fibroblasts. Microarray analysis identified multifunctional genes modulated by steroids, quantitative RT-PCR (qRT-PCR) mRNA expression, enzymatic assay aromatase activity, scratch assay cell migration, immunocytochemistry α-smooth muscle actin (α-SMA), and collagen gel fibroblast contraction. All steroidogenic components were present, although only keratinocytes expressed the organic anion organic anion transporter protein (OATP) 2B1 transporter. Both expressed the G-protein-coupled estrogen receptor (GPER1). Steroids modulated multifunctional genes, up-regulating genes important in repair and aging [angiopoietin-like 4 (ANGPTL4), chemokine (C-X-C motif) ligand 1 (CXCL1), lamin B1 (LMNB1), and thioredoxin interacting protein (TXNIP)]. DHEA-sulfate (DHEA-S), DHEA, and 17β-estradiol stimulated keratinocyte and fibroblast migration at early (4 h) and late (24-48 h) time points, suggesting involvement of genomic and nongenomic signaling. Migration was blocked by aromatase and steroid sulfatase (STS) inhibitors confirming intracrine synthesis to estrogen. Testosterone had little effect, implying it is not an intermediate. Steroids stimulated fibroblast contraction but not α-SMA expression. Mechanical wounding reduced fibroblast aromatase activity but increased keratinocyte activity, amplifying the bioavailability of intracellular estrogen. Cultured fibroblasts and keratinocytes provide a biologically relevant model system to investigate the complex pathways of sex steroid intracrinology in human skin. © FASEB.

Periodontitis and risk of psoriasis: a systematic review and meta-analysis.

PubMed

Ungprasert, P; Wijarnpreecha, K; Wetter, D A

2017-05-01

The association between periodontitis and systemic diseases has been increasingly recognized. However, the data on the association between periodontitis and psoriasis are still limited. To summarize all available data on the association between periodontitis and the risk of psoriasis. Two investigators independently searched published studies indexed in MEDLINE and EMBASE databases from inception to July 2016 using a search strategy that included terms for psoriasis and periodontitis. Studies were included if the following criteria were met: (i) case-control or cohort study comparing the risk of psoriasis in subjects with and without periodontitis; (ii) subjects without periodontitis were used as comparators in cohort studies while participants without psoriasis were used as controls in case-control studies; and (iii) effect estimates and 95% confidence intervals (CI) were provided. Point estimates and standard errors from each study were extracted and combined together using the generic inverse variance technique described by DerSimonian and Laird. Two cohort studies and three case-control studies met the inclusion criteria and were included in the meta-analysis. The pooled risk ratio of psoriasis in patients with periodontitis versus comparators was 1.55 (95% CI, 1.35-1.77). The statistical heterogeneity was insignificant with an I 2 of 18%. Subgroup analysis according to study design revealed a significantly higher risk among patients with periodontitis with a pooled RR of 1.50 (95% CI, 1.37-1.64) for cohort studies and a pooled RR of 2.33 (95% CI, 1.51-3.60) for case-control studies. Patients with periodontitis have a significantly elevated risk of psoriasis. © 2016 European Academy of Dermatology and Venereology.

The Challenge of Managing Psoriasis: Unmet Medical Needs and Stakeholder Perspectives.

PubMed

Feldman, Steven R; Goffe, Bernard; Rice, Gary; Mitchell, Matthew; Kaur, Mandeep; Robertson, Debbie; Sierka, Debra; Bourret, Jeffrey A; Evans, Tamara S; Gottlieb, Alice

2016-12-01

Psoriasis is a debilitating chronic inflammatory autoimmune disease affecting approximately 7.4 million adults in the United States. Plaque psoriasis is the most common form, affecting 80% to 90% of patients. To describe the impact and challenges that psoriasis presents for various stakeholders, and to provide nondermatologist healthcare decision makers with information to enhance their contributions to drug and pharmacy benefit design discussions. Psoriasis carries an increased risk for early mortality and an increased prevalence of comorbidities, including psoriatic arthritis, cardiovascular disease, and diabetes. It is also associated with anxiety, depression, and social isolation, and can negatively impact patients' relationships, productivity, and careers. The physical, psychologic, social, and economic impact of psoriasis, plus the associated stigma, result in cumulative impairment over a patient's lifetime. The current treatments for moderate-to-severe psoriasis include topical therapy, phototherapy, and systemic drugs (nonbiologic and biologic); however, patient satisfaction remains low, combination therapy and treatment switching are common, and many patients remain untreated or undertreated. Clinicians should consider the patient holistically, and should select treatment based on a range of factors, including disease severity (with physical and psychosocial manifestations), susceptibility to cumulative life-course impairment (considering personality, behavior, and cognition), comorbidities, concomitant medication, and patient preference. It is estimated that the total annual direct cost of treating psoriasis in the United States in 2015 exceeded $12.2 billion. Psoriasis is a complex disease, and appropriate management is correspondingly complex. Newer psoriasis treatments provide improved efficacy and safety versus traditional treatments, but challenges remain in ensuring patients access to these medications. An improved understanding of the barriers to

The Challenge of Managing Psoriasis: Unmet Medical Needs and Stakeholder Perspectives

PubMed Central

Feldman, Steven R.; Goffe, Bernard; Rice, Gary; Mitchell, Matthew; Kaur, Mandeep; Robertson, Debbie; Sierka, Debra; Bourret, Jeffrey A.; Evans, Tamara S.; Gottlieb, Alice

2016-01-01

Background Psoriasis is a debilitating chronic inflammatory autoimmune disease affecting approximately 7.4 million adults in the United States. Plaque psoriasis is the most common form, affecting 80% to 90% of patients. Objectives To describe the impact and challenges that psoriasis presents for various stakeholders, and to provide nondermatologist healthcare decision makers with information to enhance their contributions to drug and pharmacy benefit design discussions. Discussion Psoriasis carries an increased risk for early mortality and an increased prevalence of comorbidities, including psoriatic arthritis, cardiovascular disease, and diabetes. It is also associated with anxiety, depression, and social isolation, and can negatively impact patients' relationships, productivity, and careers. The physical, psychologic, social, and economic impact of psoriasis, plus the associated stigma, result in cumulative impairment over a patient's lifetime. The current treatments for moderate-to-severe psoriasis include topical therapy, phototherapy, and systemic drugs (nonbiologic and biologic); however, patient satisfaction remains low, combination therapy and treatment switching are common, and many patients remain untreated or undertreated. Clinicians should consider the patient holistically, and should select treatment based on a range of factors, including disease severity (with physical and psychosocial manifestations), susceptibility to cumulative life-course impairment (considering personality, behavior, and cognition), comorbidities, concomitant medication, and patient preference. It is estimated that the total annual direct cost of treating psoriasis in the United States in 2015 exceeded $12.2 billion. Conclusion Psoriasis is a complex disease, and appropriate management is correspondingly complex. Newer psoriasis treatments provide improved efficacy and safety versus traditional treatments, but challenges remain in ensuring patients access to these medications. An

Psoriasis in childhood: effective strategies to improve treatment adherence

PubMed Central

Shah, Kara N; Cortina, Sandra; Ernst, Michelle M; Kichler, Jessica C

2015-01-01

Psoriasis is a relatively common chronic inflammatory skin disease in children for which there is no cure. Most children have mild disease that can be managed with topical therapy as opposed to phototherapy or systemic therapy. Despite the mild presentation of psoriasis in most children, the disease can have a significant impact on quality of life due to the need for ongoing treatment, the frequently visible nature of the cutaneous manifestations, and the social stigma that is associated with psoriasis. Adherence to treatment, in particular topical therapy, is often poor in adults and compromises response to therapy and medical provider management strategies. Multiple factors that may contribute to nonadherence in adults with psoriasis have been identified, including lack of education on the disease and expectations for management, issues related to ease of use and acceptability of topical medications, and anxiety regarding possible medication side effects. There is currently no published data on adherence in the pediatric psoriasis population; however, poor adherence is often suspected when patients fail to respond to appropriate therapy. General strategies used to assess adherence in other pediatric disease populations can be applied to children with psoriasis, and interventions that reflect experience in other chronic dermatologic disorders such as atopic dermatitis may also be helpful for medical providers caring for children with psoriasis. PMID:29387581

A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis.

