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ABSTRACT: BACKGROUND: MicroRNA (miRNA) is an upcoming research area and quantitative reverse transcriptase in real-time (qPCR) is an important tool in the investigation. The small non-coding RNA candidates used for normalization in psoriatic skin biopsies have never been sufficiently validated. OBJECTIVES: To identify a reliable normalization method for miRNA analysis with qPCR in psoriatic skin. METHODS: 5 miRNA candidates previously used for normalization in psoriatic skin were identified through search in the literature. 5 new candidates were uncovered using the NormFinder algorithm on miRNA microArray data. The candidates were validated in paired psoriatic biopsies, biopsies from patients during treatment and normal healthy skin with qPCR. The stability of the miRNAs was determined with NormFinder and geNorm. The dispersion of data was determined before and after use of different normalization approaches. RESULTS: In lesional and nonlesional skin the two algorithms ranked the candidates similarly with an excellent correlation (R(2) =0.95). miR-26a had the best stability, whereas the commonly used RNU48 had less favourable stability. The same results were seen within the dispersion of the data, including biopsies from lesional, nonlesional, treated psoriatic skin and normal healthy skin. CONCLUSIONS: This is the first study to validate the reliability of miRNA candidates for normalization by qPCR in psoriatic skin. From this study we conclude that miR-26a is the best candidates and better than those previously used. miR-26a can be used for miRNA normalization in future studies with psoriatic skin. This article is protected by copyright. All rights reserved.
British Journal of Dermatology 04/2013; · 3.67 Impact Factor
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ABSTRACT: Background: The Jak/STAT signalling pathway is known to play an important role in many cellular processes including inflammation. The activation of STAT1 is dependent on tyrosine701 and serine727 phosphorylation, which leads to the formation of the STAT dimer and modulation of STAT1 activity, respectively. Objective: The aim of this study was to determine STAT1 expression and activation in psoriatic skin. Methods: Biopsies were collected from psoriatic patients. mRNA expression was evaluated by qPCR whereas the protein and phosphorylation level of STAT1 were evaluated by Western blotting. STAT1 localization was determined by immunofluorescence analysis and STAT1-induced transcriptional activity was analysed in cultured human keratinocytes by a reporter assay. Results: The expression of STAT1 was demonstrated to be significantly increased at both mRNA and protein level in lesional psoriatic skin. In addition, the phosphorylation level of STAT1(Tyr701) and STAT1(Ser727) was significantly increased in lesional compared with nonlesional psoriatic skin. Luciferase assays showed a significant induction of the STAT1-induced transcriptional activity when stimulating cultured human keratinocytes with either IFNα or IFNγ. STAT1(Ser727) phosphorylation induced by IFNα, IFNγ or UVB was mediated by a PKCδ and p38 MAPK dependent mechanism in human keratinocytes, whereas IFNα-induced STAT1(Tyr701) phosphorylation was mediated by a PKCδ dependent mechanism. Conclusions: This study demonstrates for the first time that the phosphorylation level of STAT1(Tyr701) and STAT1(Ser727) is increased in lesional psoriatic skin. In addition, specific signalling pathways leading to this phosphorylation have been identified. Together, our data indicate an important role of STAT1 in the pathogenesis of psoriasis.
British Journal of Dermatology 09/2012; · 3.67 Impact Factor
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ABSTRACT: Background: The p38 mitogen-activated protein kinase (MAPK) plays an important role in inflammatory processes and displays increased activity in psoriasis. The dual specificity phosphatase 1 (DUSP1) is an important negative regulator of p38 MAPK activity. Objectives: To study mRNA expression of DUSP1 in normal human epidermal keratinocytes (NHEKs) stimulated with proinflammatory cytokines and to investigate DUSP1 in psoriatic skin. Methods: NHEKs were cultured in vitro and punch biopsies were obtained from the skin of patients with psoriasis vulgaris and atopic dermatitis. mRNA expression was analysed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: In NHEKs IL-1β induced DUSP1 mRNA expression in a rapid and time-dependent manner through the p38 MAPK/mitogen- and stress activated kinase (MSK) signalling pathway. DUSP1 mRNA expression was demonstrated to be significantly downregulated in psoriatic skin lesions as compared with paired samples of nonlesional psoriatic skin. This was in contrast to atopic dermatitis. The downregulation of DUSP1 mRNA in lesional psoriatic skin was not explained by difference in the mRNA expression of the potential DUSP1 transcript stability-affecting proteins Hu antigen R (HuR) or tristetraprolin (TTP). Furthermore, DUSP1 mRNA expression was demonstrated not to increase during the early course of treatment with the anti-TNF-α antibody adalimumab. Conclusions: In lesional psoriatic skin the p38 MAPK negative feedback mechanism provided by DUSP1 seems to be inhibited. Downregulation of DUSP1 may contribute to the sustained inflammatory response seen in psoriasis.
