Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling

Pflegerl, Pamina; Vesely, Paul; Hantusch, Brigitte; Schlederer, Michaela; Zenz, Rainer; Janig, Elke; Steiner, Günter; Meixner, Arabella; Petzelbauer, Peter; Wolf, Peter; Soleiman, Afschin; Egger, Gerda; Moriggl, Richard; Kishimoto, Tadamitsu; Wagner, Erwin F.; Kenner, Lukas

doi:10.1073/pnas.0910371106

Cited by 59 publications

(61 citation statements)

References 37 publications

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“…The involvement of Stat transcription factors in the regulation of IL10 is of special interest because Stat3 has been demonstrated to be increased in SLE T cells (19,20). Conflicting data exist regarding Stat5 in SLE (21,22).…”

Section: Discussionmentioning

confidence: 99%

Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Hedrich

Rauen

Apostolidis

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

149

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The immune-regulatory cytokine IL-10 plays a central role during innate and adaptive immune responses. IL-10 is elevated in the serum and tissues of patients with systemic lupus erythematosus (SLE), an autoimmune disorder characterized by autoantibody production, immune-complex formation, and altered cytokine expression. Because of its B cell-promoting effects, IL-10 may contribute to autoantibody production and tissue damage in SLE. We aimed to determine molecular events governing T cell-derived IL-10 expression in health and disease. We link reduced DNA methylation of the IL10 gene with increased recruitment of Stat family transcription factors. Stat3 and Stat5 recruitment to the IL10 promoter and an intronic enhancer regulate gene expression. Both Stat3 and Stat5 mediate trans-activation and epigenetic remodeling of IL10 through their interaction with the histone acetyltransferase p300. In T cells from SLE patients, activation of Stat3 is increased, resulting in enhanced recruitment to regulatory regions and competitive replacement of Stat5, subsequently promoting IL-10 expression. A complete understanding of the molecular events governing cytokine expression will provide new treatment options in autoimmune disorders, including SLE. The observation that altered activation of Stat3 influences IL-10 expression in T cells from SLE patients offers molecular targets in the search for novel target-directed treatment options.

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Section: Discussionmentioning

confidence: 99%

Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Hedrich

Rauen

Apostolidis

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

149

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“…Biopsy samples (B10 mg) prepared from colon tissue were snap frozen in liquid nitrogen. The intestine was fixed in 4% paraformaldehyde and prepared for both immunohistochemistry and pathology evaluation using an established method (Stevceva et al, 1999;Williams et al, 2001;Pflegerl et al, 2009). Flushed lumen contents were homogenized, collected by centrifugation and either snap frozen for DNA and RNA purification or fixed in 2% paraformaldehyde overnight at 4 1C and then stored in 70% ethanol/30% phosphate-buffered saline at À 20 1C until analysis (see Supplemental Methods for more details).…”

Section: Animal Experimentsmentioning

confidence: 99%

Phylotype-level 16S rRNA analysis reveals new bacterial indicators of health state in acute murine colitis

et al. 2012

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Human inflammatory bowel disease and experimental colitis models in mice are associated with shifts in intestinal microbiota composition, but it is unclear at what taxonomic/phylogenetic level such microbiota dynamics can be indicative for health or disease. Here, we report that dextran sodium sulfate (DSS)-induced colitis is accompanied by major shifts in the composition and function of the intestinal microbiota of STAT1 À / À and wild-type mice, as determined by 454 pyrosequencing of bacterial 16S rRNA (gene) amplicons, metatranscriptomics and quantitative fluorescence in situ hybridization of selected phylotypes. The bacterial families Ruminococcaceae, Bacteroidaceae, Enterobacteriaceae, Deferribacteraceae and Verrucomicrobiaceae increased in relative abundance in DSS-treated mice. Comparative 16S rRNA sequence analysis at maximum possible phylogenetic resolution identified several indicator phylotypes for DSS treatment, including the putative mucin degraders Akkermansia and Mucispirillum. The analysis additionally revealed strongly contrasting abundance changes among phylotypes of the same family, particularly within the Lachnospiraceae. These extensive phylotype-level dynamics were hidden when reads were grouped at higher taxonomic levels. Metatranscriptomic analysis provided insights into functional shifts in the murine intestinal microbiota, with increased transcription of genes associated with regulation and cell signaling, carbohydrate metabolism and respiration and decreased transcription of flagellin genes during inflammation. These findings (i) establish the first in-depth inventory of the mouse gut microbiota and its metatranscriptome in the DSS colitis model, (ii) reveal that family-level microbial community analyses are insufficient to reveal important colitisassociated microbiota shifts and (iii) support a scenario of shifting intra-family structure and function in the phylotype-rich and phylogenetically diverse Lachnospiraceae in DSS-treated mice.

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“…It is also well known that the symptoms of systemic lupus erythematosus are exacerbated by sun exposure. Pflegerl et al [32] reported that challenging JUNB ∆ep mice with UVB irradiation enhanced the severity of their lupus-like lesions. It has also been published that DAXX-depleted fibroblasts are resistant to UVB-and oxidative-stress-induced cell death [33].…”

Section: Discussionmentioning

confidence: 99%

UVB-dependent changes in the expression of fast-responding early genes is modulated by huCOP1 in keratinocytes

Fazekas

Polyánka

Bebes

et al. 2014

Journal of Photochemistry and Photobiology B: Biology

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Ultraviolet (UV) B is the most prominent physical carcinogen in the environment leading to the development of various skin cancers. We have previously demonstrated that the human ortholog of the Arabidopsis thaliana constitutive photomorphogenesis 1 (COP1) protein, huCOP1, is expressed in keratinocytes in a UVB-regulated manner and is a negative regulator of p53 as a posttranslational modifier. However, it was not known whether huCOP1 plays a role in mediating the UVB-induced early transcriptional responses of human keratinocytes. In this study, we report that stable siRNA-mediated silencing of huCOP1 affects the UVB response of several genes within 2 h of irradiation, indicating that altered huCOP1 expression sensitizes the cells toward UVB.Pathway analysis identified a molecular network in which 13 of the 30 examined UVB-regulated genes were organized around three central proteins. Since the expression of the investigated genes was upregulated by UVB in the siCOP1 cell line, we hypothesize that huCOP1 is a repressor of the identified pathway. Several members of the network have been implicated previously in the pathogenesis of non-melanoma skin cancers; therefore, clarifying the role of huCOP1 in these skin diseases may have clinical relevance in the future.

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Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling

Abstract: Systemic lupus erythematosus (SLE) is

Cited by 59 publications

References 37 publications

Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Phylotype-level 16S rRNA analysis reveals new bacterial indicators of health state in acute murine colitis

UVB-dependent changes in the expression of fast-responding early genes is modulated by huCOP1 in keratinocytes

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