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Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway.
- Source :
-
PloS one [PLoS One] 2021 Feb 01; Vol. 16 (2), pp. e0246050. Date of Electronic Publication: 2021 Feb 01 (Print Publication: 2021). - Publication Year :
- 2021
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Abstract
- Pseudomonas aeruginosa (Pa) infection is a major cause of airway inflammation in immunocompromised and cystic fibrosis (CF) patients. Mitogen-activated protein (MAP) and tyrosine kinases are integral to inflammatory responses and are therefore potential targets for novel anti-inflammatory therapies. We have determined the involvement of specific kinases in Pa-induced inflammation. The effects of kinase inhibitors against p38MAPK, MEK 1/2, JNK 1/2, Syk or c-Src, a combination of a p38MAPK with Syk inhibitor, or a novel narrow spectrum kinase inhibitor (NSKI), were evaluated against the release of the proinflammatory cytokine/chemokine, IL-6 and CXCL8 from BEAS-2B and CFBE41o- epithelial cells by Pa. Effects of a Syk inhibitor against phosphorylation of the MAPKs were also evaluated. IL-6 and CXCL8 release by Pa were significantly inhibited by p38MAPK and Syk inhibitors (p<0.05). Phosphorylation of HSP27, but not ERK or JNK, was significantly inhibited by Syk kinase inhibition. A combination of p38MAPK and Syk inhibitors showed synergy against IL-6 and CXCL8 induction and an NSKI completely inhibited IL-6 and CXCL8 at low concentrations. Pa-induced inflammation is dependent on p38MAPK primarily, and Syk partially, which is upstream of p38MAPK. The NSKI suggests that inhibiting specific combinations of kinases is a potent potential therapy for Pa-induced inflammation.<br />Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Previously Matthew S. Coates was employed by Respivert Ltd. Garth W. Rapeport and Kazuhiro Ito were co-founders and employees of Respivert Ltd. During the period of the research G. W. Rapeport and K. Ito were co-founders and employees of Pulmocide Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Subjects :
- Cell Line
Cell Survival
Epithelial Cells cytology
Epithelial Cells metabolism
Humans
Phosphorylation
Signal Transduction
Bronchi cytology
Epithelial Cells microbiology
Interleukin-6 metabolism
Interleukin-8 metabolism
Pseudomonas aeruginosa physiology
Syk Kinase metabolism
p38 Mitogen-Activated Protein Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 16
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 33524056
- Full Text :
- https://doi.org/10.1371/journal.pone.0246050