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Leptin is an adipocyte-derived cytokine secreted mostly by adipose tissue. Serum leptin levels are elevated in obese individuals and correlate positively with body mass index (BMI). Interestingly, serum leptin levels are also elevated in patients with psoriasis and correlate positively with disease severity. Psoriasis is associated with obesity; patients with psoriasis have a higher incidence of obesity, and obese individuals have a higher risk of developing psoriasis. Additionally, obese patients with psoriasis experience a more severe degree of psoriasis. In this study, we hypothesised that leptin may link psoriasis and obesity and plays an aggravating role in psoriasis. To investigate leptin's role in psoriasis, we applied the widely accepted imiquimod (IMQ)-induced psoriasis-like skin inflammation mouse model on leptin-deficient ( ob/ob) mice and evaluated psoriasis severity. Moreover, we stimulated human keratinocytes with leptin and investigated the effect on proliferation and expression of pro-inflammatory proteins. In ob/ob mice, clinical signs of erythema, infiltration and scales in dorsal skin and inflammation in ear skin, as measured by ear thickness, were attenuated and compared with wt mice. Moreover, IL-17A and IL-22 mRNA expression levels, as well as increased epidermal thickness, were significantly less induced. In vitro, the effect of leptin stimulation on human keratinocytes demonstrated increased proliferation and induced secretion of several pro-inflammatory proteins; two hallmarks of psoriasis. In conclusion, leptin deficiency attenuated IMQ-induced psoriasis-like skin inflammation in a mouse model, and leptin stimulation induced a pro-inflammatory phenotype in human keratinocytes, thus, supporting an aggravating role of leptin in psoriasis. [ABSTRACT FROM AUTHOR]

The epidermal-derived "alarmins" high-mobility group box 1 (HMGB1) protein and interleukin-33 (IL-33) are upregulated in patients with atopic dermatitis. However, their capacity as pro-inflammatory cytokines and their derived effects on skin barrier regulation are poorly elucidated. We investigated the impact of HMGB1 and IL-33 on gene transcription, protein expression and epidermal differentiation across 3 distinct keratinocyte in vitro models. Primary keratinocytes from healthy donors were used in submerged monolayer cultures, 3D human epidermis equivalents and 3D human skin equivalents. All keratinocyte models underwent 96-h stimulation with HMGB1 (100 μM) or IL-33 (100 ng/ml) using IL-4 (50 ng/ml) as positive control of regulation and vehicle as negative control. We found that HMGB1 and IL-33 downregulated transcription of several genes from members of the epidermal differentiation complex, including filaggrin. Furthermore, HMGB1 downregulated the expression of the encoded proteins in the upper epidermis. Finally, IL-33 and HMGB1 ultimately led to impaired epidermal growth and maturation. In conclusion, HMGB1 and IL-33 could play a significant role in the atopic dermatitis pathophysiology due to negative regulation of structural proteins, stratum corneum formation and epidermal growth. [ABSTRACT FROM AUTHOR]

Psoriasis is a common immune-mediated, chronic, inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although TNFα- and IL-17A-targeting drugs have recently proven to be highly effective, the molecular mechanism underlying the pathogenesis of psoriasis remains poorly understood. We found that expression of the atypical IκB member IκB (inhibitor of NF-κB) ζ, a selective coactivator of particular NF-κB target genes, was strongly increased in skin of patients with psoriasis. Moreover, in human keratinocytes IκBζ was identified as a direct transcriptional activator of TNFα/IL-17A-inducible psoriasis-associated proteins. Using genetically modified mice, we found that imiquimod-induced psoriasis-like skin inflammation was completely absent in IκBζ-deficient mice, whereas skin inflammation was still inducible in IL-17A- and TNFα-deficient mice. IκBζ deficiency also conferred resistance against IL-23-induced psoriasis. In addition, local abrogation of IκBζ function by intradermal injection of IκBζ siRNA abolished psoriasis-like skin inflammation. Taken together, we identify IκBζ as a hitherto unknown key regulator of IL-17A-driven effects in psoriasis. Thus, targeting IκBζ could be a future strategy for treatment of psoriasis, and other inflammatory diseases for which IL-17 antagonists are currently tested in clinical trials. [ABSTRACT FROM AUTHOR]

