المؤلفون: Altonsy, Mohammed O., Kurwa, Habib A., Lauzon, Gilles J., Amrein, Matthias, Gerber, Anthony N., Almishri, Wagdi, Mydlarski, Paule Régine

المصدر: Immunity, Inflammation & Disease; Mar2020, Vol. 8 Issue 1, p62-79, 18p

مصطلحات موضوعية: CORYNEBACTERIUM, SMALL interfering RNA, TUMOR necrosis factors, ENZYME-linked immunosorbent assay, INFLAMMATORY mediators

مستخلص: Introduction: Corynebacterium tuberculostearicum (C. t.) is a ubiquitous bacterium that colonizes human skin. In contrast to other members of the genus Corynebacterium, such as toxigenic Corynebacterium diphtheriae or the opportunistic pathogen Corynebacterium jeikeium, several studies suggest that C. t. may play a role in skin health and disease. However, the mechanisms underlying these effects remain poorly understood. Methods: To investigate whether C. t. induces inflammatory pathways in primary human epidermal keratinocytes (HEKs) and human cutaneous squamous carcinoma cells (SCCs), cell culture, reverse transcription‐polymerase chain reaction (PCR), enzyme‐linked immunosorbent assay, immunofluorescence microscopy, Western blot, chromatin immunoprecipitation‐PCR, small interfering RNA knockdown and luciferase reporter expression system were used. Results: Herein, we demonstrate that C. t. upregulates the messenger RNA (mRNA) and protein levels of inflammatory mediators in two human skin cell lines, HEKs and SCCs. We further show activation of the canonical nuclear factor‐κB (NF‐κB) pathway in response to C. t. infection, including phosphorylation of the inhibitor of κB (IκB), the nuclear translocation of NF‐κB subunit (NF‐κB‐P65) and the recruitment of NF‐κB‐P65 and RNA polymerase to the NF‐κB response elements at the promoter region of the inflammatory genes. Lastly, the data confirm that C. t.‐induced tumor necrosis factor mRNA expression in HEKs is toll‐like receptor 2 (TLR2) dependent. Conclusion: Our results offer a mechanistic model for C. t.‐induced inflammation in human keratinocytes via TLR2 and activation of IκB kinase and downstream signaling through the canonical NF‐κB pathway. Relevance to chronic inflammatory diseases of the skin and cutaneous oncology is discussed. [ABSTRACT FROM AUTHOR]

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المؤلفون: Altonsy, Mohammed O., Sasse, Sarah K., Phang, Tzu L., Gerber, Anthony N.

مصطلحات موضوعية: Inflammation, Transcriptional Activation, Base Sequence, Tumor Necrosis Factor-alpha, Intracellular Signaling Peptides and Proteins, NF-kappa B, Nuclear Proteins, Introns, Cell Line, DNA-Binding Proteins, stomatognathic diseases, Receptors, Glucocorticoid, Gene Expression Regulation, Humans, Gene Regulation, hormones, hormone substitutes, and hormone antagonists, Tumor Necrosis Factor alpha-Induced Protein 3

الوصف: TNF expression is elevated in asthma and other inflammatory airway diseases that are commonly treated with glucocorticoid-based therapies, but the impact of glucocorticoids on negative feedback control of TNF is not well understood. We analyzed the effect of dexamethasone, a potent synthetic glucocorticoid, on TNF-regulated gene expression in cultured airway epithelial cells. Although dexamethasone-mediated activation of the glucocorticoid receptor (GR) potently repressed expression of IL1β, IL8, and several other pro-inflammatory TNF targets, the expression of anti-inflammatory TNF targets such as TNFAIP3 (A20) and NFKBIA was selectively spared or augmented by dexamethasone treatment. Despite divergent effects on gene expression, GR and NF-κB occupancy at the TNFAIP3 locus and GR-repressed targets was similar. A co-occupied intronic TNFAIP3 regulatory element mediated cooperative enhancement of transcription by GR and NF-κB that required the presence of a functional GR binding site (GBS). GBS exchanges between reporters for TNFAIP3 and FKBP5, a canonical GR-induced target, revealed substantial latitude in the GBS sequence requirements for GR/NF-κB cooperation, suggesting that the TNFAIP3 GBS acts primarily as a docking site in this context. Supporting this notion, a selective GR ligand with only weak agonist activity for induction of FKBP5 enabled robust GR/NF-κB cooperative induction of a mutant TNFAIP3 reporter harboring the FKBP5 GBS. Taken together, our data support a model in which the expression of anti-inflammatory targets of TNF is maintained during treatment with glucocorticoids through context-dependent cooperation between GR and NF-κB.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::3112a3f9d94c8e1b99c900d9094610e9Test
https://europepmc.org/articles/PMC3961651Test/

المؤلفون: Gerber, Anthony N.^1,2, Masuno, Kiriko¹, Diamond, Marc I.^3,4 marc.diamond@ucsf.edu

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 3/24/2009, Vol. 106 Issue 12, p4929-4934. 6p. 1 Diagram, 5 Graphs.

مصطلحات موضوعية: *GLUCOCORTICOID receptors, *INFLAMMATION, *GENETIC regulation, *BIOSYNTHESIS, *DRUG approval, *CYTOKINES

مستخلص: Glucocorticoids are widely used to suppress inflammation and treat various immune-mediated diseases. Some glucocorticoid receptor (GR)-regulated genes mediate the therapeutic response, whereas others cause debilitating side effects. To discover selective modulators of the GR response, we developed a high-throughput, multiplexed system to monitor regulation of 4 promoters simultaneously. An initial screen of 1,040 natural products and Food and Drug Administration-approved drugs identified modulators that caused GR to regulate only a subset of its target promoters. Some compounds selectively inhibited GR-mediated gene activation without altering the repression of cytokine expression by GR. This approach will facilitate identification of genes and small molecules that augment beneficial effects of GR and diminish deleterious ones. Our results have important implications for the development of GR modulators and the identification of cross-talk pathways that control selective GR gene regulation. [ABSTRACT FROM AUTHOR]