title: Thiazolidinediones inhibit airway smooth muscle release of the chemokine CXCL10: in vitro comparison with current asthma therapies.
abstract: BACKGROUND
  Activated mast cells are present within airway smooth muscle (ASM) bundles in eosinophilic asthma. ASM production of the chemokine CXCL10 plays a role in their recruitment. Thus the effects of glucocorticoids (fluticasone, budesonide), long-acting β2-agonists (salmeterol, formoterol) and thiazolidinediones (ciglitazone, rosiglitazone) on CXCL10 production by ASM cells (ASMC) from people with and without asthma were investigated in vitro.
  
  
  METHODS
  Confluent serum-deprived cells were treated with the agents before and during cytokine stimulation for 0-24 h. CXCL10 protein/mRNA, IκB-α levels and p65 activity were measured using ELISA, RT PCR, immunoblotting and p65 activity assays respectively. Data were analysed using ANOVA followed by Fisher's post-hoc test.
  
  
  RESULTS
  Fluticasone and/or salmeterol at 1 and 100 nM inhibited CXCL10 release induced by IL-1β and TNF-α, but not IFNγ or all three cytokines (cytomix). The latter was also not affected by budesonide and formoterol. In asthmatic ASMC low salmeterol, but not formoterol, concentrations increased cytomix-induced CXCL10 release and at 0.01 nM enhanced NF-κB activity. Salmeterol 0.1 nM together with fluticasone 0.1 and 10 nM still increased CXCL10 release. The thiazolidinediones ciglitazone and rosiglitazone (at 25 and 100 μM) inhibited cytomix-induced CXCL10 release but these inhibitory effects were not prevented by the PPAR-g antagonist GW9662. Ciglitazone did not affect early NF-κB activity and CXCL10 mRNA production.
  
  
  CONCLUSIONS
  Thus the thiazolidinediones inhibited asthmatic ASMC CXCL10 release under conditions when common asthma therapies were ineffective or enhanced it. They may provide an alternative strategy to reduce mast cell-ASM interactions and restore normal airway physiology in asthma.
authors.affiliation: Respiratory Research Group, Faculty of Pharmacy, The University of Sydney, A15, Science Rd, Sydney, NSW 2006, Australia.
authors.forename: Petra
authors.initials: P
authors.lastname: Seidel
authors.forename: Hatem
authors.initials: H
authors.lastname: Alkhouri
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lalor
authors.forename: Janette K
authors.initials: JK
authors.lastname: Burgess
authors.forename: Carol L
authors.initials: CL
authors.lastname: Armour
authors.forename: J Margaret
authors.initials: JM
authors.lastname: Hughes
mesh_terms: D000328:Adult; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism*; D054357:Chemokine CXCL10 / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D045162:Thiazolidinediones / Q000008:administration & dosage*
chemical_list: D018927:Anti-Asthmatic Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D045162:Thiazolidinediones