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Keratinocytes are involved in protecting the body from infections and environmental challenges, but also in inflammatory conditions like psoriasis. DNA has emerged as a potent stimulator of innate immune responses, but there is largely no information of how keratinocytes respond to cytosolic DNA. In this study, we report that human keratinocytes are tolerant to cytoplasmic DNA. However, if treated with inflammatory cytokines, keratinocytes gained the capacity to respond to DNA through a mechanism antagonized by the antimicrobial peptide LL37, proposed to be involved in activation and regulation of skin inflammation. The DNA sensor IFN-inducible protein 16 (IFI16) colocalized with DNA and the signaling molecule stimulator of IFN genes (STING) in the cytoplasm only in cytokine-stimulated cells, correlating with recruitment of the essential kinase TANK-binding kinase 1. Moreover, IFI16 was essential for DNA-driven innate immune responses in keratinocytes. Finally, IFI16 was upregulated in psoriasis skin lesions and localized to the cytoplasm in a subpopulation of cells. Collectively, this work suggests that inflammatory environments in the skin can lead to breakdown of tolerance for DNA in keratinocytes, which could contribute to the development of inflammatory diseases.

The mitogen-activated protein kinases (MAPKs) are known to play a key role in the regulation of cytokine expression in several cell types. MAPK signal-integrating kinase 1 (Mnk1) is a kinase activated through both the stress- and cytokine-activated p38 MAPK pathway and the classical extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. In this study, we demonstrate that in cultured normal human keratinocytes Mnk1 and its downstream target eukaryotic initiation factor 4E (eIF4E) are phosphorylated in a time-dependent manner in response to stimulation with anisomycin or interleukin (IL)-1beta. Both the stimuli are well-recognized activators of the p38 MAPK pathway. Furthermore, we show that the Mnk inhibitor CGP57380 is capable of inhibiting the phosphorylation of eIF4E in keratinocytes, and that the abolishment of eIF4E phosphorylation dramatically decreases the anisomycin-induced protein release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), IL-1beta and IL-6 as well as the IL-1beta-induced protein release of TNF-alpha. Therefore, we propose that Mnk1 might contribute to the expression of pro-inflammatory cytokines found in inflammatory skin diseases.

Mitogen- and stress-activated protein kinase 1 (MSK1) is a downstream target of both the p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinases (MAPKs). MSK1 stimulates transcription of different pro-inflammatory genes through activation of transcription factors. The purpose of this study was to investigate the expression and activation of MSK1 in lesional psoriatic skin and its role in cytokine production in cultured normal human keratinocytes. Western blotting revealed a consistent and significant increase in phosphorylated (activated) MSK1(Ser376) in lesional psoriatic skin. Immunofluorescence staining revealed the phosphorylated MSK1(Thr581) to be localized in the basal layers of the epidermis in lesional psoriatic skin. No staining was found in non-lesional psoriatic skin. Cultured human keratinocytes incubated with anisomycin or IL-1beta resulted in the phosphorylation of the p38 MAPK and MSK1(Ser376). MSK1(Ser376) phosphorylation was inhibited by pre-incubation with the p38 inhibitor SB 202190. Transfection of the keratinocytes with specific MSK1 small interfering RNA resulted in 80% reduction of MSK1 expression and 51, 40, and 31% decrease in IL-6, IL-8, and tumor necrosis factor-alpha protein production, respectively. This study demonstrates for the first time the expression of MSK1 in epidermal keratinocytes and increased activation focally in psoriatic epidermis. As MSK1 regulates the production of pro-inflammatory cytokines, it may play a role in the pathogenesis of psoriasis.