PubMed

Weidinger, Stephan; Willis-Owen, Saffron A G; Kamatani, Yoichiro; Baurecht, Hansjörg; Morar, Nilesh; Liang, Liming; Edser, Pauline; Street, Teresa; Rodriguez, Elke; O'Regan, Grainne M; Beattie, Paula; Fölster-Holst, Regina; Franke, Andre; Novak, Natalija; Fahy, Caoimhe M; Winge, Mårten C G; Kabesch, Michael; Illig, Thomas; Heath, Simon; Söderhäll, Cilla; Melén, Erik; Pershagen, Göran; Kere, Juha; Bradley, Maria; Lieden, Agne; Nordenskjold, Magnus; Harper, John I; McLean, W H Irwin; Brown, Sara J; Cookson, William O C; Lathrop, G Mark; Irvine, Alan D; Moffatt, Miriam F

2013-12-01

Atopic dermatitis (AD) is the most common dermatological disease of childhood. Many children with AD have asthma and AD shares regions of genetic linkage with psoriasis, another chronic inflammatory skin disease. We present here a genome-wide association study (GWAS) of childhood-onset AD in 1563 European cases with known asthma status and 4054 European controls. Using Illumina genotyping followed by imputation, we generated 268 034 consensus genotypes and in excess of 2 million single nucleotide polymorphisms (SNPs) for analysis. Association signals were assessed for replication in a second panel of 2286 European cases and 3160 European controls. Four loci achieved genome-wide significance for AD and replicated consistently across all cohorts. These included the epidermal differentiation complex (EDC) on chromosome 1, the genomic region proximal to LRRC32 on chromosome 11, the RAD50/IL13 locus on chromosome 5 and the major histocompatibility complex (MHC) on chromosome 6; reflecting action of classical HLA alleles. We observed variation in the contribution towards co-morbid asthma for these regions of association. We further explored the genetic relationship between AD, asthma and psoriasis by examining previously identified susceptibility SNPs for these diseases. We found considerable overlap between AD and psoriasis together with variable coincidence between allergic rhinitis (AR) and asthma. Our results indicate that the pathogenesis of AD incorporates immune and epidermal barrier defects with combinations of specific and overlapping effects at individual loci.

A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis

PubMed Central

Weidinger, Stephan; Willis-Owen, Saffron A.G.; Kamatani, Yoichiro; Baurecht, Hansjörg; Morar, Nilesh; Liang, Liming; Edser, Pauline; Street, Teresa; Rodriguez, Elke; O'Regan, Grainne M.; Beattie, Paula; Fölster-Holst, Regina; Franke, Andre; Novak, Natalija; Fahy, Caoimhe M.; Winge, Mårten C.G.; Kabesch, Michael; Illig, Thomas; Heath, Simon; Söderhäll, Cilla; Melén, Erik; Pershagen, Göran; Kere, Juha; Bradley, Maria; Lieden, Agne; Nordenskjold, Magnus; Harper, John I.; Mclean, W.H. Irwin; Brown, Sara J.; Cookson, William O.C.; Lathrop, G. Mark; Irvine, Alan D.; Moffatt, Miriam F.

2013-01-01

Atopic dermatitis (AD) is the most common dermatological disease of childhood. Many children with AD have asthma and AD shares regions of genetic linkage with psoriasis, another chronic inflammatory skin disease. We present here a genome-wide association study (GWAS) of childhood-onset AD in 1563 European cases with known asthma status and 4054 European controls. Using Illumina genotyping followed by imputation, we generated 268 034 consensus genotypes and in excess of 2 million single nucleotide polymorphisms (SNPs) for analysis. Association signals were assessed for replication in a second panel of 2286 European cases and 3160 European controls. Four loci achieved genome-wide significance for AD and replicated consistently across all cohorts. These included the epidermal differentiation complex (EDC) on chromosome 1, the genomic region proximal to LRRC32 on chromosome 11, the RAD50/IL13 locus on chromosome 5 and the major histocompatibility complex (MHC) on chromosome 6; reflecting action of classical HLA alleles. We observed variation in the contribution towards co-morbid asthma for these regions of association. We further explored the genetic relationship between AD, asthma and psoriasis by examining previously identified susceptibility SNPs for these diseases. We found considerable overlap between AD and psoriasis together with variable coincidence between allergic rhinitis (AR) and asthma. Our results indicate that the pathogenesis of AD incorporates immune and epidermal barrier defects with combinations of specific and overlapping effects at individual loci. PMID:23886662

Transcriptional Profiling of Ectoderm Specification to Keratinocyte Fate in Human Embryonic Stem Cells

PubMed Central

Tadeu, Ana Mafalda Baptista; Lin, Samantha; Hou, Lin; Chung, Lisa; Zhong, Mei; Zhao, Hongyu; Horsley, Valerie

2015-01-01

In recent years, several studies have shed light into the processes that regulate epidermal specification and homeostasis. We previously showed that a broad-spectrum γ–secretase inhibitor DAPT promoted early keratinocyte specification in human embryonic stem cells triggered to undergo ectoderm specification. Here, we show that DAPT accelerates human embryonic stem cell differentiation and induces expression of the ectoderm protein AP2. Furthermore, we utilize RNA sequencing to identify several candidate regulators of ectoderm specification including those involved in epithelial and epidermal development in human embryonic stem cells. Genes associated with transcriptional regulation and growth factor activity are significantly enriched upon DAPT treatment during specification of human embryonic stem cells to the ectoderm lineage. The human ectoderm cell signature identified in this study contains several genes expressed in ectodermal and epithelial tissues. Importantly, these genes are also associated with skin disorders and ectodermal defects, providing a platform for understanding the biology of human epidermal keratinocyte development under diseased and homeostatic conditions. PMID:25849374

Psoriasis.

PubMed

Nestle, Frank O

2008-01-01

Psoriasis is one of the most common chronic inflammatory disorders with a strong genetic background. Recent progress in the understanding of both the immunological as well as the genetic basis has provided an unprecedented opportunity to move scientific insights from the bench to bedside. Based on insights from laboratory research, targeted immunotherapies are now available for the benefit of patients suffering from psoriasis. The success of these therapies has validated insights into disease pathogenesis and also provides the opportunity to increase our understanding about the pathways underpinning autoimmune-type inflammation in the skin.

Psoriasis.

PubMed

Di Meglio, Paola; Villanova, Federica; Nestle, Frank O

2014-08-01

Psoriasis is a common chronic inflammatory skin disease with a spectrum of clinical phenotypes and results from the interplay of genetic, environmental, and immunological factors. Four decades of clinical and basic research on psoriasis have elucidated many of the pathogenic mechanisms underlying disease and paved the way to effective targeted therapies. Here, we review this progress and identify future directions of study that are supported by a more integrative research approach and aim at further improving the patients' life. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Cutting Edge: A Critical Functional Role for IL-23 in Psoriasis

PubMed Central

Tonel, Giulia; Conrad, Curdin; Laggner, Ute; Di Meglio, Paola; Grys, Katarzyna; McClanahan, Terrill K.; Blumenschein, Wendy M.; Qin, Jian-Zhong; Xin, Hong; Oldham, Elizabeth; Kastelein, Robert; Nickoloff, Brian J.; Nestle, Frank O.

2013-01-01

Interleukin-23 is a key cytokine involved in the generation of Th17 effector cells. Clinical efficacy of an anti-p40 mAb blocking both IL-12 and IL-23 and disease association with single nucleotide polymorphisms in the IL23R gene raise the question of a functional role of IL-23 in psoriasis. In this study, we provide a comprehensive analysis of IL-23 and its receptor in psoriasis and demonstrate its functional importance in a disease-relevant model system. The expression of IL-23 and its receptor was increased in the tissues of patients with psoriasis. Injection of a mAb specifically neutralizing human IL-23 showed IL-23–dependent inhibition of psoriasis development comparable to the use of anti-TNF blockers in a clinically relevant xenotransplant mouse model of psoriasis. Together, our results identify a critical functional role for IL-23 in psoriasis and provide the rationale for new treatment strategies in chronic epithelial inflammatory disorders. PMID:20956338

Cutting edge: A critical functional role for IL-23 in psoriasis.

PubMed

Tonel, Giulia; Conrad, Curdin; Laggner, Ute; Di Meglio, Paola; Grys, Katarzyna; McClanahan, Terrill K; Blumenschein, Wendy M; Qin, Jian-Zhong; Xin, Hong; Oldham, Elizabeth; Kastelein, Robert; Nickoloff, Brian J; Nestle, Frank O

2010-11-15

Interleukin-23 is a key cytokine involved in the generation of Th17 effector cells. Clinical efficacy of an anti-p40 mAb blocking both IL-12 and IL-23 and disease association with single nucleotide polymorphisms in the IL23R gene raise the question of a functional role of IL-23 in psoriasis. In this study, we provide a comprehensive analysis of IL-23 and its receptor in psoriasis and demonstrate its functional importance in a disease-relevant model system. The expression of IL-23 and its receptor was increased in the tissues of patients with psoriasis. Injection of a mAb specifically neutralizing human IL-23 showed IL-23-dependent inhibition of psoriasis development comparable to the use of anti-TNF blockers in a clinically relevant xenotransplant mouse model of psoriasis. Together, our results identify a critical functional role for IL-23 in psoriasis and provide the rationale for new treatment strategies in chronic epithelial inflammatory disorders.

Effect of a family history of psoriasis and age on comorbidities and quality of life in patients with moderate to severe psoriasis: Results from the ARIZONA study.

