Pharmacological Modulation of Endotoxin-Induced Release of IL-26 in Human Primary Lung Fibroblasts
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). Her...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00956/full |
| _version_ | 1828367465377169408 |
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| author | Karlhans Fru Che Jitong Sun Jitong Sun Anders Linden Anders Linden |
| author_facet | Karlhans Fru Che Jitong Sun Jitong Sun Anders Linden Anders Linden |
| author_sort | Karlhans Fru Che |
| collection | DOAJ |
| description | 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-κB, 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-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. |
| first_indexed | 2024-04-14T05:58:18Z |
| format | Article |
| id | doaj.art-c5b14cf9d04e4f37908e0e62de5322ff |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-14T05:58:18Z |
| publishDate | 2019-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-c5b14cf9d04e4f37908e0e62de5322ff2022-12-22T02:08:51ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-08-011010.3389/fphar.2019.00956471804Pharmacological Modulation of Endotoxin-Induced Release of IL-26 in Human Primary Lung FibroblastsKarlhans Fru Che0Jitong Sun1Jitong Sun2Anders Linden3Anders Linden4Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenUnit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Immunology, Genetics and Pathology, Experimental and Clinical Oncology, Uppsala University, Uppsala, SwedenUnit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Respiratory Disease and Allergy, Karolinska University Hospital Solna, Stockholm, SwedenBackground: 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-κB, 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-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.https://www.frontiersin.org/article/10.3389/fphar.2019.00956/fullanticholinergicbeta-agonistbronchodilatorglucocorticoidIL-26IL-8 |
| spellingShingle | Karlhans Fru Che Jitong Sun Jitong Sun Anders Linden Anders Linden Pharmacological Modulation of Endotoxin-Induced Release of IL-26 in Human Primary Lung Fibroblasts Frontiers in Pharmacology anticholinergic beta-agonist bronchodilator glucocorticoid IL-26 IL-8 |
| title | Pharmacological Modulation of Endotoxin-Induced Release of IL-26 in Human Primary Lung Fibroblasts |
| title_full | Pharmacological Modulation of Endotoxin-Induced Release of IL-26 in Human Primary Lung Fibroblasts |
| title_fullStr | Pharmacological Modulation of Endotoxin-Induced Release of IL-26 in Human Primary Lung Fibroblasts |
| title_full_unstemmed | Pharmacological Modulation of Endotoxin-Induced Release of IL-26 in Human Primary Lung Fibroblasts |
| title_short | Pharmacological Modulation of Endotoxin-Induced Release of IL-26 in Human Primary Lung Fibroblasts |
| title_sort | pharmacological modulation of endotoxin induced release of il 26 in human primary lung fibroblasts |
| topic | anticholinergic beta-agonist bronchodilator glucocorticoid IL-26 IL-8 |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.00956/full |
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