Studies on switch between interleukin (IL)‐17 inhibitors are scarce. We assessed the effectiveness of brodalumab in patients with previous treatment failure of IL‐17A inhibitor(s). Patients with psoriasis and previous treatment failure of an IL‐17A inhibitor were treated with brodalumab at standard dose. Effectiveness was assessed after 12, 26, and 52 weeks of treatment. The primary outcome was the proportion of patients that had achieved an absolute psoriasis area and severity index (PASI) ≤2 and/or a relative reduction of PASI of 75% (PASI75) at week 12. Plasma cytokine levels were measured at baseline and after 12 weeks of treatment. In total, 20 patients were included, seven (35%) were female, the median age was 50 years, and the median baseline PASI was 13.5. Analyzing the data using nonresponder imputation, 14 (70%) patients had achieved either PASI75 and/or PASI ≤2, 8 (40%) had achieved PASI90, and three (15%) had achieved PASI100 at week 12. In total, nine patients (45%) completed the 52‐weeks trial and seven patients (35%) still had PASI75 throughout 52 weeks. Seventeen out of 20 patients experienced any adverse events (AEs) during 52 weeks with no serious AEs or deaths. Patients responding to treatment had lower levels of tumor necrosis factor (TNF)‐α and IL‐6 at baseline compared with those who did not respond to treatment (TNF‐α, p = 0.041, IL‐6, p = 0.0054). In conclusion, treatment with brodalumab despite previous treatment failure with an IL‐17A inhibitor can be effective and well‐tolerated. [ABSTRACT FROM AUTHOR]

Keratinocytes are the key cellular target for IL‐17A‐mediated effects in psoriasis and HSP90 is important for IL‐17A‐mediated signalling. RGRN‐305 is a novel HSP90 inhibitor reported to reduce psoriatic phenotypes in preclinical animal models. The aim of this study was to investigate the effect of RGRN‐305 on a psoriasis‐like inflammatory response in human keratinocytes in vitro. Using RT‐qPCR, we demonstrated a significantly increased expression of the HSP90 isoforms HSP90AB1, HSP90B1 and TRAP1 in lesional compared with non‐lesional psoriatic skin. In a psoriasis‐like setting where keratinocytes were stimulated with TNFα and/or IL‐17A, we analysed the mRNA expression using the NanoString nCounter technology and demonstrated that the HSP90 inhibitor RGRN‐305 significantly reduced the IL‐17A‐ and TNFα‐induced gene expression of a number of proinflammatory genes, including the psoriasis‐associated genes CCL20, NFKBIZ, IL36G and IL23A. In agreement with the mRNA data, the protein level of CCL20, IκBζ and IL‐36γ were inhibited by RGRN‐305 as demonstrated by western blotting and ELISA. Interestingly, when keratinocytes were stimulated with a TLR3 agonist, RGRN‐305 also demonstrated potent immunomodulatory effects, significantly inhibiting poly(I:C)‐induced expression of the proinflammatory genes TNFα, IL1B, IL6 and IL23A. Taken together, our data support a role for HSP90 not only in the pathogenesis of psoriasis, but also in broader immune responses. Therefore, HSP90 provides an attractive target for the treatment of psoriasis and other diseases where the innate immune system plays an important role. [ABSTRACT FROM AUTHOR]

TNFα-, IL-23- and IL-17-targeting drugs are highly effective in the treatment of psoriasis. However, the precise molecular mechanism remains unknown. In psoriatic skin, the presence of Langerhans cells ( LCs) is reduced, but the role of LC is poorly understood. The purpose of this study was to investigate the impact of TNFα and IL-23/ IL-17 on the presence of LC in the skin during treatment. Therefore, psoriatic skin was investigated before and after 4 days of adalimumab or ustekinumab treatment. Furthermore, TNFα and IL-17A stimulation was investigated in an ex vivo model of epidermis and dermis from healthy normal skin kept in cultures at an air-liquid interphase for 4 days. In a gene array analysis, we found that the two LC markers, CD1a and CD207, were among the most up- or downregulated genes in psoriatic skin after anti- TNFα therapy. Validation showed that both mRNA expression and protein level followed the same pattern and became significantly upregulated after 4 days of treatment. No changes were seen after ustekinumab treatment. In the ex vivo skin model, a decrease in the CD1a level was seen after TNFα stimulation and it was caused by LC migration from epidermis. No response in LC migration was seen after IL-17A stimulation. Taken together, we demonstrated that changes in the LC level in epidermis precede the histological and clinical changes during adalimumab treatment in psoriatic skin. Furthermore, TNFα plays a prominent role in orchestrating LC migration in the skin. This seems not to be the true for the IL-23/ IL-17A pathway. [ABSTRACT FROM AUTHOR]