British Journal of Dermatology 08/2012; · 3.67 Impact Factor
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ABSTRACT: Background Topical nitrogen mustard is a chemotherapeutic agent used in treatment of mycosis fungoides (MF). Objective To evaluate the response and side effects in patients with MF and parapsoriasis treated with topical nitrogen mustard. Methods A retrospective study of treatment response in 116 patients diagnosed with MF and 71 patients with parapsoriasis and treated with topical nitrogen mustard from 1991 to 2009. Results Overall response rate and complete response (CR) rate was 91.4% and 53.4% in patients with MF and 90.1% and 40.8% in patients with parapsoriasis, respectively. Relapse following CR was observed in 67.7% in patients with MF and 62.1% in patients with parapsoriasis. Freedom-from-relapse was higher in patients with T1-T2 than in T3 disease (P < 0.01). Progressive disease (PD) occurred in 25.0% and 26.8% in patients with MF and parapsoriasis, respectively. Progression-free survival was similar in patients with T1-T2 compared with T3 (P = 0.79) and T4 disease (P = 0.22) and lower in patients with parapsoriasis with <10% than >10% skin involvement (P = 0.05). Conclusion The present study confirms that topical nitrogen mustard is a safe and effective therapy. The treatment response in patients with parapsoriasis was not statistically different from the response in patients with MF. This supports, that parapsoriasis is not a distinct entity, but an early stage of MF. Nitrogen mustard should therefore still be considered as an important treatment modality in patients with early stages (parapsoriasis) and later stages of MF either as monotherapy or in combination with other topical or systemic therapies.
Journal of the European Academy of Dermatology and Venereology 01/2012; · 2.98 Impact Factor
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ABSTRACT: Langerhans cell histiocytosis (LCH) is characterized by abnormal proliferation and infiltration of Langerhans cells in different organs. The skin is frequently involved either as unisystem or multisystem disease.
To review the clinical response and side-effects of nitrogen mustard therapy in LCH in children and adults with unisystem or multisystem disease.
This retrospective study includes 10 children and four adults with LCH, treated with nitrogen mustard from 1975 to 2010. The median extent of skin involvement was 46% (range 5-100%).
Overall, 13 patients had complete or partial response. Although eight patients achieved a complete response with a median time of 12·3months (range 36 days to 1·9 years), six of these patients ultimately relapsed. One patient, who had unisystem disease limited to the skin, initially showed progression of her cutaneous lesions with nitrogen mustard treatment. Although subsequently the cutaneous lesions completely regressed, concomitant systemic involvement was noted. Four other patients similarly experienced improvement of their skin lesions with treatment, but also exhibited progression of the LCH systemically. The patients were treated with other therapies prior and adjunctive to nitrogen mustard. However, five patients had progression to other organs, despite regression of skin lesions, which supports that the treatment effect in the skin is related to topical nitrogen mustard. Six patients developed contact dermatitis to nitrogen mustard.
Topical nitrogen mustard can be an effective and safe therapy in both children and adults with cutaneous LCH, although relapses are common.
British Journal of Dermatology 10/2011; 166(3):642-5. · 3.67 Impact Factor
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ABSTRACT: Total skin electron beam therapy (TSEBT) is a powerful treatment for cutaneous T-cell lymphoma (CTCL). Based on the occurrence of relapses with low radiation doses, doses of 30-36Gy are commonly used but most patients still eventually relapse and repeat treatment courses are limited due to the cumulative toxicity. Complete response (CR) rates are about 60-90% for T2-4 stages with a 5-year relapse-free survival of 10-25% for stages IB-III.
To evaluate prospectively the efficacy of low-dose TSEBT (10Gy) in terms of complete cutaneous response rate, overall response rate and response duration in CTCL.
Ten patients with stage IB-IV mycosis fungoides (MF) were treated in an open-label manner with four fractions of TSEBT 1Gy weekly to a total skin dose of 10Gy. Treatment responses were assessed at 1 and 3months after treatment and subsequently at least every 6months for a total period of 2years or to disease relapse or progression.
