Synergy between Interleukin-1 β , Interferon- γ , and Glucocorticoids to Induce TLR2 Expression Involves NF- κ B, STAT1, and the Glucocorticoid Receptor.

Autor:	Bansal A; Departments of Physiology and Pharmacology (A.B., K.K., S.G., A.T., P.C., A.N.-B., M.M.M., A.M., R.N.) and Medicine (C.K., R.L.), Lung Health Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada., Kooi C; Departments of Physiology and Pharmacology (A.B., K.K., S.G., A.T., P.C., A.N.-B., M.M.M., A.M., R.N.) and Medicine (C.K., R.L.), Lung Health Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada., Kalyanaraman K; Departments of Physiology and Pharmacology (A.B., K.K., S.G., A.T., P.C., A.N.-B., M.M.M., A.M., R.N.) and Medicine (C.K., R.L.), Lung Health Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada., Gill S; Departments of Physiology and Pharmacology (A.B., K.K., S.G., A.T., P.C., A.N.-B., M.M.M., A.M., R.N.) and Medicine (C.K., R.L.), Lung Health Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada., Thorne A; Departments of Physiology and Pharmacology (A.B., K.K., S.G., A.T., P.C., A.N.-B., M.M.M., A.M., R.N.) and Medicine (C.K., R.L.), Lung Health Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada., Chandramohan P; Departments of Physiology and Pharmacology (A.B., K.K., S.G., A.T., P.C., A.N.-B., M.M.M., A.M., R.N.) and Medicine (C.K., R.L.), Lung Health Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada., Necker-Brown A; Departments of Physiology and Pharmacology (A.B., K.K., S.G., A.T., P.C., A.N.-B., M.M.M., A.M., R.N.) and Medicine (C.K., R.L.), Lung Health Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada., Mostafa MM; Departments of Physiology and Pharmacology (A.B., K.K., S.G., A.T., P.C., A.N.-B., M.M.M., A.M., R.N.) and Medicine (C.K., R.L.), Lung Health Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada., Milani A; Departments of Physiology and Pharmacology (A.B., K.K., S.G., A.T., P.C., A.N.-B., M.M.M., A.M., R.N.) and Medicine (C.K., R.L.), Lung Health Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada., Leigh R; Departments of Physiology and Pharmacology (A.B., K.K., S.G., A.T., P.C., A.N.-B., M.M.M., A.M., R.N.) and Medicine (C.K., R.L.), Lung Health Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada., Newton R; Departments of Physiology and Pharmacology (A.B., K.K., S.G., A.T., P.C., A.N.-B., M.M.M., A.M., R.N.) and Medicine (C.K., R.L.), Lung Health Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada rnewton@ucalgary.ca.
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2023 Dec 15; Vol. 105 (1), pp. 23-38. Date of Electronic Publication: 2023 Dec 15.
DOI:	10.1124/molpharm.123.000740
Abstrakt:	Glucocorticoids act via the glucocorticoid receptor (GR; NR3C1) to downregulate inflammatory gene expression and are effective treatments for mild to moderate asthma. However, in severe asthma and virus-induced exacerbations, glucocorticoid therapies are less efficacious, possibly due to reduced repressive ability and/or the increased expression of proinflammatory genes. In human A549 epithelial and primary human bronchial epithelial cells, toll-like receptor (TLR)-2 mRNA and protein were supra -additively induced by interleukin-1 β (IL-1 β ) plus dexamethasone (IL-1 β +Dex), interferon- γ (IFN- γ ) plus dexamethasone (IFN- γ +Dex), and IL-1 β plus IFN- γ plus dexamethasone (IL-1 β +IFN- γ +Dex). Indeed, ∼34- to 2100-fold increases were apparent at 24 hours for IL-1 β +IFN- γ +Dex, and this was greater than for any single or dual treatment. Using the A549 cell model, TLR2 induction by IL-1 β +IFN- γ +Dex was antagonized by Org34517, a competitive GR antagonist. Further, when combined with IL-1 β , IFN- γ , or IL-1 β +IFN- γ , the enhancements by dexamethasone on TLR2 expression required GR. Likewise, inhibitor of κ B kinase 2 inhibitors reduced IL-1 β +IFN- γ +Dex-induced TLR2 expression, and TLR2 expression induced by IL-1 β +Dex, with or without IFN- γ , required the nuclear factor (NF)- κ B subunit, p65. Similarly, signal transducer and activator of transcription (STAT)-1 phosphorylation and γ -interferon-activated sequence-dependent transcription were induced by IFN- γ These, along with IL-1 β +IFN- γ +Dex-induced TLR2 expression, were inhibited by Janus kinase (JAK) inhibitors. As IL-1 β +IFN- γ +Dex-induced TLR2 expression also required STAT1, this study reveals cooperation between JAK-STAT1, NF- κ B, and GR to upregulate TLR2 expression. Since TLR2 agonism elicits inflammatory responses, we propose that synergies involving TLR2 may occur within the cytokine milieu present in the immunopathology of glucocorticoid-resistant disease, and this could promote glucocorticoid resistance. SIGNIFICANCE STATEMENT: This study highlights that in human pulmonary epithelial cells, glucocorticoids, when combined with the inflammatory cytokines interleukin-1 β (IL-1 β ) and interferon- γ (IFN- γ ), can synergistically induce the expression of inflammatory genes, such as TLR2. This effect involved positive combinatorial interactions between NF- κ B/p65, glucocorticoid receptor, and JAK-STAT1 signaling to synergistically upregulate TLR2 expression. Thus, synergies involving glucocorticoid enhancement of TLR2 expression may occur in the immunopathology of glucocorticoid-resistant inflammatory diseases, including severe asthma. (Copyright © 2023 by The Author(s).)
Databáze:	MEDLINE
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