Tripartite motif-containing protein 21 ( TRIM21) regulates pro-inflammatory cytokines and type I interferons and acts as an autoantigen in certain autoimmune diseases, but TRIM21 has not been investigated in psoriasis. It has been suggested that TRIM21 may have a dual function; in the early phase of inflammation, it may function as a stimulator; but upon immune stimulation, its ubiquitinating mode of action may shift from stabilization to degradation of IRF3 causing inhibition of the immune responses. The imiquimod ( IMQ)-induced psoriasis-like mouse model displays features similar to those of human psoriasis. However, chronicity is lacking in this model. We investigated whether the role of TRIM21 in psoriasis was pro-inflammatory or anti-inflammatory. We hypothesized that a shift of the TRIM21-ubiquitinating mode of action may explain the lack of chronicity in the IMQ-induced psoriasis-like mouse model. We showed that TRIM21 expression is increased in lesional psoriatic skin and in the early phase of IMQ-induced inflammation both in vitro and in vivo. Surprisingly, inflammation was significantly less pronounced in TRIM21 knockout mice than in wild-type mice as shown by ear thickness measured at days 8, 9 and 10 after treatment start, by spleen weight as a marker of systemic effect of IMQ at 10 days after treatment start and by expression of IL-12p40 at days 3 and 10 after treatment start and IL-17A at day 3 after treatment start. Therefore, induction of TRIM21 expression cannot explain the lack of chronicity in the IMQ-induced psoriasis-like skin inflammation mouse model. [ABSTRACT FROM AUTHOR]

The JAK/STAT signaling pathway is suggested to play an important role in the pathogenesis of psoriasis, and recently JAK/STAT inhibitors have shown promising results in psoriasis treatment. The present study aimed to characterize the role of STAT2 in psoriasis. We demonstrated an increased expression of STAT2 and an increased level of phosphorylated/activated STAT2 in lesional compared with nonlesional psoriatic skin. Gene silencing of STAT2 by siRNA in human keratinocytes revealed that upon IFNα stimulation CXCL11 and CCL5 were the only two cytokines, among 102 analyzed, found to be regulated through a STAT2-dependent mechanism. Moreover, the regulation of CXCL11 and CCL5 depended on IRF9, but not on STAT1 and STAT6. The CXCL11 and CCL5 expression was increased in lesional compared with nonlesional psoriatic skin, and analysis demonstrated positive correlation between the expression of CXCL11 and IFNγ and between the expression of CCL5 and IFNγ in lesional psoriatic skin. In contrast, no correlation between the expression of CXCL11 and IL-17A and the expression of CCL5 and IL-17A in lesional psoriatic skin was found. Our data suggest that STAT2 plays a role in the psoriasis pathogenesis by regulating the expression of CXCL11 and CCL5, and thereby attracting IFNγ-producing immune cells to the skin. [ABSTRACT FROM AUTHOR]

Background: Psoriasis is an inflammatory disease characterized by leukocyte skin infiltration. Interestingly, recent works suggest that the migration of dendritic cells (DCs) is abnormal in psoriatic skin. DCs have significant role in regulating the function of T lymphocytes, at least in part influenced by the local environment of cytokines. In psoriatic skin lesions the expression of IL-20 is highly up-regulated. It is unclear if this cytokine has any influence on DCs. Methods: Here, we investigated the influence of IL-20 in monocyte-derived dendritic cell (MDDCs) in vitro. This work addressed IL-20 effects on DC maturation, receptor expression and signaling. By use of extra cellular matrix components mimicking the skin environment, we also studied the functional effects of IL-20 on the chemotactic migration of DCs. Based on the recent finding that CD18 integrin are shed during migration of myeloid leukocytes, the concentration of these adhesion molecules was measured in MDDCs culture supernatants post migration. Results: Following stimulation with IL-20, immature human MDDCs enhanced the expression of the co-stimulatory molecule CD86, further enabling activation of the p38 MAPK, but not the STAT3, pathway. IL-20 increased the migration of MDDCs in a biphasic response narrowly controlled by the interleukin concentration. A concomitant change in the shedding of CD18 integrins suggested that these adhesion molecules play a role in the migration of the MDDCs through the extracellular matrix layer. Conclusion: Taken together, our findings points to a possible, yet subtle, role of IL-20 in DCs migration. The biphasic response suggests that the aberrant IL-20 expression in psoriasis impedes DC migration, which could be a part of the processes that precipitates the dysregulated inflammatory response associated with this disease. [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]

Mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2) are two kinases phosphorylated by both ERK1/2 and p38 MAPK. Recently, MSK1 and 2 have been reported to act as negative regulators of acute inflammation. In this study, we investigated the role of MSK1/2 in chronic skin inflammation using an oxazolone-induced allergic contact dermatitis model in MSK1/2 knockout mice and wild-type mice. MSK1/2 knockout mice were demonstrated to have significantly increased inflammation compared with wild-type mice. This was measured by an increased ear thickness, elevated infiltration of neutrophils in the skin and increased inflammatory histological changes. Furthermore, we found significantly elevated levels of the proinflammatory cytokines Tumor necrosis factor-α (TNF-α), IL-1β and IL-6 at both mRNA and protein levels in MSK1/2 knockout mice compared with wild-type mice after oxazolone treatment. In addition, the mRNA expression of the chemokine Thymus and activation regulated chemokine (TARC) was demonstrated to be significantly elevated in oxazolone-treated MSK1/2 knockout mice compared with wild-type mice. The increased expression of TARC was paralleled by increased infiltration of cells positive for the TARC receptor, CCR4, in the dermis of MSK1/2 knockout mice. Our results indicate that MSK1/2 are involved in the activation of feedback mechanisms that dampen oxazolone-induced skin inflammation. [ABSTRACT FROM AUTHOR]

Background: IL-24 (melanoma differentiation-associated gene-7 (mda-7)), a member of the IL-10 cytokine family, possesses the properties of a classical cytokine as well as tumor suppressor effects. The exact role of IL-24 in the immune system has not been defined but studies have indicated a role for IL-24 in inflammatory conditions such as psoriasis. The tumor suppressor effects of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and p38 mitogen-activated protein kinase (MAPK)- mediated apoptosis. Current knowledge on the regulation of IL-24 expression is sparse. Previous studies have suggested that mRNA stabilization is of major importance to IL-24 expression. Yet, the mechanisms responsible for the regulation of IL-24 mRNA stability remain unidentified. As p38 MAPK is known to regulate gene expression by interfering with mRNA degradation we examined the role of p38 MAPK in the regulation of IL-24 gene expression in cultured normal human keratinocytes. Methodology/Principal Findings: In the present study we show that anisomycin- and IL-1β- induced IL-24 expression is strongly dependent on p38 MAPK activation. Studies of IL-24 mRNA stability in anisomycin-treated keratinocytes reveal that the p38 MAPK inhibitor SB 202190 accelerates IL-24 mRNA decay suggesting p38 MAPK to regulate IL-24 expression by mRNA-stabilizing mechanisms. The insertion of the 39 untranslated region (UTR) of IL-24 mRNA in a tet-off reporter construct induces degradation of the reporter mRNA. The observed mRNA degradation is markedly reduced when a constitutively active mutant of MAPK kinase 6 (MKK6), which selectively activates p38 MAPK, is co-expressed. Conclusions/Significance: Taken together, we here report p38 MAPK as a regulator of IL-24 expression and determine interference with destabilization mediated by the 39 UTR of IL-24 mRNA as mode of action. As discussed in the present work these findings have important implications for our understanding of IL-24 as a tumor suppressor protein as well as an immune modulating cytokine. [ABSTRACT FROM AUTHOR]

