The Plant Derivative Compound A Inhibits the Production of Corticosteroid-resistant Chemokines by Airway Smooth Muscle Cells.
journal contributionposted on 10.07.2015, 10:39 by Adelina Gavrila, Latifa Chachi, Omar Tliba, Christopher Brightling, Yassine Amrani
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 cytokine-induced GC resistance in human airway smooth muscle (ASM) cells. Healthy and asthmatic ASM cells were treated with TNFα/IFNγ for 24 hr in the presence or absence of CpdA. ELISA and qPCR assays were used to assess the effect of CpdA on chemokine expression. Activation of GRα by CpdA was assessed by qPCR, immunostaining and receptor antagonism using RU486. An effect of CpdA on the transcription factor IRF-1 was investigated using immunoblot, immunostaining and 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 Glucocorticoid-induced Leucine Zipper (GILZ) while transiently inducing MAPK phosphatase 1 (MKP-1) at both mRNA and protein levels. CpdA inhibitory action was not associated with GRαnuclear translocation nor prevented by RU486 antagonism. Activation of IRF-1 by TNFα/IFNγ 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 show that CpdA inhibits the production of GC-resistant chemokines via GRα-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 treat GC resistance in asthma.