Original Research ARTICLE
Pharmacological modulation of endotoxin-induced release of IL-26 in human primary lung fibroblasts
- 1Karolinska Institute (KI), Sweden
- 2Uppsala University, Sweden
Background: Interleukin-26 (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 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 (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-κB, JNK1-3, p38, and ERK1/2. 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 ofin the phosphorylation of NF-κB, 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-κB. The β2-adrenoceptor agonist salbutamol caused modest inhibition of the endotoxin-induced release of IL-26 and IL-8, paralleled by a decreased phosphorylation of NF-κB, 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-κB, 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.
Keywords: anti-cholinergic, bronchodilator, , Beta-agonist, IL-26, IL-6, IL-8, , fibroblast, MAP kinases, NF-kB, Cortisone
Received: 13 May 2019;
Accepted: 26 Jul 2019.
Copyright: © 2019 Che, Sun and Lindén. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Karlhans F. Che, Karolinska Institute (KI), Solna, Sweden, email@example.com