Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE12109 | GEO | 2008/07/15
SECONDARY ACCESSION(S): PRJNA113803
REPOSITORIES: GEO
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Project description:In this study, we shought to identify the cytokines produced by skin-resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors. Experiment Overall Design: In this study, primary keratinocytes were treated with either IL-17, IL-22 or IFNg for 24 hours then harvested for RNA extraction and subsequent gene array analysis
2008-10-24 | E-GEOD-12109 | biostudies-arrayexpress
Project description:Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines, yet the relative contribution of interferon (IFN)-gamma, interleukin (IL)-17 and IL-22 on disease pathogenesis is still unknown.In this study, we sought to identify the cytokines produced by skin-resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors.We used intracellular cytokine staining and flow cytometry to evaluate T cell cytokine production, and immunohistochemistry and double-label immunofluorescence to localize cytokine receptors in skin. Gene array analysis of cytokine-treated keratinocytes was performed using moderated paired t-test controlling for false discovery rate using the Benjamini-Hochberg procedure.We demonstrate that T-helper cells producing IL-17, IL-22 and/or IFN-gamma, as well as the cells bearing cognate cytokine receptors, are present in normal human skin. Keratinocytes stimulated with IL-17 expressed chemokines that were different from those induced by IFN-gamma, probably contributing to the influx of neutrophils, dendritic cells and memory T cells into the psoriatic lesion. In contrast, IL-22 downregulated genes associated with keratinocyte differentiation and caused epidermal alterations in an organotypic skin model.Our results suggest that the Th17 cytokines IL-17 and IL-22 mediate distinct downstream pathways that contribute to the psoriatic phenotype: IL-17 is more proinflammatory, while IL-22 retards keratinocyte differentiation.
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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:Primary HBE cells were stimulated with IL-22 and IL-17, and gene expression was studied using an Affymetrix platform microarray, in order to investigate which genes may be upregulated or downregulated in response to these cytokines. Of particular interest was the host defense genes such as antimicrobial peptides, which have been shown to be upregulated by IL-22 and IL-17 in skin keratinocytes. Keywords: cytokine effect
2008-01-23 | GSE10240 | GEO
Project description:Primary HBE cells were stimulated with IL-22 and IL-17, and gene expression was studied using an Affymetrix platform microarray, in order to investigate which genes may be upregulated or downregulated in response to these cytokines. Of particular interest was the host defense genes such as antimicrobial peptides, which have been shown to be upregulated by IL-22 and IL-17 in skin keratinocytes. Experiment Overall Design: There were 4 conditions to this study (media, IL-22, IL-17 and IL-22+17) and there were 3 biological replicates of each condition. Experiment Overall Design: Gene expression study using one timepoint of 24 hours after stimulating these primary cells with the above conditions
2008-06-11 | E-GEOD-10240 | biostudies-arrayexpress
Project description:BackgroundThe interleukin (IL)-23/IL-17 immune axis is of central importance in psoriasis. However, the impact of IL-17 family cytokines other than IL-17A in psoriasis has not been fully established.ObjectivesTo elucidate the contribution of IL-17 family cytokines in psoriasis.MethodsTo address the expression and localization of IL-17 family cytokines, lesional and nonlesional skin samples from patients with psoriasis were analysed by several complementary methods, including quantitative polymerase chain reaction, immunoassays, in situ hybridization and immunohistochemistry. Mechanistic studies assessing the functional activity of IL-17 family cytokines were performed using ex vivo cultured human skin biopsies and primary human keratinocytes.ResultsWe demonstrated that IL-17A, IL-17F, IL-17A/F and IL-17C are expressed at increased levels in psoriasis lesional skin and induce overlapping gene expression responses in ex vivo cultured human skin that correlate with the transcriptomic signature of psoriasis skin. Furthermore, we showed that brodalumab, in contrast to ixekizumab, normalizes gene expression responses induced by the combination of IL-17A, IL-17F, IL-17A/F and IL-17C in human keratinocytes.ConclusionsSeveral IL-17 ligands signalling through IL-17RA are overexpressed in psoriasis skin and induce similar psoriasis-related inflammatory pathways demonstrating their relevance in relation to therapeutic intervention in psoriasis.
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Project description:Th17 cells are a distinct lineage of effector CD4(+) T cells characterized by their production of interleukin (IL)-17. We demonstrate that Th17 cells also expressed IL-22, an IL-10 family member, at substantially higher amounts than T helper (Th)1 or Th2 cells. Similar to IL-17A, IL-22 expression was initiated by transforming growth factor beta signaling in the context of IL-6 and other proinflammatory cytokines. The subsequent expansion of IL-22-producing cells was dependent on IL-23. We further demonstrate that IL-22 was coexpressed in vitro and in vivo with both IL-17A and IL-17F. To study a functional relationship among these cytokines, we examined the expression of antimicrobial peptides by primary keratinocytes treated with combinations of IL-22, IL-17A, and IL-17F. IL-22 in conjunction with IL-17A or IL-17F synergistically induced the expression of beta-defensin 2 and S100A9 and additively enhanced the expression of S100A7 and S100A8. Collectively, we have identified IL-22 as a new cytokine expressed by Th17 cells that synergizes with IL-17A or IL-17F to regulate genes associated with skin innate immunity.
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Project description:To understand the role of epidermal keratinocytes in immunopathology of skin diseases with predominant T helper (Th) cell responses, we measured the genome-wide transcriptional profile of human keratinocytes in response to IFNgamma, IL-4, IL-17A or IL-22, major cytokines produced by Th1, Th2, Th17 or Th22 cells, respectively. IL-6 was also included in the transcriptional profile analysis because a variety of pro-inflammatory stimuli stimulate human keratinocytes to produce IL-6 that has an autocrine or paracrine role in epidermal immunity. We aimed to discover commonly expressed genes in human keratinocytes in response to pro-inflammatory cytokines, which would be associated with common pathophysiological responses in various skin diseases such as skin permeability barrier disruption or epidermal hyperplasia. Normal human keratinocytes (NHKs) were stimulated with IFNγ, IL-4, IL-6, IL-17A and IL-22 for 24 hours and harvested for total RNA extraction and hybridization on Affymetrix microarrays.
2014-10-02 | E-GEOD-53751 | biostudies-arrayexpress
Project description:The interleukin (IL)-20 subfamily of cytokines consists of IL-19, IL-20, IL-22, IL-24, and IL-26, and the expression of IL-20, IL-22, and IL-24 is reported to be higher in the colon of patients with ulcerative colitis. Although the receptors for these cytokines are highly expressed in the colon epithelium, their effects on epithelial renewal are not clearly understood. This study evaluated the effects of IL-20, IL-22, and IL-24 in epithelial renewal using the LS174T human colon cancer epithelial cell line. LS174T cells were treated with IL-20, IL-22, and IL-24 (25, 50, and 100 ng/mL) and a live-cell imaging system was used to evaluate the effects on cell proliferation. Following treatment, the signaling pathways contributing to cell proliferation were investigated through Western blotting in LS174T cells and downstream transcriptional changes through qRT-PCR in LS174T cells, and RNA-Seq in primary murine intestinal epithelial cells. Our results demonstrated that only IL-22 promoted LS174T cell proliferation, mediated via extracellular-signal-regulated kinase (ERK)1/2-mediated downstream regulation of p90RSK, c-Jun, and transcriptional changes of TRIM15 and STOM. IL-22 also promoted expression of ERK1/2-independent genes such as DDR2, LCN2, and LRG1, which are known to be involved in cell proliferation and migration. This study suggests that IL-22 induces cell proliferation in highly proliferative cells such as intestinal epithelial cells.
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