PubMed

López-Estebaranz, Jose Luis; Sánchez-Carazo, Jose Luis; Sulleiro, Sara

2016-04-01

Psoriasis is a chronic inflammatory skin disease whose clinical characteristics vary from patient to patient. We aimed to analyze how comorbidities and quality of life (QoL, as per the Dermatology Life Quality Index [DLQI]) may be affected by a family history of psoriasis and by age. The ARIZONA study was a multicenter, cross-sectional study in 1022 adult patients diagnosed with moderate to severe psoriasis at least 6 months prior to inclusion. The severity of psoriasis and the proportion of patients with comorbidities were not affected by the presence of a family history. The regression analysis revealed that the presence of a family history of psoriasis was associated with the effect on the patient's QoL (P = 0.002), regardless of disease severity. The mean DLQI total score varied significantly across age groups (5.1 ± 5.3 for the 18-30-year group, 5.7 ± 6.5 for the 31-60-year group and 3.8 ± 5.1 for the >60-year group; P = 0.001). In conclusion, the presence of a family history of psoriasis appears to disrupt QoL in patients with moderate to severe psoriasis, but it hardly affected the prevalence of comorbid conditions. The effect of age on QoL was particularly noticeable in younger patients, highlighting its negative impact. As expected, older patients appeared to be burdened with a higher number of comorbidities than their younger counterparts. © 2015 Japanese Dermatological Association.

HLA-Cw*0602 associates with a twofold higher prevalence of positive streptococcal throat swab at the onset of psoriasis: a case control study.

PubMed

Mallbris, Lotus; Wolk, Katarina; Sánchez, Fabio; Ståhle, Mona

2009-05-29

The influence of streptococcal infections in the pathogenesis of psoriasis is not yet understood. In vitro data suggest that streptococcal factors influence T-cell function in psoriasis in a HLA-dependent manner, but studies designed to measure the HLA-C/Streptococci interaction are lacking. In the present study, we hypothesized that there is a statistical interaction between the result of streptococcal throat cultures and the presence of the HLA-Cw*0602 allele in psoriasis patients. We performed a case control study using the "Stockholm Psoriasis Cohort" consisting of patients consecutively recruited within 12 months of disease onset (Plaque psoriasis = 439, Guttate psoriasis = 143), matched to healthy controls (n = 454) randomly chosen from the Swedish Population Registry. All individuals underwent physical examination including throat swabs and DNA isolation for HLA-Cw*0602 genotyping. The prevalence of positive streptococcal throat swabs and HLA-Cw*0602 was compared between patients and controls and expressed as odds ratios with 95% confidence intervals. Associations were evaluated separately for guttate and plaque psoriasis by Fisher's exact test. Regardless of disease phenotype, the prevalence of positive streptococcal throat swabs in HLA-Cw*0602 positive patients was twice the prevalence among HLA-Cw*0602 negative patients (OR = 5.8 C.I. = 3.57-9.67, p < 0.001), while no difference was observed among Cw*0602 positive versus negative controls. The corresponding odds ratios for the guttate and plaque psoriasis phenotypes were 3.5 (CI = 1.5-8.7, p = 0.01) and 2.3 (CI = 1.0-5.1, p = 0.02) respectively. These findings suggest that among HLA-Cw*0602 positive psoriasis patients, streptococci may contribute to the onset or exacerbation of the inflammatory process independent of the disease phenotype. However, studies on the functional interaction between HLA-C and streptococcal factors are needed.

HLA-Cw*0602 associates with a twofold higher prevalence of positive streptococcal throat swab at the onset of psoriasis: a case control study

PubMed Central

Mallbris, Lotus; Wolk, Katarina; Sánchez, Fabio; Ståhle, Mona

2009-01-01

Background The influence of streptococcal infections in the pathogenesis of psoriasis is not yet understood. In vitro data suggest that streptococcal factors influence T-cell function in psoriasis in a HLA-dependent manner, but studies designed to measure the HLA-C/Streptococci interaction are lacking. In the present study, we hypothesized that there is a statistical interaction between the result of streptococcal throat cultures and the presence of the HLA-Cw*0602 allele in psoriasis patients. Methods We performed a case control study using the "Stockholm Psoriasis Cohort" consisting of patients consecutively recruited within 12 months of disease onset (Plaque psoriasis = 439, Guttate psoriasis = 143), matched to healthy controls (n = 454) randomly chosen from the Swedish Population Registry. All individuals underwent physical examination including throat swabs and DNA isolation for HLA-Cw*0602 genotyping. The prevalence of positive streptococcal throat swabs and HLA-Cw*0602 was compared between patients and controls and expressed as odds ratios with 95% confidence intervals. Associations were evaluated separately for guttate and plaque psoriasis by Fisher's exact test. Results Regardless of disease phenotype, the prevalence of positive streptococcal throat swabs in HLA-Cw*0602 positive patients was twice the prevalence among HLA-Cw*0602 negative patients (OR = 5.8 C.I. = 3.57–9.67, p < 0.001), while no difference was observed among Cw*0602 positive versus negative controls. The corresponding odds ratios for the guttate and plaque psoriasis phenotypes were 3.5 (CI = 1.5–8.7, p = 0.01) and 2.3 (CI = 1.0–5.1, p = 0.02) respectively. Conclusion These findings suggest that among HLA-Cw*0602 positive psoriasis patients, streptococci may contribute to the onset or exacerbation of the inflammatory process independent of the disease phenotype. However, studies on the functional interaction between HLA-C and streptococcal factors are needed. PMID:19480679

MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes.

PubMed

Rebane, Ana; Runnel, Toomas; Aab, Alar; Maslovskaja, Julia; Rückert, Beate; Zimmermann, Maya; Plaas, Mario; Kärner, Jaanika; Treis, Angela; Pihlap, Maire; Haljasorg, Uku; Hermann, Helen; Nagy, Nikoletta; Kemeny, Lajos; Erm, Triin; Kingo, Külli; Li, Mei; Boldin, Mark P; Akdis, Cezmi A

2014-10-01

Chronic skin inflammation in atopic dermatitis (AD) is associated with elevated expression of proinflammatory genes and activation of innate immune responses in keratinocytes. microRNAs (miRNAs) are short, single-stranded RNA molecules that silence genes via the degradation of target mRNAs or inhibition of translation. The aim of this study was to investigate the role of miR-146a in skin inflammation in AD. RNA and protein expression was analyzed using miRNA and mRNA arrays, RT-quantitative PCR, Western blotting, and immunonohistochemistry. Transfection of miR-146a precursors and inhibitors into human primary keratinocytes, luciferase assays, and MC903-dependent mouse model of AD were used to study miR-146a function. We show that miR-146a expression is increased in keratinocytes and chronic lesional skin of patients with AD. miR-146a inhibited the expression of numerous proinflammatory factors, including IFN-γ-inducible and AD-associated genes CCL5, CCL8, and ubiquitin D (UBD) in human primary keratinocytes stimulated with IFN-γ, TNF-α, or IL-1β. In a mouse model of AD, miR-146a-deficient mice developed stronger inflammation characterized by increased accumulation of infiltrating cells in the dermis, elevated expression of IFN-γ, CCL5, CCL8, and UBD in the skin, and IFN-γ, IL-1β, and UBD in draining lymph nodes. Both tissue culture and in vivo experiments in mice demonstrated that miR-146a-mediated suppression in allergic skin inflammation partially occurs through direct targeting of upstream nuclear factor kappa B signal transducers caspase recruitment domain-containing protein 10 and IL-1 receptor-associated kinase 1. In addition, human CCL5 was determined as a novel, direct target of miR-146a. Our data demonstrate that miR-146a controls nuclear factor kappa B-dependent inflammatory responses in keratinocytes and chronic skin inflammation in AD. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights

Common variants explain a large fraction of the variability in the liability to psoriasis in a Han Chinese population.

PubMed

Yin, Xianyong; Wineinger, Nathan E; Cheng, Hui; Cui, Yong; Zhou, Fusheng; Zuo, Xianbo; Zheng, Xiaodong; Yang, Sen; Schork, Nicholas J; Zhang, Xuejun

2014-01-30

Psoriasis is a common inflammatory skin disease with a known genetic component. Our previously published psoriasis genome-wide association study identified dozens of novel susceptibility loci in Han Chinese. However, these markers explained only a small fraction of the estimated heritable component of psoriasis. To better understand the unknown yet likely polygenic architecture in psoriasis, we applied a linear mixed model to quantify the variation in the liability to psoriasis explained by common genetic markers (minor allele frequency > 0.01) in a Han Chinese population. We explored the polygenic genetic architecture of psoriasis using genome-wide association data from 2,271 Han Chinese individuals. We estimated that 34.9% (s.e. = 6.0%, P = 9 × 10-9) of the variation in the liability to psoriasis is captured by common genotyped and imputed variants. We discuss these results in the context of the strong association between HLA variants and psoriasis. We also show that the variance explained by each chromosome is linearly correlated to its length (R2 = 0.27, P=0.01), and quantify the impact of a polygenic effect on the prediction and diagnosis of psoriasis. Our results suggest that psoriasis has a substantial polygenic component, which not only has implications for the development of genetic diagnostics and prognostics for psoriasis, but also suggests that more individual variants contributing to psoriasis may be detected if sample sizes in future association studies are increased.

Current challenges and emerging drug delivery strategies for the treatment of psoriasis.