IL-17C is a member of the IL-17 family of cytokines. The expression of IL-17C has been demonstrated to be strongly induced by TNFα in human keratinocytes, and recently the level of IL-17C was found to be increased in the inflammatory skin disease psoriasis. However, little is known about the molecular mechanisms involved in the regulation of IL-17C. Here, we show that pretreatment of cultured human keratinocytes with the inhibitor of κB kinase 2 inhibitor, SC-514, resulted in a significant reduction in both IL-17C mRNA and protein expression, indicating the significance of this pathway in the regulation of IL-17C. NP-κB binding sites were identified upstream from the IL-17C gene, and by electrophoretic mobility shift assay NF-κB was shown to bind to all three identified binding sites. Moreover, NF-κB binding to these sites was inducible by TNFα. Supershift analysis revealed binding of the NF-κB subunits p65 and p50 to all three NP-κB binding sites. To determine the contribution of NF-κB in IL-17C expression, we conducted luciferase gene reporter experiments and demonstrated that a 3204-bp promoter fragment of IL-17C containing three putative NP-κB binding sites was strongly activated by TNFα. Interestingly, mutations of the three NP-κB binding sites revealed that one specific NP-κB binding site was crucial for the TNFα-mediated IL-17C induction because mutation of this specific site completely abolished TNFα-induced IL-17C promoter activation. We conclude that the activation of NP-κB (p65/p50) is crucial for the TNPα-induced stimulation of IL-17C expression in human keratinocytes. [ABSTRACT FROM AUTHOR]

The inflammasome is a cytosolic multiprotein complex with two major functions: recognizing pathogen-associated molecular patterns and reacting to these through activation of the proinflammatory cytokines IL-1β and IL-18. In this study, we characterized the expression of inflammasome components in psoriatic skin and other common inflammatory skin diseases. Human skin biopsy specimens, cultured primary human keratinocytes, and peripheral blood mononuclear cells (PBMCs) were analyzed using quantitative reverse transcriptase-PCR (RT-PCR) and semiquantitative western blotting. mRNA expression of the inflammasome components NALP1, NALP3, ASC, caspase-1, caspase-4, and caspase-5 was detected in psoriatic skin. Interestingly, we found an extensive, 20-fold upregulation (P<0.01) of caspase-5 mRNA in lesional compared with nonlesional psoriatic skin, whereas caspase-1, caspase-4, and ASC (apoptosis-associated speck-like protein with CARD domain) mRNAs were upregulated by only 1.5- to 2.6-fold (P<0.01). Caspase-5 mRNA was not increased in biopsies from other inflammatory skin diseases, suggesting that this finding could be psoriasis specific. In vitro experiments revealed that caspase-5 mRNA was induced in primary keratinocytes as well as PBMCs stimulated with IFN-γ. Inhibition studies suggested that caspase-5 mRNA upregulation was mediated through the NF-κB pathway. Our findings suggest that caspase-5 and the inflammasome may have an important role in the inflammatory response in psoriasis. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinase (MAPK) AP kinase 2 (MK2) is a serine/threonine kinase that is phosphorylated and activated by p38 MAPK. MK2 regulates the expression of various proinflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-8. Recently, MK2 was demonstrated to be activated in lesional psoriatic epidermis. This study investigates for the first time the role of MK2 in skin inflammation using the model of oxazolone-induced acute allergic contact dermatitis in mice. We show that oxazolone treatment leads to increased expression and sustained activation of both p38 MAPK and MK2. The inflammatory response was determined by ear thickness, myeloperoxidase activity, and histology after oxazolone challenge. Pretreatment with the p38 MAPK inhibitor SB202190 and genetic ablation of MK2 inhibit this inflammatory response. In particular, IL-1β and, to a smaller but significant extent, also TNF-α and IFN-γ expression were decreased in MK2 knockout mice compared with wild-type mice. These results indicate that MK2 is a potential target for the treatment of inflammatory skin diseases.Journal of Investigative Dermatology (2009) 129, 891–898; doi:10.1038/jid.2008.322; published online 6 November 2008 [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to analyze the expression of the two proinflammatory cytokines IL-20 and IL-24 and their shared receptors in rheumatoid arthritis and spondyloarthropathy. IL-20 was increased in plasma of rheumatoid arthritis patients compared with osteoarthritis patients and IL-24 was increased in synovial fluid and plasma of rheumatoid arthritis and spondyloarthropathy patients compared with osteoarthritis patients. IL-20 and IL-24 mRNA was only present at low levels in the synovium. In the synovial membrane, IL-20 protein was present in mononuclear cells and neutrophil granulocytes whereas IL-24 protein was observed in endothelial cells and mononuclear cells. IL-20 receptor type 1 and IL-22 receptor were expressed by granulocytes in the synovial fluid. In synovial fluid mononuclear cell cultures, stimulation with recombinant human IL-20 or recombinant human IL-24 induced monocyte chemoattractant protein 1 (CCL2/MCP-1) secretion, but not tumour necrosis factor α mRNA synthesis or IL-6 secretion. Both IL-20 and IL-24 showed correlations to CCL2/MCP-1 in plasma from rheumatoid arthritis and spondyloarthropathy patients. This study associates IL-20 and IL-24 to the synovium of rheumatoid arthritis and spondyloarthropathy and results indicate that the two cytokines contribute to disease pathogenesis through recruitment of neutrophil granulocytes and induction of CCL2/MCP-1. [Copyright &y& Elsevier]