Patients achieved an overall response rate of 90%. The rate of CR or very good partial response (VGPR; <1% skin affected with patches/plaques) was 70%. The median response duration was 5·2months (range 83-469days) for CR and VGPR. Adverse effects were generally mild to moderate in severity.
Low-dose TSEBT (10Gy) gave a satisfactory response rate and was well tolerated in patients with MF stage IB-IV. Future studies should determine if the combination of low-dose TSEBT with other agents could increase the rate of CR and response duration.
British Journal of Dermatology 10/2011; 166(2):399-404. · 3.67 Impact Factor
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ABSTRACT: Dimethylfumarate (DMF) is used in the treatment of psoriasis. Macrophage migration inhibitory factor (MIF) is elevated in patients with severe psoriasis. We studied the effect of DMF on the MIF-induced activation of the mitogen- and stress-activated kinase 1 (MSK1) and p90 kDa ribosomal S6 kinase (RSK1) signaling pathways which regulate the proliferation of human keratinocytes via transcription factors.
The effects of DMF on the MIF-induced activation of MSK1, RSK1, cAMP-responsive element-binding protein (CREB), Cox-2 and c-Jun, JunB and p53 were studied by Western blotting using phospho-specific antibodies.
DMF inhibited the MIF-induced phosphorylation of MSK1, RSK1, CREB and JunB, and reduced Cox-2 expression and the proliferation of cultured human keratinocytes. The expression of p-p53 (S15) was induced simultaneously with the inhibition of Cox-2. Addition of DMF before MIF induced nuclear expression of p-c-Jun (S63) and c-Jun. Transfection with small interfering MSK1 and RSK1 RNA before MIF incubation stimulated p-p53 (S15) and nuclear p-c-Jun (S63) similarly to DMF.
Our results indicate that the specific inhibitory effects of DMF on RSK1 and MSK1 activation together with the induction of p-c-Jun (S63) and p-p53 (S15) lead to the inhibition of keratinocyte proliferation, partly explaining the anti-psoriatic effect of DMF.
Agents and Actions 02/2011; 60(7):643-53. · 1.59 Impact Factor
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ABSTRACT: Anti-TNFα therapies are well established for severe psoriasis; however, their mechanism of action in disease resolution is not fully understood. p38 mitogen-activated protein kinase (MAPK) is a kinase known to play a key role in the pathogenesis of psoriasis.
To elucidate the early effects of adalimumab, a human monoclonal anti-TNFα antibody, on the expression of interleukins in psoriatic skin.
Biopsies from patients with psoriasis were examined before and after the start of adalimumab therapy. mRNA expression of cytokines were measured with quantitative polymerase chain reaction. p38 MAPK and signal transducer and activator of transcription 3 (STAT3) were analysed by Western blotting and immunofluorescence analyses, and IL-17A and IL-17C were examined with immunohistochemistry.
The increased mRNA level of IL-1β, IL-8, IL-17C and IL-20 in lesional psoriatic skin was already significantly reduced 4 days after the start of adalimumab treatment, i.e. before clinical and histological improvement was detectable. The mRNA expression of the Th17-derived cytokines IL-17A, IL-17F and IL-22 as well as the dendritic cell product IL-23/IL-12 (p40) were not significantly reduced until 2 weeks after the start of treatment, whereas the mRNA expression of IL-23 (p19) and the Th1 cytokines IFN-γ and IL-2 were reduced late in disease resolution. IL-1β, IL-8 and IL-20 are all known to be regulated by p38 MAPK. IL-17C was produced by cultured human keratinocytes and this production was also mediated by a p38 MAPK dependent mechanism. Moreover, the early effects of adalimumab included the phosphorylation of p38 MAPK, but not STAT3 phosphorylation.
This study indicates that an important mechanism of action of anti-TNFα therapy in psoriasis is a reduction in p38 MAPK phosphorylation and a subsequent decrease in the expression of p38 MAPK regulated genes.
