Amplification of poly(I:C)-induced interleukin-6 production in human bronchial epithelial cells by priming with interferon-γ
Abstract Proinflammatory cytokine interleukin (IL)-6 was associated with disease severity in patients with COVID-19. The mechanism underlying the excessive IL-6 production by SARS-Cov-2 infection remains unclear. Respiratory viruses initially infect nasal or bronchial epithelial cells that produce v...
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| Format: | Article |
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Nature Portfolio
2023-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-48422-9 |
| _version_ | 1827603985604804608 |
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| author | Norikazu Okuma Masa-aki Ito Tomoyoshi Shimizu Atsuya Hasegawa Shin’ya Ohmori Kazuki Yoshida Isao Matsuoka |
| author_facet | Norikazu Okuma Masa-aki Ito Tomoyoshi Shimizu Atsuya Hasegawa Shin’ya Ohmori Kazuki Yoshida Isao Matsuoka |
| author_sort | Norikazu Okuma |
| collection | DOAJ |
| description | Abstract Proinflammatory cytokine interleukin (IL)-6 was associated with disease severity in patients with COVID-19. The mechanism underlying the excessive IL-6 production by SARS-Cov-2 infection remains unclear. Respiratory viruses initially infect nasal or bronchial epithelial cells that produce various inflammatory mediators. Here, we show that pretreatment of human bronchial epithelial cells (NCl-H292) with interferon (IFN)-γ (10 ng/mL) markedly increased IL-6 production induced by the toll-like receptor (TLR) 3 agonist poly(I:C) (1 µg/mL) from 0.4 ± 0.1 to 4.1 ± 0.4 ng/mL (n = 3, P < 0.01). A similar effect was observed in human alveolar A549 and primary bronchial epithelial cells. TLR3 knockdown using siRNA in NCl-H292 cells diminished the priming effects of IFN-γ on poly(I:C)-induced IL-6 production. Furthermore, the Janus kinase (JAK) inhibitor tofacitinib (1 µM) inhibited IFN-γ-induced upregulation of TLR3, and suppressed poly(I:C)-induced IL-6 production. Quantitative chromatin immunoprecipitation revealed that IFN-γ stimulated histone modifications at the IL-6 gene locus. Finally, IFN-γ priming significantly increased lung IL-6 mRNA and protein levels in poly(I:C)-administrated mice. Thus, priming bronchial epithelial cells with IFN-γ increases poly(I:C)-induced IL-6 production via JAK-dependent TLR3 upregulation and chromatin remodeling at the IL-6 gene locus. These mechanisms may be involved in severe respiratory inflammation following infection with RNA viruses. |
| first_indexed | 2024-03-09T05:50:38Z |
| format | Article |
| id | doaj.art-c2d706c146ae4e36a76d2261a56c4cae |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T05:50:38Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-c2d706c146ae4e36a76d2261a56c4cae2023-12-03T12:17:33ZengNature PortfolioScientific Reports2045-23222023-11-0113111110.1038/s41598-023-48422-9Amplification of poly(I:C)-induced interleukin-6 production in human bronchial epithelial cells by priming with interferon-γNorikazu Okuma0Masa-aki Ito1Tomoyoshi Shimizu2Atsuya Hasegawa3Shin’ya Ohmori4Kazuki Yoshida5Isao Matsuoka6Laboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareLaboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareLaboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareLaboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareLaboratory of Allergy, Faculty of Pharmacy, Takasaki University of Health and WelfareLaboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareLaboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareAbstract Proinflammatory cytokine interleukin (IL)-6 was associated with disease severity in patients with COVID-19. The mechanism underlying the excessive IL-6 production by SARS-Cov-2 infection remains unclear. Respiratory viruses initially infect nasal or bronchial epithelial cells that produce various inflammatory mediators. Here, we show that pretreatment of human bronchial epithelial cells (NCl-H292) with interferon (IFN)-γ (10 ng/mL) markedly increased IL-6 production induced by the toll-like receptor (TLR) 3 agonist poly(I:C) (1 µg/mL) from 0.4 ± 0.1 to 4.1 ± 0.4 ng/mL (n = 3, P < 0.01). A similar effect was observed in human alveolar A549 and primary bronchial epithelial cells. TLR3 knockdown using siRNA in NCl-H292 cells diminished the priming effects of IFN-γ on poly(I:C)-induced IL-6 production. Furthermore, the Janus kinase (JAK) inhibitor tofacitinib (1 µM) inhibited IFN-γ-induced upregulation of TLR3, and suppressed poly(I:C)-induced IL-6 production. Quantitative chromatin immunoprecipitation revealed that IFN-γ stimulated histone modifications at the IL-6 gene locus. Finally, IFN-γ priming significantly increased lung IL-6 mRNA and protein levels in poly(I:C)-administrated mice. Thus, priming bronchial epithelial cells with IFN-γ increases poly(I:C)-induced IL-6 production via JAK-dependent TLR3 upregulation and chromatin remodeling at the IL-6 gene locus. These mechanisms may be involved in severe respiratory inflammation following infection with RNA viruses.https://doi.org/10.1038/s41598-023-48422-9 |
| spellingShingle | Norikazu Okuma Masa-aki Ito Tomoyoshi Shimizu Atsuya Hasegawa Shin’ya Ohmori Kazuki Yoshida Isao Matsuoka Amplification of poly(I:C)-induced interleukin-6 production in human bronchial epithelial cells by priming with interferon-γ Scientific Reports |
| title | Amplification of poly(I:C)-induced interleukin-6 production in human bronchial epithelial cells by priming with interferon-γ |
| title_full | Amplification of poly(I:C)-induced interleukin-6 production in human bronchial epithelial cells by priming with interferon-γ |
| title_fullStr | Amplification of poly(I:C)-induced interleukin-6 production in human bronchial epithelial cells by priming with interferon-γ |
| title_full_unstemmed | Amplification of poly(I:C)-induced interleukin-6 production in human bronchial epithelial cells by priming with interferon-γ |
| title_short | Amplification of poly(I:C)-induced interleukin-6 production in human bronchial epithelial cells by priming with interferon-γ |
| title_sort | amplification of poly i c induced interleukin 6 production in human bronchial epithelial cells by priming with interferon γ |
| url | https://doi.org/10.1038/s41598-023-48422-9 |
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