Caspase-1 belongs to the group of inflammatory caspases and is the activating enzyme for the proinflammatory cytokine IL-18, a cytokine known to play an important role in the pathogenesis of psoriasis. The purpose of this study was to determine the expression of caspase-1 in psoriatic skin and the signaling mechanisms involved in stress-induced activation of caspase-1 and IL-18. Interestingly, increased caspase-1 activity in lesional compared with non-lesional psoriatic skin was seen. In vitro experiments in cultured human keratinocytes demonstrated anisomycin-induced, p38 mitogen-activated protein kinase (p38 MAPK)-dependent increased secretion of procaspase-1 and active caspase-1. Furthermore, anisomycin increased the mRNA expression of IL-18 through a p38 MAPK-dependent but caspase-1-independent mechanism, reaching a maximum level after 12 hours of stimulation. Finally, anisomycin caused a rapid (4 hours) increase in the secretion of proIL-18 and active IL-18. Secretion of active IL-18 was mediated through a p38 MAPK/caspase-1-dependent mechanism, whereas secretion of proIL-18 was mediated by a p38 MAPK-dependent but caspase-1-independent mechanism. These data demonstrate that the activity of caspase-1 is increased in psoriatic skin and that IL-18 secretion is regulated by a p38 MAPK/caspase-1-dependent mechanism, making caspase-1 a potential target in the treatment of psoriasis.Journal of Investigative Dermatology (2007) 127, 2857–2864; doi:10.1038/sj.jid.5700922; published online 28 June 2007 [ABSTRACT FROM AUTHOR]

IL-20 is a novel member of the IL-10 cytokine family with pleiotropic effects. Current knowledge of what triggers and regulates IL-20 gene expression is sparse. The aim of this study was to investigate the regulation of IL-20 expression in cultured normal human keratinocytes. The expression of IL-20 was rapidly induced by proinflammatory stimuli, in particular IL-1β, IL-6, and UVB irradiation. Using kinase inhibitors and small-interfering RNA, we discovered that the p38 mitogen-activated protein kinase (MAPK) as well as inhibitory κB kinase -NF-κB signaling pathways are crucial for IL-20 expression. By electrophoretic mobility shift assay two κB-binding sites were identified upstream from the start codon in the IL-20 gene. Supershift analysis revealed binding of the p50/p65 heterodimer. Furthermore, the p38 MAPK was shown to exert its effects on IL-20 expression through activation of the downstream kinase mitogen- and stress-activated kinase 1 (MSK1), indicating transactivation of NF-κB driven IL-20 messenger RNA transcription as an important mechanism of action. IL-20 is assumed to be a key cytokine in the pathogenesis of psoriasis and possibly cancer, and therefore the p38 MAPK, MSK1, and NF-κB may be important new molecular targets for the modulation of IL-20 expression in these diseases.Journal of Investigative Dermatology (2007) 127, 1326–1336. doi:10.1038/sj.jid.5700713; published online 25 January 2007 [ABSTRACT FROM AUTHOR]