British Journal of Dermatology 12/2010; 163(6):1194-204. · 3.67 Impact Factor
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ABSTRACT: Background Anti-TNFα therapies are well established for severe psoriasis; however, their mechanism of action in disease resolution is not fully understood. p38 mitogen-activated protein kinase (MAPK) is a kinase known to play a key role in the pathogenesis of psoriasis.Objectives To elucidate the early effects of adalimumab, a human monoclonal anti-TNFα antibody, on the expression of interleukins in psoriatic skin.Patients and methods Biopsies from patients with psoriasis were examined before and after the start of adalimumab therapy. mRNA expression of cytokines were measured with quantitative polymerase chain reaction. p38 MAPK and signal transducer and activator of transcription 3 (STAT3) were analysed by Western blotting and immunofluorescence analyses, and IL-17A and IL-17C were examined with immunohistochemistry.Results The increased mRNA level of IL-1β, IL-8, IL-17C and IL-20 in lesional psoriatic skin was already significantly reduced 4 days after the start of adalimumab treatment, i.e. before clinical and histological improvement was detectable. The mRNA expression of the Th17-derived cytokines IL-17A, IL-17F and IL-22 as well as the dendritic cell product IL-23/IL-12 (p40) were not significantly reduced until 2 weeks after the start of treatment, whereas the mRNA expression of IL-23 (p19) and the Th1 cytokines IFN-γ and IL-2 were reduced late in disease resolution. IL-1β, IL-8 and IL-20 are all known to be regulated by p38 MAPK. IL-17C was produced by cultured human keratinocytes and this production was also mediated by a p38 MAPK dependent mechanism. Moreover, the early effects of adalimumab included the phosphorylation of p38 MAPK, but not STAT3 phosphorylation.Conclusions This study indicates that an important mechanism of action of anti-TNFα therapy in psoriasis is a reduction in p38 MAPK phosphorylation and a subsequent decrease in the expression of p38 MAPK regulated genes.
British Journal of Dermatology 11/2010; 163(6):1194 - 1204. · 3.67 Impact Factor
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ABSTRACT: The pathogenesis of psoriasis and the mechanisms of action of antitumour necrosis factor (TNF)-α therapies are incompletely understood.
To investigate the early molecular effects of adalimumab in psoriatic skin.
Biopsies taken from patients with psoriasis were examined before and after the onset of adalimumab therapy. TNF-α protein level and mRNA expression were measured by enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction, respectively. The activities of p38 mitogen-activated protein kinase (MAPK) and extracellular regulated kinase 1 and 2 (ERK1/2) as well as the downstream kinases MAPK-activated protein kinase 2 (MK2) and mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2) were measured by Western blot analyses.
We demonstrated that clinical and histological improvements were detected from day 14. The increased activity of p38 MAPK in lesional psoriatic skin was significantly inhibited by adalimumab already at day 4. The activities of ERK1/2, MSK1/2 and MK2 were reduced at the end of study (day 84) when the level of TNF-α in lesional psoriatic skin reached the nonlesional level, and the Psoriasis Area and Severity Index score was reduced.
The rapid inhibition of p38 MAPK by adalimumab in lesional psoriatic skin preceded clinical and histological improvements, demonstrating an association between TNF-α neutralization and p38 MAPK inhibition. Thus, inhibition of p38 MAPK may be a novel mechanism by which adalimumab mediates its antipsoriatic effect.
British Journal of Dermatology 03/2010; 162(6):1216-23. · 3.67 Impact Factor
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ABSTRACT: Overexpression of the eukaryotic initiation factor (eIF) 4E results in increased translation of mRNAs encoding proteins involved in cell cycle control, proliferation, apoptosis and angiogenesis. Phosphorylation of eIF4E is conducted by MAP kinase interacting serine/threonine kinase 1 and 2, and phosphorylation of eIF4E has previously been associated with increased release of proinflammatory cytokines from keratinocytes. The actions of eIF4E are counteracted by the eIF4E-binding protein 1 (4E-BP1).
To characterize the mRNA and protein expression of eIF4E, as well as the phosphorylation of eIF4E in psoriatic skin.
Biopsies were collected from patients with psoriasis. mRNA expression and protein levels of eIF4E were evaluated by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. eIF4E distribution was determined by immunofluorescence analysis.
We found a significant increase in mRNA expression and protein level of eIF4E in lesional as compared with nonlesional psoriatic skin. Immunofluorescence analysis demonstrated that eIF4E was located throughout the epidermis and was primarily cytoplasmic in distribution. The level of phosphorylated eIF4E protein was found to be strongly upregulated, and 4E-BP1 expression was also increased.
