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Induction of GITRL expression in human keratinocytes by Th2 cytokines and TNF-?: implications for atopic dermatitis.

ABSTRACT: BACKGROUND:Glucocorticoid-induced TNF receptor-related protein ligand (GITRL), a ligand for the T cell co-stimulatory molecule GITR, is expressed by keratinocytes and involved in chemokine production. The expression of GITRL in skin inflammation remains unknown. OBJECTIVES:This study investigated cytokine regulation of keratinocyte GITRL expression. METHODS:Glucocorticoid-induced TNF receptor expression was evaluated in cytokine-treated human epidermal keratinocytes (HEK)s, murine PAM 212 cell line, murine and human skin explants by real time PCR, flow cytometry and immunostaining. Functional responses to GITR fusion protein were examined by real time PCR and ELISA. GITRL expression in AD and psoriasis was studied by immunohistochemistry. RESULTS:Skin biopsies from STAT6VT transgenic mice, which develop spontaneous atopic skin inflammation, were found by immunofluoresence, to have increased keratinocyte GITRL expression. Exposure to Th2 cytokines augmented GITRL mRNA expression in the murine PAM 212 keratinocytic cell line and murine skin explants. In contrast, GITRL mRNA and protein expression was only increased in HEKs and human skin explants in the presence of the combination of TNF-? and Th2 cytokines. A synergistic effect of Th2 cytokines and GITR fusion protein on production of CCL17, the Th2 chemokine, by murine keratinocytes was demonstrated. Immunohistochemical staining showed that acute AD lesions have increased expression of GITRL compared with normal skin, chronic AD lesions and psoriatic plaques. CONCLUSIONS AND CLINICAL RELEVANCE:Our studies demonstrate that GITRL expression is augmented by Th2 cytokines and TNF-? in keratinocytes. Increased GITRL expression in acute AD skin lesions is shown. This observation suggests a link between cytokine-regulated keratinocyte GITRL expression and its role in inflammatory responses in AD.

SUBMITTER: Byrne AM

PROVIDER: S-EPMC3306062 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Induction of GITRL expression in human keratinocytes by Th2 cytokines and TNF-α: implications for atopic dermatitis.

Byrne A M AM Goleva E E Chouiali F F Kaplan M H MH Hamid Q A QA Leung D Y M DY

Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 20120401 4

<h4>Background</h4>Glucocorticoid-induced TNF receptor-related protein ligand (GITRL), a ligand for the T cell co-stimulatory molecule GITR, is expressed by keratinocytes and involved in chemokine production. The expression of GITRL in skin inflammation remains unknown.<h4>Objectives</h4>This study investigated cytokine regulation of keratinocyte GITRL expression.<h4>Methods</h4>Glucocorticoid-induced TNF receptor expression was evaluated in cytokine-treated human epidermal keratinocytes (HEK)s, ...[more]

PMID: 22417213

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Project description:Atopic dermatitis (AD) is classified as extrinsic and intrinsic, representing approximately 80% and 20% of patients with the disease, respectively. Although sharing a similar clinical phenotype, only extrinsic AD is characterized by high serum IgE levels. Because most patients with AD exhibit high IgE levels, an "allergic"/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly TH2/TH22 polarization, and epidermal barrier defects.We sought to define whether both variants share a common pathogenesis.We stratified 51 patients with severe AD into extrinsic AD (n = 42) and intrinsic AD (n = 9) groups (with similar mean disease activity/SCORAD scores) and analyzed the molecular and cellular skin pathology of lesional and nonlesional intrinsic AD and extrinsic AD by using gene expression (real-time PCR) and immunohistochemistry.A significant correlation between IgE levels and SCORAD scores (r = 0.76, P < 10(-5)) was found only in patients with extrinsic AD. Marked infiltrates of T cells and dendritic cells and corresponding epidermal alterations (keratin 16, Mki67, and S100A7/A8/A9) defined lesional skin of patients with both variants. However, higher activation of all inflammatory axes (including TH2) was detected in patients with intrinsic AD, particularly TH17 and TH22 cytokines. Positive correlations between TH17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and TH2 cytokine (IL-4 and IL-5) levels and negative correlations with differentiation products (loricrin and periplakin).Although differences in TH17 and TH22 activation exist between patients with intrinsic AD and those with extrinsic AD, we identified common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products. Our data indicate that a TH2 bias is not the sole cause of high IgE levels in patients with extrinsic AD, with important implications for similar therapeutic interventions.

Project description:BackgroundMonitoring the effects of biologic therapies in skin diseases will benefit from alternative noninvasive skin sampling techniques to evaluate immune pathways in diseased tissue early and longitudinally.ObjectiveTo establish a minimally invasive profiling of skin cytokines for diagnosis, therapeutic response monitoring, and clinical research in atopic dermatitis (AD) and other skin diseases, particularly in pediatric cohorts.MethodsWe developed a novel method for cytokine profiling in the epidermis using skin tape strips (STSs) in a setting designed to maximize the efficiency of protein extraction from STSs. This method was applied to analyze STS protein extracts from the lesional skin of children having AD (n = 41) and normal, healthy controls (n = 22). A total of 20 cytokines were probed with the ultrasensitive Mesoscale multiplex cytokine assay.ResultsA significant increase in interleukin (IL)-1b (P < .01), IL-18 (P < .001), and IL-8 (P < .001) with a decrease in IL-1a (P < .001) in the stratum corneum of AD lesional skin was found. Concurrently, an increase in markers associated with type 2 inflammatory response was readily detectable in AD lesional skin, including C-C motif chemokine ligand (CCL) 22, CCL 17, and thymic stromal lymphopoietin (TSLP). The levels of IL-1b, IL-18, and TSLP exhibited positive correlations with the AD severity index (Scoring AD index) and skin transepidermal water loss (TEWL), whereas an inverse correlation between IL-1a and Scoring AD index and IL-1a and TEWL was found. The levels of CCL17, CCL22, TSLP, IL-22, and IL-17a correlated with skin TEWL measurements.ConclusionUsing minimally invasive STS analysis, we identified cytokine profiles easily sampled in AD lesional skin. The expression of these markers correlated with disease severity and reflected changes in TEWL in lesional skin. These markers suggest new response assessment targets for AD skin.Trial registrationClinicalTrials.gov Identifier: NCT03168113.

Dataset Information

Induction of GITRL expression in human keratinocytes by Th2 cytokines and TNF-?: implications for atopic dermatitis.

Publications

Induction of GITRL expression in human keratinocytes by Th2 cytokines and TNF-α: implications for atopic dermatitis.

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