PubMed

Hoffman, Melissa B; Hill, Dane; Feldman, Steven R

2016-10-01

Psoriasis is a common skin disorder associated with physical, social, psychological and financial burden. Over the past two decades, advances in our understanding of pathogenesis and increased appreciation for the multifaceted burden of psoriasis has led to new treatment development and better patient outcomes. Yet, surveys demonstrate that many psoriasis patients are either undertreated or are dissatisfied with treatment. There are many barriers that need be overcome to optimize patient outcomes and satisfaction. This review covers the current challenges associated with each major psoriasis treatment strategy (topical, phototherapy, oral medications and biologics). It also reviews the challenges associated with the psychosocial aspects of the disease and how they affect treatment outcomes. Patient adherence, inconvenience, high costs, and drug toxicities are all discussed. Then, we review the emerging drug delivery strategies in topical, oral, and biologic therapy. By outlining current treatment challenges and emerging drug delivery strategies, we hope to highlight the deficits in psoriasis treatment and strategies for how to overcome them. Regardless of disease severity, clinicians should use a patient-centered approach. In all cases, we need to balance patients' psychosocial needs, treatment costs, convenience, and effectiveness with patients' preferences in order to optimize treatment outcomes.

A Large-Scale Genetic Association Study Confirms IL12B and Leads to the Identification of IL23R as Psoriasis-Risk Genes

PubMed Central

Cargill, Michele ; Schrodi, Steven J. ; Chang, Monica ; Garcia, Veronica E. ; Brandon, Rhonda ; Callis, Kristina P. ; Matsunami, Nori ; Ardlie, Kristin G. ; Civello, Daniel ; Catanese, Joseph J. ; Leong, Diane U. ; Panko, Jackie M. ; McAllister, Linda B. ; Hansen, Christopher B. ; Papenfuss, Jason ; Prescott, Stephen M. ; White, Thomas J. ; Leppert, Mark F. ; Krueger, Gerald G. ; Begovich, Ann B. 

2007-01-01

We performed a multitiered, case-control association study of psoriasis in three independent sample sets of white North American individuals (1,446 cases and 1,432 controls) with 25,215 genecentric single-nucleotide polymorphisms (SNPs) and found a highly significant association with an IL12B 3′-untranslated-region SNP (rs3212227), confirming the results of a small Japanese study. This SNP was significant in all three sample sets (odds ratio [OR]common 0.64, combined P [Pcomb]=7.85×10-10). A Monte Carlo simulation to address multiple testing suggests that this association is not a type I error. The coding regions of IL12B were resequenced in 96 individuals with psoriasis, and 30 additional IL12B-region SNPs were genotyped. Haplotypes were estimated, and genotype-conditioned analyses identified a second risk allele (rs6887695) located ∼60 kb upstream of the IL12B coding region that exhibited association with psoriasis after adjustment for rs3212227. Together, these two SNPs mark a common IL12B risk haplotype (ORcommon 1.40, Pcomb=8.11×10-9) and a less frequent protective haplotype (ORcommon 0.58, Pcomb=5.65×10-12), which were statistically significant in all three studies. Since IL12B encodes the common IL-12p40 subunit of IL-12 and IL-23, we individually genotyped 17 SNPs in the genes encoding the other chains of these cytokines (IL12A and IL23A) and their receptors (IL12RB1, IL12RB2, and IL23R). Haplotype analyses identified two IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (ORcommon 1.44, Pcomb=3.13×10-6). Individuals homozygous for both the IL12B and the IL23R predisposing haplotypes have an increased risk of disease (ORcommon 1.66, Pcomb=1.33×10-8). These data, and the previous observation that administration of an antibody specific for the IL-12p40 subunit to patients with psoriasis is highly efficacious, suggest that these genes play a fundamental role in psoriasis pathogenesis. PMID:17236132

How Does Chronic Cigarette Smoke Exposure Affect Human Skin? A Global Proteomics Study in Primary Human Keratinocytes.

PubMed

Rajagopalan, Pavithra; Nanjappa, Vishalakshi; Raja, Remya; Jain, Ankit P; Mangalaparthi, Kiran K; Sathe, Gajanan J; Babu, Niraj; Patel, Krishna; Cavusoglu, Nükhet; Soeur, Jeremie; Pandey, Akhilesh; Roy, Nita; Breton, Lionel; Chatterjee, Aditi; Misra, Namita; Gowda, Harsha

2016-11-01

Cigarette smoking has been associated with multiple negative effects on human skin. Long-term physiological effects of cigarette smoke are through chronic and not acute exposure. Molecular alterations due to chronic exposure to cigarette smoke remain unclear. Primary human skin keratinocytes chronically exposed to cigarette smoke condensate (CSC) showed a decreased wound-healing capacity with an increased expression of NRF2 and MMP9. Using quantitative proteomics, we identified 4728 proteins, of which 105 proteins were overexpressed (≥2-fold) and 41 proteins were downregulated (≤2-fold) in primary skin keratinocytes chronically exposed to CSC. We observed an alteration in the expression of several proteins involved in maintenance of epithelial barrier integrity, including keratin 80 (5.3 fold, p value 2.5 × 10 -7 ), cystatin A (3.6-fold, p value 3.2 × 10 -3 ), and periplakin (2.4-fold, p value 1.2 × 10 -8 ). Increased expression of proteins associated with skin hydration, including caspase 14 (2.2-fold, p value 4.7 × 10 -2 ) and filaggrin (3.6-fold, p value 5.4 × 10 -7 ), was also observed. In addition, we report differential expression of several proteins, including adipogenesis regulatory factor (2.5-fold, p value 1.3 × 10 -3 ) and histone H1.0 (2.5-fold, p value 6.3 × 10 -3 ) that have not been reported earlier. Bioinformatics analyses demonstrated that proteins differentially expressed in response to CSC are largely related to oxidative stress, maintenance of skin integrity, and anti-inflammatory responses. Importantly, treatment with vitamin E, a widely used antioxidant, could partially rescue adverse effects of CSC exposure in primary skin keratinocytes. The utility of antioxidant-based new dermatological formulations in delaying or preventing skin aging and oxidative damages caused by chronic cigarette smoke exposure warrants further clinical investigations and multi-omics research.

Real-world burden of comorbidities in US patients with psoriasis.

PubMed

Shah, Kamal; Mellars, Lillian; Changolkar, Arun; Feldman, Steven R

2017-08-01

Understanding background comorbidity rates in psoriasis can provide perspective for adverse events associated with new therapies. We sought to assess the extent of comorbidities in psoriasis patients by use of the Truven Health Analytics MarketScan database. MarketScan, comprising commercial claims representative of a large US-insured population, had 1.22 million patients with ≥1 claim with a psoriasis diagnosis between January 1, 2008, and December 31, 2014. Patients ≥18 years of age who had ≥2 health claims in any diagnosis field for psoriasis (International Classification of Diseases, 9th Revision, Clinical Modification 696.1) with a psoriasis diagnosis (index) date between July 1, 2008, and June 30, 2014, were included to allow follow-up observation time. Prevalence and incidence of 24 comorbidities were assessed in 469,097 psoriasis patients; the most common comorbidities were hyperlipidemia (45.64% and 30.83%, respectively), hypertension (42.19% and 24.19%), depression (17.91% and 12.68%), type 2 diabetes mellitus (17.45% and 8.44%), and obesity (14.38% and 11.57%). A limitation of the study was that only a certain insured population was represented. Comorbidity rates align with those described in the literature and support the concept that psoriasis patients have high rates of cardiometabolic comorbidities. This analysis highlights the potential utility of very large insurance databases for determining comorbidity prevalence in psoriasis, which may aid health care providers in managing psoriasis. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

A Case-control Study to Evaluate the Prevalence of Nonalcoholic Fatty Liver Disease Among Patients with Moderate-to-severe Psoriasis.

PubMed

Awosika, Olabola; Eleryan, Misty G; Rengifo-Pardo, Monica; Doherty, Lindsay; Martin, Lisa W; Ehrlich, Alison

2018-06-01

Objective: International case-control studies have demonstrated that psoriasis is associated with an increased prevalence of nonalcoholic fatty liver disease (NAFLD). The purpose of the present study was to establish an association of psoriasis and NAFLD in patients attending a dermatology clinic center in the United States. Design: This was an observational, case-control study. Setting: The study setting was an outpatient dermatology clinic of the George Washington Medical Faculty Associates in Washington DC. Participants: One hundred fifty-one adult patients with psoriasis and 51 control subjects were recruited. Measurements: NAFLD was diagnosed by ultrasonography after excluding secondary causes of liver disease. Regression analysis was used to assess the associations between: 1) NAFLD and psoriasis and 2) metabolic syndrome components and NAFLD among psoriasis patients. Results: NAFLD was more prevalent in patients with psoriasis (21.2% vs. 7.8%, p <0.04). However, psoriasis was not associated with NAFLD when matching for age, sex, and body mass index (BMI) (odds ratio: 2.63, 95% confidence interval [CI]: 0.51-13.6; p =0.25). As compared to patients with psoriasis but without NAFLD, those with NAFLD were more likely to have obesity (BMI: 34.9 vs. 27.2, 95% CI: 32.4-37.5 vs. 25.9-28.5; p <0.01). NAFLD in patients with psoriasis was also associated with select components of metabolic syndrome, including hyperglycemia and hyperlipidemia. Conclusion: Our findings show there is an association of psoriasis with NAFLD. Our findings also suggest an increased presence of metabolic syndrome components in patients with psoriasis and NAFLD. Trial registry: NCT00930384.

