Kim BE, Leung DY, Boguniewicz M, Howell MDLoricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol 126:332-337

Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
Clinical Immunology (Impact Factor: 3.67). 03/2008; 126(3):332-7. DOI: 10.1016/j.clim.2007.11.006
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Atopic dermatitis (AD) is characterized by a defective skin barrier which allows increased allergen and pathogen penetration. Loricrin (LOR) and involucrin (IVL) are proteins important for skin barrier formation and integrity. In this study, we demonstrate that the gene and protein expression of LOR and IVL is significantly decreased in involved (LOR: p<0.001; IVL: p<0.001) and uninvolved (LOR: p<0.001; IVL: p<0.001) skin of AD subjects, as compared to skin from healthy subjects. Using primary keratinocytes, we further demonstrate the down-regulatory effect of IL-4 and IL-13--which are over-expressed in the skin of AD patients--on LOR and IVL expression in keratinocytes. Additionally, skin biopsies from signal transducer and activator of transcription (STAT)-6 transgenic mice were deficient in the expression and production of LOR and IVL. This study suggests that Th2 cytokines inhibit expression of LOR and IVL through a STAT-6 dependent mechanism.

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Available from: Michael D Howell, Aug 13, 2014
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    • "The expression of terminal differentiation proteins (filaggrin, loricrin, involucrin) in human epidermal keratinocytes is suppressed after treatment with IL-4, IL-13, IL-22, IL-25 and IL-31 cytokines [55,70–72]. Cytokine imbalances, particularly increased Th2 and Th22 skewing, have been shown to reduce other terminal differentiation proteins, including loricrin and involucrin, and to upregulate human tissue kallikreins (serine proteases responsible for corneodesmosome protein degradation in the skin) [73] [74] [75]. The Th22 cytokine, IL-22, was shown to directly induce epidermal hyperplasia, which is a common feature of chronic AD skin [76] [77]. "
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    ABSTRACT: Atopic Dermatitis (AD) is a common inflammatory skin disease with increasing prevalence in industrialized countries. Up to one-third of adults with AD have moderate-to-severe disease, leading to a large, unmet need for effective treatments. While current therapeutics focus mainly on symptom control, major advances have been made in translational research, with the goal of developing drugs to eradicate disease. A translational revolution is now occurring in AD, similar to the one that has occurred in psoriasis over the past decade. Research has focused on elucidating immune pathways responsible for AD, including Th2, Th22, and Th17 pathways, with testing of immune antagonists specific to these axes. An IL-4R antagonist, dupilumab, is the first drug that shows great promise in phase II trials. By studying clinical and molecular responses following treatment with specific immune antagonists, our understanding of and ability to treat AD will expand. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Cytokine 12/2014; 73(2). DOI:10.1016/j.cyto.2014.11.023 · 2.66 Impact Factor
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    • "We have observed that IL-13 produced by resident NKT cells has a homeostatic function in promoting conjunctival epithelial goblet cell differentiation and mucus production (De Paiva et al., 2011). IL-13 signals through STAT6 and has been found to stimulate production of GC mucin MUC5AC directly or indirectly by suppressing production of the forkhead transcription factor FoxA2, a MUC5AC repressor (Kim et al., 2008; Oh et al., 2010; Rogers, 2003). In contrast, experimental desiccating stress increased the number of cells staining positively for the Th1 cytokine IFN-g þ in the goblet cell zones of the conjunctiva and increased the concentration of IFN-g in tears (De Paiva et al., 2007). "
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    ABSTRACT: Evidence suggests that the cytokine interferon (IFN)-γ released by natural killer and CD4(+) T cells contributes to the conjunctival goblet cell (GC) loss in dry eye. The purpose of this study was to investigate if topical neutralization of IFN-γ prevents or alleviates GC loss in an experimental desiccating stress (DS) model of dry eye. In this study, we found that topical IFN-γ neutralization significantly decreased DS-induced conjunctival GC loss. This was accompanied by decreased epithelial apoptosis, and increased IL-13 and decreased FoxA2 expression in the forniceal conjunctiva. To establish that IFN-γ produced by pathogenic CD4(+) T cells contributes to DS-induced GC loss, adoptive transfer of CD4(+) T cells isolated from DS exposed donors to naïve RAG-1(-/-) recipient mice was performed. Similar to the donor mice, topical IFN-γ neutralization decreased conjunctival GC loss, suppressed apoptosis and increased IL-13 expression in adoptive transfer recipients. In summary, this study demonstrated that topical neutralization of IFN-γ prevents GC loss via modulating apoptosis and maintaining IL-13 signaling.
    Experimental Eye Research 12/2013; 118. DOI:10.1016/j.exer.2013.11.011 · 2.71 Impact Factor
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    • "The identification of loss-of-function variants in the filaggrin gene (FLG) caused a shift in the research paradigm from mainly focusing on immune related genes to genetic factors that regulate the formation of the epidermal barrier [5]. Controversially, however, existing and evolving evidence suggests that type-2 T helper (Th2) cytokines can modulate the expression of proteins that are essential for the formation and integrity of the epidermal barrier [6-8]. "
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    ABSTRACT: Eczema is a prevalent skin disease that is mainly characterized by systemic deviation of immune response and defective epidermal barrier. Th2 cytokines, such as IL-13, and transcription factor STAT6 are key elements in the inflammatory response that characterize allergic disorders, including eczema. Previous genetic association studies showed inconsistent results for the association of single nucleotide polymorphisms (SNPs) with eczema. Our aim was to investigate whether SNPs in IL13 and STAT6 genes, which share a biological pathway, have an interactive effect on eczema risk. Data from two independent population-based studies were analyzed, namely the Isle of Wight birth cohort study (IOW; n = 1,456) and for the purpose of replication the Swansea PAPA (Poblogaeth Asthma Prifysgol Abertawe; n = 1,445) cross-sectional study. Log-binomial regressions were applied to (i) account for the interaction between IL13 (rs20541) and STAT6 (rs1059513) polymorphisms and (ii) estimate the combined effect, in terms of risk ratios (RRs), of both risk factors on the risk of eczema. Under a dominant genetic model, the interaction term [IL13 (rs20541) x STAT6 (rs1059513)] was statistically significant in both studies (IOW: adjusted Pinteraction = 0.046; PAPA: Pinteraction = 0.037). The assessment of the combined effect associated with having risk genotypes in both SNPs yielded a 1.52-fold increased risk of eczema in the IOW study (95% confidence interval (CI): 1.05 -- 2.20; P = 0.028) and a 2.01-fold higher risk of eczema (95% CI: 1.29 -- 3.12; P = 0.002) in the PAPA study population. Our study adds to the current knowledge of genetic susceptibility by demonstrating for the first time an interactive effect between SNPs in IL13 (rs20541) and STAT6 (rs1059513) on the occurrence of eczema in two independent samples. Findings of this report further support the emerging evidence that points toward the existence of genetic effects that occur via complex networks involving gene-gene interactions (epistasis).
    BMC Medical Genetics 07/2013; 14(1):67. DOI:10.1186/1471-2350-14-67 · 2.08 Impact Factor
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