Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway

PLoS One. 2021 Feb 1;16(2):e0246050. doi: 10.1371/journal.pone.0246050. eCollection 2021.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bronchi / cytology*
  • Cell Line
  • Cell Survival
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology*
  • Humans
  • Interleukin-6 / metabolism*
  • Interleukin-8 / metabolism*
  • Phosphorylation
  • Pseudomonas aeruginosa / physiology*
  • Signal Transduction
  • Syk Kinase / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • CXCL8 protein, human
  • Interleukin-6
  • Interleukin-8
  • Syk Kinase
  • p38 Mitogen-Activated Protein Kinases

Grants and funding

Matthew S. Coates received funding for this project from Respivert Ltd. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. During the period of the research Garth W. Rapeport and Kazuhiro Ito were co-founders/employed by Pulmocide Ltd. The funder provided support in the form of salaries for authors [GWR and KI], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.