Protective effect of indigo naturalis extract against oxidative stress in cultured human keratinocytes.

PubMed

Lin, Yin-Ku; Chen, Hsiao-Wen; Yang, Sien-Hung; Leu, Yann-Lii; Huang, Yu-Hsiang; Yen, Hsiu-Chuan

2012-02-15

Indigo naturalis is used in traditional Chinese medicine to treat various skin disorders. The aims were to explore the effect of indigo naturalis on suppressing oxidative stress and protein modifications by hydrogen peroxide (H(2)O(2)) and 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product, in cultured primary human keratinocytes. Indigo naturalis extract at a dose that did not cause cytotoxicity was added to cultured keratinocytes in the absence or the presence of H(2)O(2) or HNE. The degree of cytotoxicity, levels of reactive oxygen species (ROS), and amount of protein carbonyl groups were evaluated. Indigo naturalis extract at the concentration of 10μg/ml had no protective effect against H(2)O(2) or HNE-induced cytotoxicity, but decreased intracellular levels of ROS after H(2)O(2) treatment and suppressed the increase of protein carbonyl groups induced by HNE. Indigo naturalis possesses an inhibitory effect on formation of intracellular ROS induced by exogenous ROS and protein modification induced by HNE in human keratinocytes, which is relevant to the alleviation of inflammatory skin diseases. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Human papilloma virus infection and psoriasis: Did human papilloma virus infection trigger psoriasis?

PubMed

Jain, Sonia P; Gulhane, Sachin; Pandey, Neha; Bisne, Esha

2015-01-01

Psoriasis is an autoimmune chronic inflammatory skin disease known to be triggered by streptococcal and HIV infections. However, human papilloma virus infection (HPV) as a triggering factor for the development of psoriasis has not been reported yet. We, hereby report a case of plaque type with inverse psoriasis which probably could have been triggered by genital warts (HPV infection) and discuss the possible pathomechanisms for their coexistence and its management.

Fibroblast extracellular matrix gene expression in response to keratinocyte-releasable stratifin.

PubMed

Ghaffari, Abdi; Li, Yunyaun; Karami, Ali; Ghaffari, Mazyar; Tredget, Edward E; Ghahary, Aziz

2006-05-15

Termination of wound-healing process requires a fine balance between connective tissue deposition and its hydrolysis. Previously, we have demonstrated that keratinocyte-releasable stratifin, also known as 14-3-3 sigma protein, stimulates collagenase (MMP-1) expression in dermal fibroblasts. However, role of extracellular stratifin in regulation of extracellular matrix (ECM) factors and other matrix metalloproteinases (MMPs) in dermal fibroblast remains unexplored. To address this question, large-scale ECM gene expression profile were analyzed in human dermal fibroblasts co-cultured with keratinocytes or treated with recombinant stratifin. Superarray pathway-specific microarrays were utilized to identify upregulation or downregulation of 96 human ECM and adhesion molecule genes. RT-PCR and Western blot were used to validate microarray expression profiles of selected genes. Comparison of gene profiles with the appropriate controls showed a significant (more than twofold) increase in expression of collagenase-1, stromelysin-1 and -2, neutrophil collagenase, and membrane type 5 MMP in dermal fibroblasts treated with stratifin or co-cultured with keratinocytes. Expression of type I collagen and fibronectin genes decreased in the same fibroblasts. The results of a dose-response experiment showed that stratifin stimulates the expression of stromelysin-1 (MMP-3) mRNA by dermal fibroblasts in a concentration-dependent fashion. Furthermore, Western blot analysis of fibroblast-conditioned medium showed a peak in MMP-3 protein levels 48 h following treatment with recombinant stratifin. In a lasting-effect study, MMP-3 protein was detected in fibroblast-condition medium for up to 72 h post removal of stratifin. In conclusion, our results suggest that keratinocyte-releasable stratifin plays a major role in induction of ECM degradation by dermal fibroblasts through stimulation of key MMPs, such as MMP-1 and MMP-3. Therefore, stratifin protein may prove to be a useful target for

METEORIN-LIKE is a cytokine associated with barrier tissues and alternatively activated macrophages

PubMed Central

Ushach, Irina; Burkhardt, Amanda M.; Martinez, Cynthia; Hevezi, Peter A.; Gerber, Peter Arne; Buhren, Bettina Alexandra; Schrumpf, Holger; Valle-Rios, Ricardo; Vazquez, Monica I.; Homey, Bernhard; Zlotnik, Albert

2014-01-01

Cytokines are involved in many functions of the immune system including initiating, amplifying and resolving immune responses. Through bioinformatics analyses of a comprehensive database of gene expression (BIGE: Body Index of Gene Expression) we observed that a small secreted protein encoded by a poorly characterized gene called meteorin-like (METRNL), is highly expressed in mucosal tissues, skin and activated macrophages. Further studies indicate that Metrnl is produced by Alternatively Activated Macrophages (AAM) and M-CSF cultured bone marrow macrophages (M2-like macrophages). In the skin, METRNL is expressed by resting fibroblasts and IFNγ-treated keratinocytes. A screen of human skin-associated diseases showed significant over-expression of METRNL in psoriasis, prurigo nodularis, actinic keratosis and atopic dermatitis. METRNL is also up-regulated in synovial membranes of human rheumatoid arthritis. Taken together, these results indicate that Metrnl represents a novel cytokine, which is likely involved in both innate and acquired immune responses. PMID:25486603

A Clinician's Guide to the Diagnosis and Treatment of Candidiasis in Patients with Psoriasis.

PubMed

Armstrong, April W; Bukhalo, Michael; Blauvelt, Andrew

2016-08-01

Many of the molecular pathways associated with psoriasis pathogenesis are also involved in host defense mechanisms that protect against common pathogens. Candida can stimulate the production of cytokines that trigger or exacerbate psoriasis, and many systemic psoriasis treatments may put patients at increased risk for developing oral, cutaneous, and genitourinary candidiasis. Therefore, dermatologists should regularly screen patients with psoriasis for signs of Candida infection, and take steps to effectively treat these infections to prevent worsening of psoriasis symptoms. This review provides an overview of candidiasis epidemiology in patients with psoriasis, followed by a primer on the diagnosis and treatment of superficial Candida infections, with specific guidance for patients with psoriasis. Candidiasis in patients with psoriasis typically responds to topical or oral antifungal therapy. While biologic agents used to treat moderate-to-severe psoriasis, such as tumor necrosis factor-α inhibitors and interleukin-17 inhibitors, are known to increase patients' risk of developing localized candidiasis, the overall risk of infection is low, and candidiasis can be effectively managed in most patients while receiving systemic psoriasis therapies. Thus, the development of candidiasis does not usually necessitate changes to psoriasis treatment regimens.

The hair root pattern after calcipotriol treatment for scalp psoriasis.

PubMed

Kuijpers, A L; van Baar, H M; van Gasselt, M W; van de Kerkhof, P C

1995-09-01

Scalp psoriasis is associated with hair loss and an increased telogen/anagen ratio. Topical treatment of scalp psoriasis (with corticosteroids, dithranol or tar) results in decreased scaling, induration and erythema of the plaques. Calcipotriol is effective in the treatment of psoriasis vulgaris. However, the potent growth-inhibiting potential of this compound might theoretically induce hair loss. A study was designed to find out to what extent calcipotriol treatment modulates the percentage of anagen and telogen hair during treatment of scalp psoriasis. A group of 26 patients participated in a placebo-controlled dose-finding study on the efficacy of calcipotriol in scalp psoriasis. Hair plucks before and after treatment were taken. The telogen/anagen ratio remained unaffected during 6 weeks of calcipotriol treatment. No correlation was demonstrated between efficacy of treatment and quantification of telogen/anagen ratio. It can be concluded that the growth-inhibiting potential of calcipotriol is not reflected in the in vivo hair growth pattern during calcipotriol treatment.

The Effect of Secretory Factors of Adipose-Derived Stem Cells on Human Keratinocytes

PubMed Central

Moon, Kyoung Mi; Park, Ye-Hyoung; Lee, Jae Seol; Chae, Yong-Byung; Kim, Moon-Moo; Kim, Dong-Soo; Kim, Byung-Woo; Nam, Soo-Wan; Lee, Jong-Hwan

2012-01-01

The beneficial effects of adipose-derived stem cell conditioned medium (ADSC-CM) on skin regeneration have been reported. Although the mechanism of how ADSC-CM promotes skin regeneration is unclear, ADSC-CM contained various growth factors and it is an excellent raw material for skin treatment. ADSC-CM produced in a hypoxia condition of ADSC—in other words, Advanced Adipose-Derived Stem cell Protein Extract (AAPE)—has great merits for skin regeneration. In this study, human primary keratinocytes (HKs), which play fundamental roles in skin tissue, was used to examine how AAPE affects HK. HK proliferation was significantly higher in the experimental group (1.22 μg/mL) than in the control group. DNA gene chip demonstrated that AAPE in keratinocytes (p < 0.05) notably affected expression of 290 identified transcripts, which were associated with cell proliferation, cycle and migration. More keratinocyte wound healing and migration was shown in the experimental group (1.22 μg/mL). AAPE treatment significantly stimulated stress fiber formation, which was linked to the RhoA-ROCK pathway. We identified 48 protein spots in 2-D gel analysis and selected proteins were divided into 64% collagen components and 30% non-collagen components as shown by the MALDI-TOF analysis. Antibody array results contained growth factor/cytokine such as HGF, FGF-1, G-CSF, GM-CSF, IL-6, VEGF, and TGF-β3 differing from that shown by 2-D analysis. Conclusion: AAPE activates HK proliferation and migration. These results highlight the potential of the topical application of AAPE in the treatment of skin regeneration. PMID:22312315

Mortality in patients with psoriasis. A retrospective cohort study.

