Pharmacological Modulation of Endotoxin-Induced Release of IL-26 in Human Primary Lung Fibroblasts

Uppsala universitet, Experimentell och klinisk onkologi Karolinska Inst, Inst Environm Med, Unit Lung & Airway Res, Stockholm, Sweden 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 FRONTIERS MEDIA SA 2019

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 e

anticholinergic; beta-agonist; bronchodilator; glucocorticoid; IL-26; IL-8; fibroblast; MAP kinase; Pharmacology and Toxicology; Farmakologi och toxikologi; Article in journal; info:eu-repo/semantics/article; text

10.3389.fphar.2019.00956

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UPE oai:DiVA.org:uu-394067
doi:10.3389/fphar.2019.00956
ISI:000483323200001
1234425421

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