Reconstituted human epidermis cultures treated with IL-1 family cytokines for 24 hours.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE25400 | GEO | 2010/11/17
SECONDARY ACCESSION(S): PRJNA134137
REPOSITORIES: GEO
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Project description:Analysis of stratified epidermal cultures treated with IL-1a, IL-1F5, IL-1F6, IL-1F8 and IL-1F9 to determine the effects of these cytokines at 24h. Results provide insight into the role of IL-1 family cytokines in the pathogenesis of psoriasis. 16 samples. 2 untreated controls, 14 cytokine treated
2010-11-17 | E-GEOD-25400 | biostudies-arrayexpress
Project description:Background: IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro. Methodology/Principal Findings: Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that CEBPβ, the transcription factor regulating IL-17-responsive genes, is expressed in differentiated KCs. Conclusions/Significance: The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the “RHE” genes in psoriasis patients treated in vivo with this IL-17 antagonist. RHE samples were treated with IFNg, IL-22 and IL-17 and compared with control
2014-02-28 | E-GEOD-52361 | biostudies-arrayexpress
Project description:Background: IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro. Methodology/Principal Findings: Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that CEBPβ, the transcription factor regulating IL-17-responsive genes, is expressed in differentiated KCs. Conclusions/Significance: The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the “RHE” genes in psoriasis patients treated in vivo with this IL-17 antagonist.
2014-02-28 | GSE52361 | GEO
Project description:The IL-23/IL-17 immune axis is of central importance in psoriasis. However, the contribution of IL-17 family cytokines other than IL-17A to drive skin inflammation in psoriasis has not been fully established. To further elucidate the role of individual IL-17 family cytokines in psoriasis, we investigated their expression and localization in psoriasis skin at the mRNA and protein level. Moreover, we investigated the gene expression signatures induced by individual IL-17 family cytokines in human skin ex vivo as well as modulation of responses induced by the combination of IL-17 family cytokines in human keratinocytes by brodalumab, a human monoclonal antibody targeting the IL-17RA, versus the IL-17A blocking antibody ixekizumab. We demonstrate that IL-17A, IL-17AF, IL-17F and IL-17C are expressed at increased levels in psoriasis lesional skin and induce inflammatory gene expression signatures in human skin ex vivo that correlate with those observed in psoriasis. Furthermore, we show that brodalumab, in contrast to ixekizumab, fully blocks gene expression responses induced by the combination of IL-17A, IL-17AF, IL-17F and IL-17C in human keratinocytes. These findings suggest that inhibition of several IL-17 family cytokines, e.g. by targeting of the IL-17RA receptor, could be a favored mechanism to obtain a profound suppression of the inflammatory processes in psoriasis and thereby achieve high levels of skin clearance and sustained efficacy in patients with psoriasis.
2021-04-07 | GSE158448 | GEO
Project description:Psoriasis is a chronic inflammatory disease of the skin for which no cure has emerged. Its complex etiology requires the development of an in vitro model that appropriately recapitulates the physiopathology of this disease. In this study, we exploited the self-assembly method in order to develop a new tissue-engineered model of psoriatic skin substitutes. To circumvent the addition of immune cells, we supplemented the reconstructed psoriatic substitutes with a cocktail of four cytokines, TNF-α, IL-1α, IL-6 and IL-17, and monitored their impact on global gene expression by DNA microarray. The cytokines-supplemented substitutes have a more irregular epidermis, with protuberances and much thinner areas. Most interestingly, gene profiling on microarrays identified several genes reported as being deregulated psoriasis skin in vivo. Indeed, expression of the S100A12, IL8, DEFB4A and KYNU genes increased dramatically compared to their level in normal skin substitutes (P <0.005 to <0.05). In addition, the ACSBG1 gene, reported to be repressed in psoriasis, was also repressed in the cytokines-supplemented psoriatic substitutes compared to the controls (P <0.005). The product encoded by the genes deregulated in the cytokines-supplemented substitutes belong to biological pathways, such as the inflammatory and the immune responses, that are similarly altered in psoriasis in vivo. In conclusion, addition of cytokines to involved psoriatic substitutes alters the transcriptome of these cells in a manner similar to that observed with psoriasis in vivo. The addition of this pro-inflammatory cocktail, comparable cytokine in vivo psoriasis, prepares us for the next step: the characterization of the model once added immune cells. Tissue-engineered psoriatic human skin (TEPHS) cultivated with (number of replicates: 3) or without (number of replicates: 3) Cytokines (IL-17a, IL-6, IL1a, TNF-a).
2015-04-11 | E-GEOD-67762 | biostudies-arrayexpress
Project description:Psoriasis is a chronic inflammatory disease of the skin for which no cure has emerged. Its complex etiology requires the development of an in vitro model that appropriately recapitulates the physiopathology of this disease. In this study, we exploited the self-assembly method in order to develop a new tissue-engineered model of psoriatic skin substitutes. To circumvent the addition of immune cells, we supplemented the reconstructed psoriatic substitutes with a cocktail of four cytokines, TNF-α, IL-1α, IL-6 and IL-17, and monitored their impact on global gene expression by DNA microarray. The cytokines-supplemented substitutes have a more irregular epidermis, with protuberances and much thinner areas. Most interestingly, gene profiling on microarrays identified several genes reported as being deregulated psoriasis skin in vivo. Indeed, expression of the S100A12, IL8, DEFB4A and KYNU genes increased dramatically compared to their level in normal skin substitutes (P <0.005 to <0.05). In addition, the ACSBG1 gene, reported to be repressed in psoriasis, was also repressed in the cytokines-supplemented psoriatic substitutes compared to the controls (P <0.005). The product encoded by the genes deregulated in the cytokines-supplemented substitutes belong to biological pathways, such as the inflammatory and the immune responses, that are similarly altered in psoriasis in vivo. In conclusion, addition of cytokines to involved psoriatic substitutes alters the transcriptome of these cells in a manner similar to that observed with psoriasis in vivo. The addition of this pro-inflammatory cocktail, comparable cytokine in vivo psoriasis, prepares us for the next step: the characterization of the model once added immune cells.