We have demonstrated for the first time that the level of total and phosphorylated eIF4E and the expression of 4E-BP1 are increased in lesional psoriatic skin. As eIF4E-regulated proteins have been reported to be upregulated in psoriasis, it appears that the increase in eIF4E is only incompletely counteracted by 4E-BP1. Therefore, eIF4E might contribute to the pathogenesis of psoriasis.
British Journal of Dermatology 06/2009; 161(5):1059-66. · 3.67 Impact Factor
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British Journal of Dermatology 04/2009; 160(6):1359-61. · 3.67 Impact Factor
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ABSTRACT: Th17 cells are a lineage of proinflammatory T helper cells producing interleukin (IL)-17. The importance of Th17 cells in inflammation and autoimmunity has now been recognized. The IL-17 cytokine family consists of six isoforms (IL-17A-IL-17F) whereas five members of the IL-17 receptor (IL-17R) family have been identified (IL-17RA-IL-17RE).
To characterize the expression of the IL-17 isoforms and receptors in lesional and nonlesional psoriatic skin. Methods Keratome and punch biopsies taken from patients with psoriasis were examined by enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction in order to measure the IL-17 isoforms and receptors.
We demonstrated significantly increased mRNA expression of IL-17A, IL-17C and IL-17F in psoriatic skin. In contrast, the mRNA expression of IL-17B and IL-17D was significantly decreased in lesional compared with nonlesional skin, while IL-17E mRNA was undetectable. The increased mRNA expression of IL-17A, IL-17C and IL-17F was paralleled by an increased protein accumulation of these cytokines in psoriatic skin. Analysis of the IL-17R mRNA expression revealed significantly impaired mRNA expression of IL-17RB, IL-17RC, IL-17RD and IL-17RE in lesional psoriatic skin, whereas the mRNA expression of IL-17RA was similar in lesional and nonlesional psoriatic skin.
This study characterizes the mRNA profile of the IL-17 isoforms and receptors in psoriatic skin lesions. Furthermore, we demonstrate for the first time augmented protein levels of IL-17A, IL-17C and IL-17F in psoriatic skin lesions, indicating a possible role for IL-17C in addition to IL-17A and IL-17F in the pathogenesis of psoriasis.
British Journal of Dermatology 11/2008; 160(2):319-24. · 3.67 Impact Factor
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ABSTRACT: It is reported that Nuclear factor-kappaB (NF-kappaB) activation is dysregulated in chronic inflammatory diseases like psoriasis, rheumatoid arthritis and cancer, resulting in an over expression of pro-inflammatory cytokines and an inhibition of apoptosis. We studied NF-kappaB activation and the induction of interleukin 8 (IL-8) and p53 gene expression in an interleukin 1beta (IL-1beta) stimulated HepG2 cell line.
NF-kappaB induced IL-8 and p53 protein production was studied using specific siRNA, an IkappaB kinase 2 inhibitor, and mitogen activated protein kinase (MAPK) inhibitors. Results were analyzed by different techniques including Western blotting and ELISA.
IL-1beta induced both the IL-8 and p53 mRNA expression and protein production of IL-8, but not p53. Knockdown of NF-kappaB p65 expression with siRNA strongly reduced IL-8 production and significantly induced protein levels of p53. An IkappaB kinase 2 inhibitor, sc514, also strongly reduced IL-8 and significantly induced p53 protein levels. Using three MAPK inhibitors we showed that p38 MAPK and JNK dependent mechanisms are involved in the regulation of the IL-8 and p53 protein expression.
Our results indicate that IL-8 and p53 protein expression is regulated through inverse activation of the p38 MAPK and the JNK pathways and the NF-kappaB p65 expression.
Inflammation Research 08/2008; 57(7):329-39. · 2.11 Impact Factor
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ABSTRACT: Interleukin (IL)-20 and IL-19 are recently discovered members of the IL-10 family of cytokines. The skin of transgenic mice overexpressing IL-20 shows histological changes resembling some of those seen in psoriasis, i.e. thickened epidermis, hyperkeratosis and a compact stratum corneum. IL-19 and IL-20, as well as their receptor complexes, IL-20Ralpha/IL-20Rbeta and IL-22Ralpha/IL-20Rbeta, are expressed in human skin.
To study the dynamics of IL-19 and IL-20 gene expression as well as the expression of their receptor subunits in psoriatic skin lesions.
