Effect of the plant derivative compound a on the production of corticosteroid-resistant chemokines in airway smooth muscle cells

Adelina Gavrila, Latifa Chachi, Omar Tliba, Christopher Brightling, Yassine Amrani

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Preclinical models of human conditions including asthma showed the therapeutic potential of Compound A (CpdA), a dissociated glucocorticoid (GC) receptor (GRα) ligand. Whether CpdA inhibits GC resistance, a central feature of severe asthma, has not been addressed. We investigated whether CpdA modulates cytokineinduced GC resistance in human airway smooth muscle (ASM) cells. Healthy and asthmaticASMcells were treated with TNF-α /IFN-γ for 24 hours in the presence or absence of CpdA. ELISA and quantitative PCR assays were used to assess the effect of CpdA on chemokine expression. Activation of GRα by CpdA was assessed by quantitative PCR, immunostaining, and receptor antagonism using RU486. An effect ofCpdAon the transcription factor interferon regulatory factor 1 (IRF-1) was investigated using immunoblot, immunostaining, and small interfering RNA (siRNA) knockdown. CpdA inhibited production of fluticasone-resistant chemokines CCL5, CX3CL1, and CXCL10 at protein and mRNA levels in both asthmatic and healthy cells. CpdA failed to induce expression of GC-induced Leucine Zipper while transiently inducing mitogen-activated protein kinase phosphatase 1 (MKP-1) at both mRNA and protein levels. CpdA inhibitory action was not associated with GRα nuclear translocation, nor was it prevented by RU486 antagonism. Activation of IRF-1 by TNF-α /IFN-γ was inhibited by CpdA. IRF-1 siRNA knockdown reduced cytokine-induced CCL5 and CX3CL1 production. siRNA MKP-1 prevented the inhibitory effect of CpdA on cytokine-induced CXCL10 production. For the first time,we showthatCpdAinhibits the production of GC-resistant chemokines via GRa-independent mechanisms involving the inhibition of IRF-1 and up-regulation of MKP-1. Thus, targeting CpdA-sensitive pathways in ASM cells represents an alternative therapeutic approach to treatGCresistance in asthma.

Original languageEnglish (US)
Pages (from-to)728-737
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume53
Issue number5
DOIs
StatePublished - Nov 2015

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Keywords

  • Asthma therapies
  • Chemokines
  • Refractory patients
  • Severe asthma
  • Transcription factors

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