2015-04-11 | GSE67762 | GEO
Project description:IL-6 inhibition has been unsuccessful in treating psoriasis, despite high levels of tissue and serum IL-6 in patients. Additionally, de novo psoriasis onset has been reported following IL-6 blockade in rheumatoid arthritis patients. To explore mechanisms underlying these clinical observations, we backcrossed an established psoriasiform mouse model (IL-17C+ mice) with IL-6 deficient mice (IL-17C+KO) and examined the cutaneous phenotype. IL-17C+KO mice initially exhibited decreased skin inflammation, however this decrease was transient and reversed rapidly, concomitant with increases in skin Tnf, Il36α/β/γ, Il24, epigen and S100a8/a9 to levels higher than those found in IL-17C+ mice. Comparison of IL-17C+ and IL-17C+KO mouse skin transcriptomes with that of human psoriasis skin, revealed significant correlation among transcripts of psoriasis patient skin and IL-17C+KO mouse skin, and confirmed an exacerbation of the inflammatory signature in IL-17C+KO mice that aligns closely with human psoriasis. Transcriptional analyses of IL-17C+ and IL-17C+KO primary keratinocytes confirmed increased expression of proinflammatory molecules, suggesting that in the absence of IL-6, keratinocytes increase production of numerous additional proinflammatory cytokines. These preclinical findings may provide insight into why arthritis patients being treated with IL-6 inhibitors develop new onset psoriasis and why IL-6 blockade for the treatment of psoriasis has not been clinically effective.
2017-08-01 | GSE86139 | GEO
Project description:IL-6 inhibition has been unsuccessful in treating psoriasis, despite high levels of tissue and serum IL-6 in patients. Additionally, de novo psoriasis onset has been reported following IL-6 blockade in rheumatoid arthritis patients. To explore mechanisms underlying these clinical observations, we backcrossed an established psoriasiform mouse model (IL-17C+ mice) with IL-6 deficient mice (IL-17C+KO) and examined the cutaneous phenotype. IL-17C+KO mice initially exhibited decreased skin inflammation, however this decrease was transient and reversed rapidly, concomitant with increases in skin Tnf, Il36α/β/γ, Il24, epigen and S100a8/a9 to levels higher than those found in IL-17C+ mice. Comparison of IL-17C+ and IL-17C+KO mouse skin transcriptomes with that of human psoriasis skin, revealed significant correlation among transcripts of psoriasis patient skin and IL-17C+KO mouse skin, and confirmed an exacerbation of the inflammatory signature in IL-17C+KO mice that aligns closely with human psoriasis. Transcriptional analyses of IL-17C+ and IL-17C+KO primary keratinocytes confirmed increased expression of proinflammatory molecules, suggesting that in the absence of IL-6, keratinocytes increase production of numerous additional proinflammatory cytokines. These preclinical findings may provide insight into why arthritis patients being treated with IL-6 inhibitors develop new onset psoriasis and why IL-6 blockade for the treatment of psoriasis has not been clinically effective.
2017-08-01 | GSE85967 | GEO
Project description:Multiple IL-17 family cytokines signaling through IL-17RA drive inflammatory pathways in psoriasis
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Project description:The clinical features of psoriasis, characterized by sharply demarcated scaly erythematous plaques, are typically so distinctive that a diagnosis can easily be made on these grounds alone. However, there is great variability in treatment response between individual patients, and this may reflect heterogeneity of inflammatory networks driving the disease. In this study, whole-genome transcriptional profiling was used to characterize inflammatory and cytokine networks in 62 lesional skin samples obtained from patients with stable chronic plaque psoriasis. We were able to stratify lesions according to their inflammatory gene expression signatures, identifying those associated with strong (37% of patients), moderate (39%) and weak inflammatory infiltrates (24%). Additionally, we identified differences in cytokine signatures with heightened cytokine-response patterns in one sub-group of lesions (IL-13-strong; 50%) and attenuation of these patterns in a second sub-group (IL-13-weak; 50%). These sub-groups correlated with the composition of the inflammatory infiltrate, but were only weakly associated with increased risk allele frequency at some psoriasis susceptibility loci (e.g., REL, TRAF3IP2 and NOS2). Our findings highlight variable points in the inflammatory and cytokine networks known to drive chronic plaque psoriasis. Such heterogeneous aspects may shape clinical course and treatment responses, and can provide avenues for development of personalized treatments. We used Affymetrix microarrays to evaluate genome-wide expression in primary human keratinocytes exposed to cytokines. Cytokine activity signatures were used to interpret the shifts in gene expression that occur in psoriasis plaques relative to normal uninvolved skin. Primary keratinocytes from three donors (subjects 1, 2, and 3) were obtained and were either untreated (control) or exposed to cytokines (IL-4, IL-13, IFN-alpha, IFN-gamma and TNF). For the IL17A samples, primary keratinocytes were obtained from six donors, with cells derived from three donors treated with IL-17A and cells derived from the other three donors left untreated (i.e., unpaired control samples).
2012-03-07 | E-GEOD-36287 | biostudies-arrayexpress