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Pharmacological Modulation of Endotoxin-Induced Release of IL-26 in Human Primary Lung Fibroblasts
Karolinska Inst, Inst Environm Med, Unit Lung & Airway Res, Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Inst Environm Med, Unit Lung & Airway Res, Stockholm, Sweden;.
Karolinska Inst, Inst Environm Med, Unit Lung & Airway Res, Stockholm, Sweden;Karolinska Univ Hosp Solna, Dept Resp Dis & Allergy, Stockholm, Sweden.
2019 (English)In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 956Article in journal (Refereed) Published
Abstract [en]

Background: Interleukin (IL)-26 is a neutrophil-mobilizing and bactericidal cytokine that is enhanced in human airways in vivo in response to endotoxin from Gram-negative bacteria. This cytokine is also enhanced in the airways during exacerbations of chronic obstructive pulmonary disease (COPD). Here, we investigated whether human primary lung fibroblasts (HLF) release IL-26 constitutively and in response to TLR4 stimulation by endotoxin and characterized the effects of bronchodilatory and anti-inflammatory drugs utilized in COPD. Methods: The HLF were stimulated with different concentrations of endotoxin. Cells were also treated with different concentrations of bronchodilatory and anti-inflammatory drugs, with and without endotoxin stimulation. Cytokine protein concentrations were quantified in the cell-free conditioned media [enzyme-linked immunosorbent assay (ELISA)], and the phosphorylation levels of intracellular signaling molecules were determined (phosphoELISA). Results: Whereas HLF displayed constitutive release of IL-26 into the conditioned medium, endotoxin markedly enhanced this release, as well as that of IL-6 and IL-8. This cytokine release was paralleled by increased phosphorylation of the intracellular signaling molecules NF-kappa B, c-Jun N-terminal kinase (JNK) 1-3, p38, and extracellular signal-regulated kinase (ERK) 1/2. The glucocorticoid hydrocortisone caused substantial inhibition of the endotoxin-induced release of IL-26, IL-6, and IL-8, an effect paralleled by a decrease of the phosphorylation of NF-kappa B, p38, and ERK1/2. The muscarinic receptor antagonist (MRA) tiotropium, but not aclidinium, caused minor inhibition of the endotoxin-induced release of IL-26 and IL-8, paralleled by a decreased phosphorylation of NF-kappa B. The beta 2-adrenoceptor agonist salbutamol caused modest inhibition of the endotoxin-induced release of IL-26 and IL-8, paralleled by a decreased phosphorylation of NF-kappa B, JNK1-3, and p38. Similar pharmacological effects were observed for the constitutive release of IL-26. Conclusions: The HLF constitute an abundant source of IL-26 that may contribute to local host defense against Gram-negative bacteria. Among the tested drugs, the glucocorticoid displayed the most powerful inhibitory effect, affecting the NF-kappa B, p38, and ERK1/2 signaling pathways. Whether or not this inhibition of IL-26 contributes to an increased risk for local infections in COPD requires further evaluation.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2019. Vol. 10, article id 956
Keywords [en]
anticholinergic, beta-agonist, bronchodilator, glucocorticoid, IL-26, IL-8, fibroblast, MAP kinase
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-394067DOI: 10.3389/fphar.2019.00956ISI: 000483323200001OAI: oai:DiVA.org:uu-394067DiVA, id: diva2:1356752
Funder
Swedish Research Council, 2016-01563AstraZenecaAvailable from: 2019-10-02 Created: 2019-10-02 Last updated: 2019-10-02Bibliographically approved

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