PubMed

Masson, Walter; Rossi, Emiliano; Galimberti, María Laura; Krauss, Juan; Navarro Estrada, José; Galimberti, Ricardo; Cagide, Arturo

2017-06-07

The immune and inflammatory pathways involved in psoriasis could favor the development of atherosclerosis, consequently increasing mortality. The objectives of this study were: 1) to assess the mortality of a population with psoriasis compared to a control group, and 2) to assess the prevalence of cardiovascular risk factors. A retrospective cohort was analyzed from a secondary database (electronic medical record). All patients with a diagnosis of psoriasis at 1-01-2010 were included in the study and compared to a control group of the same health system, selected randomly (1:1). Subjects with a history of cardiovascular disease were excluded from the study. A survival analysis was performed considering death from any cause as an event. Follow-up was extended until 30-06-2015. We included 1,481 subjects with psoriasis and 1,500 controls. Prevalence of cardiovascular risk factors was higher in the group with psoriasis. The average follow-up time was 4.6±1.7 years. Mortality was higher in psoriasis patients compared to controls (15.1 vs. 9.6 events per 1,000 person-year, P<.005). Psoriasis was seen to be significantly associated with increased mortality rates compared to the control group in the univariate analysis (HR 1.58, 95% CI 1.16-2.15, P=.004) and after adjusting for cardiovascular risk factors (HR 1.48, 95% CI 1.08-2.3, P=.014). In this population, patients with psoriasis showed a higher prevalence for the onset of cardiovascular risk factors as well as higher mortality rates during follow-up. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

What is clearance worth? Patients' stated risk tolerance for psoriasis treatments.

PubMed

Fairchild, Angelyn O; Reed, Shelby D; Johnson, F Reed; Anglin, Greg; Wolka, Anne M; Noel, Rebecca A

2017-12-01

The purpose of this study was to provide quantitative evidence of patients' tolerance for therapeutic risks associated with psoriasis treatments that could offer psoriasis improvements beyond the PASI 75 benchmark. We used a discrete-choice experiment in which respondents chose between competing psoriasis treatments characterized by benefits (i.e. reduced plaque severity, reduced plaque area), risks (i.e. 10-year risk of tuberculosis, 10-year risk of death from infection), and treatment regimen. We analyzed choice data using random-parameters logit models for psoriasis affecting the body, face, or hands. Of 927 eligible members of the National Psoriasis Foundation who completed the survey, 28% were unwilling to accept any greater risk of treatment-related infection mortality. Among the remaining 72%, respondents were willing to accept higher risks of infection-related mortality associated with treatment to completely remove plaques covering only 1% of the body, compared to reducing lesions from 10 to 1% of the affected area. This finding was more pronounced for lesions on the face. Most patients placed greater value on eliminating even very small plaques compared to avoiding treatment-related risks. The perceived importance of complete versus near-complete clearance was stronger than previously documented.

Keratinocyte-melanocyte interactions during melanosome transfer.

PubMed

Seiberg, M

2001-08-01

The epidermal-melanin unit is composed of one melanocyte and approximately 36 neighboring keratinocytes, working in synchrony to produce and distribute melanin. Melanin is synthesized in melanosomes, transferred to the dendrite tips, and translocated into keratinocytes, forming caps over the keratinocyte nuclei. The molecular and cellular mechanisms involved in melanosome transfer and the keratinocyte-melanocyte interactions required for this process are not yet completely understood. Suggested mechanisms of melanosome transfer include melanosome release and endocytosis, direct inoculation ('injection'), keratinocyte-melanocyte membrane fusion, and phagocytosis. Studies of the keratinocyte receptor protease-activated receptor-2 (PAR-2) support the phagocytosis theory. PAR-2 controls melanosome ingestion and phagocytosis by keratinocytes and exerts a regulatory role in skin pigmentation. Modulation of PAR-2 activity can enhance or decrease melanosome transfer and affects pigmentation only when there is keratinocyte-melanocyte contact. Moreover, PAR-2 is induced by UV irradiation and inhibition of PAR-2 activation results in the prevention of UVB-induced tanning. The role of PAR-2 in mediating UV-induced responses remains to be elucidated.

Association between Psoriasis and haplotypes of the IgH 3' Regulatory Region 1.

PubMed

D'Addabbo, Pietro; Serone, Eliseo; Esposito, Maria; Vaccari, Gabriele; Gargioli, Cesare; Frezza, Domenico; Bianchi, Luca

2018-08-30

The association studies of several immune-diseases with the 3' Regulatory Region 1 (3'RR1) increased interest on the role that the region plays in the immune-regulation. The 3'RR1 is a polymorphic region on human chromosome 14q32, acting as a cis-regulative element on the Immunoglobulin constant-gene locus recently considered as super-enhancer. The human 3'RR1 share large sequences with its paralogous 3'RR2, at high level of similarity. Thus, a focused investigation was necessary to discriminate each one of the duplicated components of the two regions and its specific contribution to the immunologic phenotype. One of the duplicated elements is the hs1.2 enhancer. The 3'RR1 alleles of this enhancer were demonstrated to play a role in autoimmune diseases, including Psoriasis. We sequenced a specific region internal to the 3'RR1 in hs1.2 homozygous subjects, to detect SNPs associated to the main alleles of the enhancer. We identified two alternative nine-SNPs haplotypes strictly linked to the allele *1 and *2 of hs1.2, that could be used as markers to further investigate the region and associations to pathology. Finally, we identified two haplotypes, namely E2A1 and E2A2, that strongly support the hypothesis of a relevant effect of the rs35216181 in the onset of Psoriasis when the *2 allele is present. Copyright © 2018 Elsevier B.V. All rights reserved.

Co-morbidity and age-related prevalence of psoriasis: Analysis of health insurance data in Germany.

PubMed

Augustin, Matthias; Reich, Kristian; Glaeske, Gerd; Schaefer, Ines; Radtke, Marc

2010-03-01

Epidemiological studies indicate an increased risk of co-morbidities and an association with other inflammatory diseases in psoriasis. However, most analyses have been performed on small samples of patients. The aim of this study was to evaluate the prevalence of co-morbidities in psoriasis based on a large set of health insurance data. The database of 1.3 million patients in a German nationwide statutory health insurance scheme was analysed. Data-sets of patients with confirmed psoriasis were extracted and analysed for co-morbidities. Of 1,344,071 subjects, 33,981 had a diagnosis of psoriasis (prevalence 2.5%). Metabolic syndrome was 2.9-fold more frequent among these patients. The most common diagnoses were arterial hypertension (35.6% in psoriasis vs. 20.6% in controls) and hyperlipidaemia (29.9% vs. 17.1%). The frequencies of rheumatoid arthritis (prevalence ratio (PR) 3.8), Crohn's disease (PR 2.1) and ulcerative colitis (PR 2.0) were also increased among patients with psoriasis. In conclusion, psoriasis is associated with significant co-morbidities that imply an elevated risk of severe complications.

Dermoscopy in differential diagnosis of palmar psoriasis and chronic hand eczema.

PubMed

Errichetti, Enzo; Stinco, Giuseppe

2016-04-01

Clinical differentiation between palmar psoriasis and chronic hand eczema may sometimes be a diagnostic challenge; in such cases histopathological analysis helps to differentiate the two conditions. In the present study, palmar psoriasis and chronic hand eczema were investigated using dermoscopy and the significance of specific dermoscopic features was assessed in order to improve their non-invasive differentiation. Ten patients with biopsy-proven palmar psoriasis and 11 patients with biopsy-proven chronic hand eczema were included in the study. We found that the presence of diffuse white scales was significant in palmar psoriasis whereas the presence of yellowish scales, brownish-orange dots/globules and yellowish-orange crusts was significant in chronic hand eczema. © 2015 Japanese Dermatological Association.

Macelignan inhibits melanosome transfer mediated by protease-activated receptor-2 in keratinocytes.

