Effect of JAK Inhibitors on Release of CXCL9, CXCL10 and CXCL11 from Human Airway Epithelial Cells

PLoS One. 2015 Jun 19;10(6):e0128757. doi: 10.1371/journal.pone.0128757. eCollection 2015.


Background: CD8+ T-cells are located in the small airways of COPD patients and may contribute to pathophysiology. CD8+ cells express the chemokine receptor, CXCR3 that binds CXCL9, CXCL10 and CXCL11, which are elevated in the airways of COPD patients. These chemokines are released from airway epithelial cells via activation of receptor associated Janus kinases (JAK). This study compared the efficacy of two structurally dissimilar pan-JAK inhibitors, PF956980 and PF1367550, and the glucocorticosteroid dexamethasone, in BEAS-2B and human primary airway epithelial cells from COPD patients and control subjects.

Methods: Cells were stimulated with either IFNγ alone or with TNFα, and release of CXCL9, CXCL10 and CXCL11 measured by ELISA and expression of CXCL9, CXCL10 and CXCL11 by qPCR. Activation of JAK signalling was assessed by STAT1 phosphorylation and DNA binding.

Results: There were no differences in the levels of release of CXCL9, CXCL10 and CXCL11 from primary airway epithelial cells from any of the subjects or following stimulation with either IFNγ alone or with TNFα. Dexamethasone did not inhibit CXCR3 chemokine release from stimulated BEAS-2B or primary airway epithelial cells. However, both JAK inhibitors suppressed this response with PF1367550 being ~50-65-fold more potent than PF956980. The response of cells from COPD patients did not differ from controls with similar responses regardless of whether inhibitors were added prophylactically or concomitant with stimuli. These effects were mediated by JAK inhibition as both compounds suppressed STAT1 phosphorylation and DNA-binding of STAT1 and gene transcription.

Conclusions: These data suggest that the novel JAK inhibitor, PF1367550, is more potent than PF956980 and that JAK pathway inhibition in airway epithelium could provide an alternative anti-inflammatory approach for glucocorticosteroid-resistant diseases including COPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Line
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / metabolism*
  • Chemokine CXCL11 / genetics
  • Chemokine CXCL11 / metabolism*
  • Chemokine CXCL9 / genetics
  • Chemokine CXCL9 / metabolism*
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism*
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Janus Kinases / antagonists & inhibitors
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors / pharmacology*
  • Receptors, CXCR3 / metabolism
  • Respiratory Mucosa / metabolism*
  • STAT1 Transcription Factor / metabolism
  • Transcription, Genetic


  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokine CXCL9
  • Protein Kinase Inhibitors
  • Receptors, CXCR3
  • STAT1 Transcription Factor
  • Janus Kinases

Grant support

This study was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London and Pfizer Inc. The funders provided the molecules under assessment. However, the funders had no role in study design, data collection and analysis, or decision to publish.