Punch biopsies from patients with plaque-type psoriasis were collected before, during and after 28 days of treatment with either calcipotriol or ciclosporin (CsA). IL-20, IL-19, IL-20Ralpha, IL-20Rbeta and IL-22Ralpha mRNA expression were determined by quantitative reverse transcriptase-polymerase chain reaction.
We found IL-19 and IL-20 mRNA expression in lesional psoriatic skin to be strongly upregulated compared with nonlesional psoriatic skin by a factor of 65 and 22, respectively. In contrast to previous reports, IL-20Ralpha and IL-20Rbeta mRNA levels showed a modest but statistically significant decrease in lesional psoriatic skin compared with nonlesional psoriatic skin. During treatment with calcipotriol or CsA, IL-19 and IL-20 mRNA levels decrease in accordance with the clinical improvement of psoriasis. Neither IL-19, IL-20, nor receptor subunit mRNA expression in lesional psoriatic skin reaches the levels of nonlesional skin during this short-term treatment. These findings are in line with the residual disease activity observed at the end of treatment.
The increased IL-19 and IL-20 mRNA expression levels in lesional psoriatic skin suggest that these two cytokines play a role in the pathogenesis of psoriasis. An imbalance in the receptor complexes for IL-19 and IL-20 might contribute to their suspected pathogenic effects.
British Journal of Dermatology 12/2005; 153(5):911-8. · 3.67 Impact Factor
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ABSTRACT: Background Interleukin (IL)-20 and IL-19 are recently discovered members of the IL-10 family of cytokines. The skin of transgenic mice overexpressing IL-20 shows histological changes resembling some of those seen in psoriasis, i.e. thickened epidermis, hyperkeratosis and a compact stratum corneum. IL-19 and IL-20, as well as their receptor complexes, IL-20Rα/IL-20Rβ and IL-22Rα/IL-20Rβ, are expressed in human skin.Objectives To study the dynamics of IL-19 and IL-20 gene expression as well as the expression of their receptor subunits in psoriatic skin lesions.Methods Punch biopsies from patients with plaque-type psoriasis were collected before, during and after 28 days of treatment with either calcipotriol or ciclosporin (CsA). IL-20, IL-19, IL-20Rα, IL-20Rβ and IL-22Rα mRNA expression were determined by quantitative reverse transcriptase–polymerase chain reaction.Results We found IL-19 and IL-20 mRNA expression in lesional psoriatic skin to be strongly upregulated compared with nonlesional psoriatic skin by a factor of 65 and 22, respectively. In contrast to previous reports, IL-20Rα and IL-20Rβ mRNA levels showed a modest but statistically significant decrease in lesional psoriatic skin compared with nonlesional psoriatic skin. During treatment with calcipotriol or CsA, IL-19 and IL-20 mRNA levels decrease in accordance with the clinical improvement of psoriasis. Neither IL-19, IL-20, nor receptor subunit mRNA expression in lesional psoriatic skin reaches the levels of nonlesional skin during this short-term treatment. These findings are in line with the residual disease activity observed at the end of treatment.Conclusions The increased IL-19 and IL-20 mRNA expression levels in lesional psoriatic skin suggest that these two cytokines play a role in the pathogenesis of psoriasis. An imbalance in the receptor complexes for IL-19 and IL-20 might contribute to their suspected pathogenic effects.
British Journal of Dermatology 10/2005; 153(5):911 - 918. · 3.67 Impact Factor
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ABSTRACT: Alterations in specific signal transduction pathways may explain the hyperproliferation and abnormal differentiation of the keratinocytes as well as the increased expression of inflammatory cytokines seen in psoriasis. Major signalling pathways used by eukaryotic cells to transduce extracellular signals into cellular responses impinge on the mitogen-activated protein kinases (MAPKs).
To investigate the expression of the MAPK p38, extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) in psoriatic skin.
Keratome biopsies were taken from patients with plaque-type psoriasis. Western blot analysis was used to determine p38, ERK and JNK activity and protein levels, whereas kinase assays were used to examine the kinase activity of p38.
We demonstrated increased levels of the phosphorylated forms of p38 and ERK1/2 in lesional psoriatic skin compared with nonlesional psoriatic skin. No abnormality was found in the activation and expression of JNK1/2. Ex vivo kinase assays confirmed the increased activation of p38, and furthermore demonstrated increased kinase activity of the p38 isoforms p38alpha, p38beta and p38delta in lesional compared with nonlesional psoriatic skin. p38gamma was not detected in the psoriatic skin. Clearance of the psoriatic lesions, induced by climatotherapy at the Dead Sea for 4 weeks, led to a normalization in the activity of both p38 and ERK1/2.