PubMed

Choi, Eun-Jung; Kang, Young-Gyu; Kim, Jaekyung; Hwang, Jae-Kwan

2011-01-01

Skin pigmentation is the result of melanosome transfer from melanocytes to keratinocytes. Protease-activated receptor-2 (PAR-2) is a key mediator of melanosome transfer, which occurs as the melanocyte extends its dendrite toward surrounding keratinocytes that take up melanosomes by phagocytosis. We investigated the effects of macelignan isolated from Myristica fragrans HOUTT. (nutmeg) on melanosome transfer and the regulation of PAR-2 in human keratinocytes (HaCaT). HaCaT cells stimulated by the PAR-2-activating peptide Ser-Leu-Ile-Gly-Arg-Leu-NH₂ (SLIGRL) were treated with macelignan; PAR-2 expression was then determined by reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunocytochemistry. We evaluated the effects of macelignan on calcium mobilization and keratinocyte phagocytosis. In addition, B16F10 melanoma cells and keratinocytes were co-cultured to assess the effects of macelignan on prostaglandin E₂ (PGE₂) secretion and subsequent dendrite formation. Macelignan decreased HaCaT PAR-2 mRNA and protein levels in a dose-dependent manner. Furthermore, macelignan markedly reduced intracellular calcium mobilization and significantly downregulated keratinocyte phagocytosis, as shown by decreased ingestion of Escherichia coli bioparticles and fluorescent microspheres. In co-culture experiments, macelignan reduced keratinocyte PGE₂ secretion, thereby preventing dendrite formation in B16F10 melanoma cells compared with SLIGRL-treated controls. Macelignan inhibits melanosome transfer by downregulating PAR-2, thereby reducing keratinocyte phagocytosis and PGE₂ secretion, which in turn inhibits dendrite formation in B16F10 melanoma cells. Taken together, our findings suggest that macelignan could be used as a natural depigmenting agent to ameliorate hyperpigmentation.

Epidemiological determinants of psoriasis.

PubMed

Islam, M T; Paul, H K; Zakaria, S M; Islam, M M; Shafiquzzaman, M

2011-01-01

A cross-sectional study was conducted on 102 cases having clinical manifestation of psoriasis with a view to evaluate the epidemiological determinants of psoriasis. Psoriasis constituted 1.49% of the total dermatological disorder. Seventy patients (68.6%) were males and thirty two (31.4%) were females with a male to female ratio of 2.18:1. The mean age was 30.76±13.17 years in male and 26.94±14.94 years in female. Sixteen (15.7%) patients had one or more family member having psoriasis with male and female in equal frequency. Regarding precipitating factors, psoriasis was developed after trauma in 4.9%, infection 3.9%, stressful life events 6.9% and drugs 2.9%; and was exacerbated after trauma in 5.9%, infection 5.9%, stressful life events 35.3% and drugs 12.7%. The disease showed improvement in summer (27.5%) and found deteriorated in winter (47.1%). Sunlight had beneficial effect in 33.3% of cases. During pregnancy improvement was observed in 50% but flare up in 22.2% of cases. Fifty percent of patients were smokers, 41.2% were non-smokers and 13.7% were ex-smokers. Forty percent had Body Mass Index (BMI) between 22 to 26 Kg/m², 40.2% had less than 22 Kg/m² and 15.7% had above 26 Kg/m². It was concluded that the prevalence of psoriasis among dermatological patients was similar to results reported in Turkey and in Northern India. The precipitating factors, such as smoking, stressful life events, infection, trauma, sunlight, pregnancy, drugs, and seasonal variations could influence the development of psoriasis and affect its clinical expression.

Keratinocyte growth factor and the expression of wound-healing-related genes in primary human keratinocytes from burn patients.

PubMed

Chomiski, Verônica; Gragnani, Alfredo; Bonucci, Jéssica; Correa, Silvana Aparecida Alves; Noronha, Samuel Marcos Ribeiro de; Ferreira, Lydia Masako

2016-08-01

To evaluate the effect of keratinocyte growth factor (KGF) treatment on the expression of wound-healing-related genes in cultured keratinocytes from burn patients. Keratinocytes were cultured and divided into 4 groups (n=4 in each group): TKB (KGF-treated keratinocytes from burn patients), UKB (untreated keratinocytes from burn patients), TKC (KGF-treated keratinocytes from controls), and UKC (untreated keratinocytes from controls). Gene expression analysis using quantitative polymerase chain reaction (qPCR) array was performed to compare (1) TKC versus UKC, (2) UKB versus UKC, (3) TKB versus UKC, (4) TKB versus UKB, (5) TKB versus TKC, and (6) UKB versus TKC. Comparison 1 showed one down-regulated and one up-regulated gene; comparisons 2 and 3 resulted in the same five down-regulated genes; comparison 4 had no significant difference in relative gene expression; comparison 5 showed 26 down-regulated and 7 up-regulated genes; and comparison 6 showed 25 down-regulated and 11 up-regulated genes. There was no differential expression of wound-healing-related genes in cultured primary keratinocytes from burn patients treated with keratinocyte growth factor.

Filaggrin-dependent secretion of sphingomyelinase protects against staphylococcal α-toxin-induced keratinocyte death.

PubMed

Brauweiler, Anne M; Bin, Lianghua; Kim, Byung Eui; Oyoshi, Michiko K; Geha, Raif S; Goleva, Elena; Leung, Donald Y M

2013-02-01

The skin of patients with atopic dermatitis (AD) has defects in keratinocyte differentiation, particularly in expression of the epidermal barrier protein filaggrin. AD skin lesions are often exacerbated by Staphylococcus aureus-mediated secretion of the virulence factor α-toxin. It is unknown whether lack of keratinocyte differentiation predisposes to enhanced lethality from staphylococcal toxins. We investigated whether keratinocyte differentiation and filaggrin expression protect against cell death induced by staphylococcal α-toxin. Filaggrin-deficient primary keratinocytes were generated through small interfering RNA gene knockdown. RNA expression was determined by using real-time PCR. Cell death was determined by using the lactate dehydrogenase assay. Keratinocyte cell survival in filaggrin-deficient (ft/ft) mouse skin biopsies was determined based on Keratin 5 staining. α-Toxin heptamer formation and acid sphingomyelinase expression were determined by means of immunoblotting. We found that filaggrin expression, occurring as the result of keratinocyte differentiation, significantly inhibits staphylococcal α-toxin-mediated pathogenicity. Furthermore, filaggrin plays a crucial role in protecting cells by mediating the secretion of sphingomyelinase, an enzyme that reduces the number of α-toxin binding sites on the keratinocyte surface. Finally, we determined that sphingomyelinase enzymatic activity directly prevents α-toxin binding and protects keratinocytes against α-toxin-induced cytotoxicity. The current study introduces the novel concept that S aureus α-toxin preferentially targets and destroys filaggrin-deficient keratinocytes. It also provides a mechanism to explain the increased propensity for S aureus-mediated exacerbation of AD skin disease. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Significant sE-Selectin levels reduction after 6 months of anti-TNF-α therapy in non-diabetic patients with moderate-to-severe psoriasis.

PubMed

Genre, Fernanda; Armesto, Susana; Corrales, Alfonso; López-Mejías, Raquel; Remuzgo-Martínez, Sara; Pina, Trinitario; Ubilla, Begoña; Mijares, Verónica; Martín-Varillas, José Luis; Rueda-Gotor, Javier; Portilla, Virginia; Dierssen-Sotos, Trinidad; González-López, Marcos Antonio; González-Vela, María Del Carmen; Blanco, Ricardo; Llorca, Javier; Hernández, José Luis; González-Gay, Miguel Ángel

2017-12-01

Psoriasis patients have high risk of atherosclerosis, characterized by endothelial dysfunction. We aimed to study the association of the endothelial activation biomarkers monocyte chemoattractant protein 1 (MCP-1), soluble (s) E-selectin and P-selectin with disease activity and severity in psoriasis patients treated with anti-TNF-α therapy. Also, to evaluate the relationship of metabolic syndrome features with these biomarkers and the effect of anti-TNF-α therapy on these molecules. Twenty-nine consecutive non-diabetic patients with moderate-to-severe psoriasis who underwent 6 months of anti-TNF-α-adalimumab therapy were studied. Metabolic and clinical evaluation was performed prior to anti-TNF-α treatment (time 0) and 6 months later. MCP-1, sE-selectin and sP-selectin serum levels were determined by ELISA. Dyslipidemic and obese patients showed higher MCP-1 levels at month 6 from the onset of anti-TNF-α therapy (p = .05 and .01, respectively). sE-selectin positively correlated with pro-inflammatory molecules such as asymmetric dimethylarginine, sP-selectin and resistin at baseline and month 6 (p < .05). sE-selectin levels significantly reduced after 6 months of therapy (p = .0006). Metabolic syndrome features are associated with endothelial activation in patients with moderate-to-severe psoriasis. Adalimumab therapy led to a reduction in sE-selectin levels, supporting the beneficial effect of anti-TNF-α therapy on mechanisms associated with the development of atherosclerosis in psoriasis.

Psoriasis as a cardiovascular risk factor: updates and algorithmic approach.