The antimicrobial peptide S100A8 is known to be upregulated in lesional psoriatic skin compared with non-lesional psoriatic skin and is believed to play a role in the pathogenesis of psoriasis. However, little is known about the signalling pathways involved in the regulation of S100A8 expression. Using quantitative real-time RT- PCR analysis, we demonstrated that stimulation with TNFα and IL-17A in combination resulted in a significant and synergistic induction of S100A8 mRNA in human keratinocytes. TNFα and IL-17A also induced the S100A8 promoter activity synergistically. This was demonstrated by a gene reporter assay in cells transfected with a luciferase plasmid construct, consisting of 3502 base pairs of the human S100A8 promoter. The TNFα- and IL-17A-mediated induction of S100A8 mRNA and protein was mediated by a p38 MAPK-dependent mechanism, as demonstrated by the use of a p38 MAPK inhibitor. Finally, adalimumab treatment for patients with psoriasis significantly decreased S100A8 mRNA at day fourteen after start of treatment, but not at day four. Taken together, this study demonstrates that the p38 MAPK signalling pathway plays a key role in the TNFα- and IL-17A-induced expression of S100A8 in cultured human keratinocytes. [ABSTRACT FROM AUTHOR]

Jak/ Tyk proteins have recently aroused as possible therapeutic targets for the treatment of psoriasis. In psoriasis, these proteins signal through STAT molecules including STAT3, and STAT3 expression and activation has been shown augmented in psoriatic lesions. Here, we characterized the expression of Jak/ Tyk proteins in lesional compared with non-lesional psoriatic skin. Jak1, Jak2 m RNA and protein and Tyk2 m RNA appeared to be downregulated, whereas Jak3 m RNA expression was increased. Moreover, STAT3 expression and activation was examined in psoriasis. STAT3 is activated at two phosphorylation sites: Tyr705 and Ser727. Both phosphorylation sites were phosphorylated in lesional psoriatic skin. The activation of STAT3 by Jak/ Tyk proteins was studied in cultured normal human keratinocytes. Tyr705 phosphorylation was induced by IL-6 and IL-20 in a Jak2-dependent manner, and moreover, phosphorylation of Tyr705 produced a strong increase in STAT3 transcriptional activity. TNFα, 12-O-Tetradecanoylphorbol 13-acetate ( TPA) and UVB irradiation induced Ser727 phosphorylation of STAT3 in an ERK1/2- and p38 MAPK-dependent manner, which resulted in a modulatory effect on STAT3 transcriptional activity. Our results demonstrate how different signalling pathways can integrate and lead to regulation of STAT3 transcriptional activity. [ABSTRACT FROM AUTHOR]

Although biological drugs in psoriasis treatment show clinical efficacy, there are still a proportion of patients in whom little treatment response is obtained. The aim of this study was to identify molecular biomarkers for treatment response and to investigate the molecular effects of ustekinumab treatment of psoriasis. The mRNA expression of various genes in skin biopsies was analysed by quantitative polymerase chain reaction (qPCR). At baseline, there was no significant clinical difference between responders and non-responders. Ten patients were clinical responders, with a mean baseline Psoriasis Area and Severity Index (PASI) score of 15.4 and a mean percentage improvement of 89.6%. No significant reduction in PASI during treatment was seen among the 5 non-responders. In the responder group, ustekinumab therapy reduced the mRNA expression of the majority of the studied genes in lesional psoriatic skin. 1I,-20, IL-21 and p40 mRNA expression in lesional psoriatic skin at baseline were significantly upregulated by factors of 2.7, 2.4 and 2.3, respectively, among non-responders compared with responders. The mRNA levels of p40, IL-20 and IL-21 at baseline may serve as potential predictors of treatment response to ustekinumab treatment. [ABSTRACT FROM AUTHOR]

Abstract: The skin-specific chemokine CCL27 is believed to play a pivotal role in establishing the inflammatory infiltrate characteristic for common inflammatory skin diseases. Through binding to the chemokine receptor 10 (CCR10), CCL27 mediates inflammation by promoting lymphocyte migration into the skin. Little is known about the regulation of CCL27 gene expression. The purpose of our study was to investigate the regulation of the IL-1β-induced CCL27 gene expression in normal human keratinocytes (NHEK). Preincubation of NHEK with the inhibitory κB (IκB) kinase (IKK) inhibitor, SC-514, or the p38 mitogen-activated protein kinase (MAPK) inhibitor, SB202190, revealed a profound reduction in both CCL27 mRNA and CCL27 protein expression indicating the significance of these pathways in the regulation of CCL27 expression. Furthermore, the impact of inhibitors of mitogen- and stress-activated kinase 1 (MSK1) or the mitogen-activated protein kinase-interacting kinases (Mnk1+2), downstream kinases of p38 MAPK, on IL-1β-induced CCL27 expression in NHEK were investigated. We identified seven NF-κB binding elements upstream from the CCL27 gene start codon using electrophoretic mobility shift assay (EMSA). Supershift analyses demonstrated the involvement of the p50/p65 NF-κB heterodimer. We conclude that IL-1β-induced CCL27 gene expression in NHEK is regulated through the p38 MAPK/MSK1/Mnk1+2 as well as the IKKβ/NF-κB signalling pathways. [Copyright &y& Elsevier]