Taken together, our results demonstrate that the activity of the MAPKs p38alpha, p38beta and p38delta and ERK1/2 are increased in lesional psoriatic skin compared with nonlesional psoriatic skin, and that clearance of psoriasis normalizes the p38 and ERK1/2 activity. Thus, p38 and ERK1/2 might be potential targets in the treatment of psoriasis.
British Journal of Dermatology 02/2005; 152(1):37-42. · 3.67 Impact Factor
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ABSTRACT: Psoriasis is a common benign skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes. The transcription factor activator protein 1 (AP-1) is known to play an important role in cell proliferation and differentiation.
To investigate AP-1 DNA binding activity in psoriatic skin.
Keratome biopsies were taken from patients with plaque-type psoriasis. Electrophoretic mobility shift assays were used to determine the AP-1 DNA binding activity, whereas Western and Northern blotting was used to determine Jun and Fos protein and mRNA expression.
We found that AP-1 DNA binding activity was almost completely abolished in lesional psoriatic skin compared with nonlesional psoriatic skin. Furthermore, experiments revealed that the protein and mRNA expression of the AP-1 subunits c-Fos, Fra-1 and c-Jun was reduced in lesional psoriatic skin compared with nonlesional psoriatic skin, whereas the protein and mRNA expression of the subunit JunB was increased. Topical application of the vitamin D analogue calcipotriol under occlusion to involved psoriatic skin for 4 days resulted in an increase in AP-1 DNA binding activity, and an increase in the protein and mRNA expression of c-Fos, Fra-1 and c-Jun, together with a decrease in JunB protein and mRNA expression.
Together, these results suggest that the activity of the transcription factor AP-1 is impaired in lesional psoriatic skin and that this impairment may be important for the disturbed epidermal growth observed in psoriasis.
British Journal of Dermatology 10/2004; 151(3):600-7. · 3.67 Impact Factor
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M Westergaard,
J Henningsen,
M L Svendsen,
C Johansen,
U B Jensen,
H D Schrøder,
I Kratchmarova,
R K Berge, L Iversen,
L Bolund,
K Kragballe,
K Kristiansen
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ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are pleiotropic regulators of growth and differentiation of many cell types. We have performed a comprehensive analysis of the expression of PPARs, transcriptional cofactors, and marker genes during differentiation of normal human keratinocytes using a combination of reverse transcriptase polymerase chain reaction, Northern and Western blotting, and immunohistochemistry. PPARdelta was the predominant PPAR subtype in human keratinocytes and highly expressed in basal cells and suprabasal cells. Induction of PPARalpha and PPARgamma expression was linked to differentiation, and accordingly, expression of PPARalpha and PPARgamma was in essence confined to suprabasal cells. Differentiation was not accompanied by significant changes in the expression of the coactivators CREB-binding protein, p300, steroid receptor coactivator 1, or the corepressors nuclear receptor corepressor and silence mediator for retinoid and thyroid hormone receptors. We critically evaluated the effects of selective PPAR ligands and a synthetic fatty acid analog, tetradecylthioacetic acid. Tetradecylthioacetic acid activated all human PPAR subtypes in the ranking order PPARdelta > PPARalpha > PPARgamma. All selective PPAR ligands marginally induced transglutaminase-1 expression with the PPARdelta-selective ligand L165041 being the most potent. The PPARalpha- and PPARgamma-selective ligands Wy14643 and BRL49653 had negligible effect on involucrin expression, whereas a dose-dependent induction was observed with L165041. Simultaneous addition of L165041 and BRL49653 synergistically induced strong involucrin expression. Additionally, L165041 potently induced CD36 mRNA expression. Administration of tetradecylthioacetic acid resulted in a dramatic decrease in proliferation and a robust upregulation of the expression of involucrin and transglutaminase. Our results indicate that tetradecylthioacetic acid may affect keratinocyte gene expression and differentiation via PPAR-dependent and PPAR-independent pathways, and that the latter play an important role.
Journal of Investigative Dermatology 05/2001; 116(5):702-12. · 6.31 Impact Factor
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Prostaglandins & other lipid mediators 12/2000; 63(1-2):25-42. · 2.70 Impact Factor
