PT  - JOURNAL ARTICLE
AU  - Christopher Rider
AU  - Suharsh Shah
AU  - Anna Miller-Larsson
AU  - David Proud
AU  - Malcolm Johnson
AU  - Mark Giembycz
AU  - Robert Newton
TI  - TNFα-induced glucocorticoid resistance: Effect of steroidal and non-steroidal GR agonists, formoterol and inhibition of inflammatory signalling
DP  - 2012 Sep 01
TA  - European Respiratory Journal
PG  - P3711
VI  - 40
IP  - Suppl 56
4099  - http://erj.ersjournals.com/content/40/Suppl_56/P3711.short
4100  - http://erj.ersjournals.com/content/40/Suppl_56/P3711.full
SO  - Eur Respir J2012 Sep 01; 40
AB  - Inhaled glucocorticoids (GCs) w/wo long-acting β2-adrenoceptor agonists (LABA) are the most effective treatment for asthma. However, GC insensitivity is a facet of severe asthma and COPD. We have examined TNFα-induced resistance to GC-dependent transcription by steroidal and non-steroidal GC receptor (GR) ligands in the absence and presence of a LABA, formoterol.METHODS: GC-dependent transcription was modeled by a simple 2×GRE-luciferase reporter in human bronchial epithelial BEAS-2B cells treated with TNFα (10 ng/ml) for 1 h prior to addition of GR ligands, and harvested after 6 h for luciferase assay.RESULTS: TNFα reduced by 43-54% the ability to drive 2×GRE-dependent transcription by dexamethasone, budesonide, fluticasone propionate or fluticasone furoate. The GCs des-ciclesonide, GW870086X, RU24858 and the non-steroidal GR agonist, GSK9027, all showed reduced maximal responses (Emax) with intrinsic activities 0.5-0.77 relative to dexamethasone. In each case, TNFα reduced Emax by a further 39-55%. Conversely, formoterol enhanced GRE-dependent transcription by each ligand and rescued the resistance induced by TNFα; these effects were proportional to the Emax of each drug. Statistically significant reversal of TNFα-induced resistance was observed with the c-jun N-terminal kinase inhibitor, JNK8, and PS-1145, an IκB kinase 2 (IKK2) inhibitor.CONCLUSIONS: TNFα induces GC resistance to steroidal GR ligands that are both full and partial agonists, as well as to a non-steroidal GR agonist. This effect is rescued by the addition of formoterol. It is possible that inhibition of inflammatory signalling may also reduce GC resistance.