PubMed

Cozzani, Emanuele; Rosa, Gianmarco; Burlando, Martina; Parodi, Aurora

2018-04-19

Although psoriasis is predominantly a chronic inflammatory skin disorder, it has been known to be associated with cardiovascular disease. Patients with psoriasis, particularly with moderate to severe forms, present an increased rate of cardiovascular mortality, myocardial infarction and stroke. However the pathophysiology of the relationship between psoriasis and cardiovascular risk and comorbidities has not yet completely known. Chronic inflammation may be considered a solid link between psoriasis and related cardiovascular events. Several cytokines and inflammatory cells play a pivotal role in the development of psoriatic lesions, resulting in angiogenesis and endothelial dysfunction. Furthermore, the imbalance between oxidative stress and anti-oxidant mechanisms in psoriatic patients may contribute to explain the pathogenesis of increased reactive oxygen species and the formation of atherosclerotic plaque. Other mechanistic pathways which may be involved in this relationship include cardiovascular effects of medications, a common genetic background and a higher prevalence of cardiovascular risk factors, which are often under-diagnosed and under-treated in psoriatic patients. Indeed, the early detection of specific markers of cardiovascular impairment, such as N-terminal pro B-type natriuretic peptide, homocysteine and YKL-40, may enable psoriatic patients at higher cardiovascular risk to be identified as soon as possible. This review examines the increased cardiovascular risk profile and high prevalence of cardiovascular disease associated with psoriasis, focusing on pathogenic links between psoriasis and atherosclerosis, serological markers of cardiovascular involvement and the implications of anti-psoriatic therapies on cardiovascular risk and proposes a flow chart, that every dermatologist should follow to screen psoriatic patients.

Paracrine Activity from Adipose-Derived Stem Cells on In Vitro Wound Healing in Human Tympanic Membrane Keratinocytes.

PubMed

Ong, Huan Ting; Redmond, Sharon L; Marano, Robert J; Atlas, Marcus D; von Unge, Magnus; Aabel, Peder; Dilley, Rodney J

2017-03-15

Stem cell therapies for tympanic membrane repair have shown initial experimental success using mesenchymal stem cells in rat models to promote healing; however, the mechanisms providing this benefit are not known. We investigated in vitro the paracrine effects of human adipose-derived stem cells (ADSCs) on wound healing mechanisms for human tympanic membrane-derived keratinocytes (hTM) and immortalized human keratinocytes (HaCaT). ADSC conditioned media (CM ADSC ) were assessed for paracrine activity on keratinocyte proliferation and migration, with hypoxic conditions for ADSC culture used to generate contrasting effects on cytokine gene expression. Keratinocytes cultured in CM ADSC showed a significant increase in cell number compared to serum-free cultures and further significant increases in hypoxic CM ADSC . Assessment of ADSC gene expression on a cytokine array showed a range of wound healing cytokines expressed and under stringent hypoxic and serum-free conditions was upregulated (VEGF A, MMP9, Tissue Factor, PAI-1) or downregulated (CXCL5, CCL7, TNF-α). Several of these may contribute to the activity of conditioned media on the keratinocytes with potential applications in TM perforation repair. VEGFA protein was confirmed by immunoassay to be increased in conditioned media. Together with gene regulation associated with hypoxia in ADSCs, this study has provided several strong leads for a stem cell-derived approach to TM wound healing.

Improving outcomes in patients with psoriasis.

PubMed

Tidman, Michael J

2013-01-01

Psoriasis is a heterogeneous inflammatory disorder that targets the skin and joints. It affects 1.3-2% of the population. The diagnosis of plaque psoriasis is usually straightforward, a helpful diagnostic clue is the tendency for silver scales to appear after gentle scratching of a lesion. Stress, streptococcal infection and drugs including beta-blockers, antimalarials and lithium may precipitate or exacerbate psoriasis. Psoriasis, especially when severe, predisposes to metabolic syndrome, and patients with psoriasis are at increased risk of ischaemic heart disease, hypertension, stroke, type 2 diabetes and hyperlipidaemia. Additionally, psoriasis sufferers appear at increased risk of uveitis, inflammatory boweldisease, lymphoma, non-melanoma skin cancer, COPD and venous thromboembolism. Psoriasis should be assessed on the basis of: severity, impact on physical, psychological and social wellbeing, symptoms of arthritis and the presence of comorbidities. Poor response to topical therapy may be as much to do with lack of compliance as with lack of efficacy. The number of treatments each day should be kept to a minimum, and patients should be reviewed after four weeks when initiating or changing topical therapy to improve adherence to treatment and assess response. The majority of patients with psoriasis can be managed in primary care, although specialist care may be necessary at some point in up to 60% of cases. Patients with erythrodermic or generalised pustular psoriasis should be referred for a same day dermatological opinion, and if psoriatic arthritis is suspected, early referral for a rheumatological opinion is recommended.

Impact of depressive symptoms on oxidative stress in patients with psoriasis.

PubMed

Karababa, Fatih; Yesilova, Yavuz; Turan, Enver; Selek, Salih; Altun, Hacer; Selek, Sahabettin

2013-01-01

Depression and anxiety disorders often accompany psoriasis. Increased reactive oxygen radicals and impaired antioxidant systems are considered to play a role both in psoriasis and depression and anxiety disorders. Accordingly, in this study, we aimed to investigate the effects of depressive and anxiety symptoms on oxidative stress in patients with psoriasis. Hospital Anxiety and Depression Scale (HADS) forms were completed by 39 psoriasis patients and 25 volunteer controls. Serum total antioxidant capacity (TAC) and total oxidant capacity (TOC) parameters were analysed in serum samples, after which oxidative stress index (OSI) was calculated in whole study population. Laboratory data were analysed with a Kruskal-Wallis test to determine the severity of HADS and the presence of psoriasis among four groups. The psoriasis patients had higher HADS scores, higher OSI and TOC levels, and lower TAC levels compared with the control group. Comparison among four groups with/without psoriasis and higher/lower HADS scores revealed statistically significant differences with regard to TAC (Kruskal-Wallis P = 0.0047) and TOC (Kruskal-Wallis P < 0.001) levels and OSI (Kruskal-Wallis P < 0.001); the difference was mainly based on the difference between cases with and without psoriasis and on HADS scores in control subjects (P < 0.05 for post hoc comparisons). TAC, TOC, and OSI levels did not differ significantly in psoriasis patients with regard to higher or lower HADS scores. Based on the findings of this study, the presence of either psoriasis or higher HADS scores in the control subjects was associated with increased oxidative stress, whereas presence of higher HADS scores did not lead to further increase in oxidative stress in psoriatic patients.

Differential Gene Expression in Primary Human Skin Keratinocytes and Fibroblasts in Response to Ionizing Radiation

PubMed Central

Warters, Raymond L.; Packard, Ann T.; Kramer, Gwen F.; Gaffney, David K.; Moos, Philip J.

2009-01-01

Although skin is usually exposed during human exposures to ionizing radiation, there have been no thorough examinations of the transcriptional response of skin fibroblasts and keratinocytes to radiation. The transcriptional response of quiescent primary fibroblasts and keratinocytes exposed to from 10 cGy to 5 Gy and collected 4 h after treatment was examined. RNA was isolated and examined by microarray analysis for changes in the levels of gene expression. Exposure to ionizing radiation altered the expression of 279 genes across both cell types. Changes in RNA expression could be arranged into three main categories: (1) changes in keratinocytes but not in fibroblasts, (2) changes in fibroblasts but not in keratinocytes, and (3) changes in both. All of these changes were primarily of p53 target genes. Similar radiation-induced changes were induced in immortalized fibroblasts or keratinocytes. In separate experiments, protein was collected and analyzed by Western blotting for expression of proteins observed in microarray experiments to be overexpressed at the mRNA level. Both Q-PCR and Western blot analysis experiments validated these transcription changes. Our results are consistent with changes in the expression of p53 target genes as indicating the magnitude of cell responses to ionizing radiation. PMID:19580510

Scleroderma keratinocytes promote fibroblast activation independent of transforming growth factor beta.

PubMed

McCoy, Sara S; Reed, Tamra J; Berthier, Celine C; Tsou, Pei-Suen; Liu, Jianhua; Gudjonsson, Johann E; Khanna, Dinesh; Kahlenberg, J Michelle

2017-11-01

SSc is a devastating disease that results in fibrosis of the skin and other organs. Fibroblasts are a key driver of the fibrotic process through deposition of extracellular matrix. The mechanisms by which fibroblasts are induced to become pro-fibrotic remain unclear. Thus, we examined the ability of SSc keratinocytes to promote fibroblast activation and the source of this effect. Keratinocytes were isolated from skin biopsies of 9 lcSSc, 10 dcSSc and 13 control patients. Conditioned media was saved from the cultures. Normal fresh primary fibroblasts were exposed to healthy control and SSc keratinocyte conditioned media in the presence or absence of neutralizing antibodies for TGF-β. Gene expression was assessed by microarrays and real-time PCR. Immunocytochemistry was performed for α-smooth muscle actin (α-SMA), collagen type 1 (COL1A1) and CCL5 expression. SSc keratinocyte conditioned media promoted fibroblast activation, characterized by increased α-SMA and COL1A1 mRNA and protein expression. This effect was independent of TGF-β. Microarray analysis identified upregulation of nuclear factor κB (NF-κB) and downregulation of peroxisome proliferator-activated receptor γ (PPAR-γ) pathways in both SSc subtypes. Scleroderma keratinocytes exhibited increased expression of NF-κB-regulated cytokines and chemokines and lesional skin staining confirmed upregulation of CCL5 in basal keratinocytes. Scleroderma keratinocytes promote the activation of fibroblasts in a TGF-β-independent manner and demonstrate an imbalance in NF-κB1 and PPAR-γ expression leading to increased cytokine and CCL5 production. Further study of keratinocyte mediators of fibrosis, including CCL5, may provide novel targets for skin fibrosis therapy. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com