title: Nonsteroidal anti-inflammatory-induced inhibition of signal transducer and activator of transcription 6 (STAT-6) phosphorylation in aspirin-exacerbated respiratory disease.
abstract: Aspirin desensitization provides long-term clinical benefits. The exact mechanisms of aspirin desensitization are not clearly understood.
  
  
  
  We sought to evaluate the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on T-cell activation of the IL-4 pathway in aspirin-sensitive patients with asthma and control subjects.
  
  
  
  A total of 11 aspirin-sensitive patients with asthma, 10 aspirin-tolerant patients with asthma, and 10 controls without asthma were studied. PBMCs were stimulated with an anti-CD3 antibody and IL-4 or IL-12, with and without the presence of NSAIDs. The expression of phosphorylated signal transducers and activators of transcription 6 (pSTAT6), phosphorylated signal transducers and activators of transcription 4, and IL-4 was detected in CD4 T cells by flow cytometry.
  
  
  
  Stimulation with a combination of anti-CD3 and IL-4 induced pSTAT6 in CD4 T cells from all subjects. The induction of pSTAT6 was significantly higher in aspirin-sensitive patients with asthma than in controls subjects. The increase in pSTAT6 was inhibited in a dose-dependent manner by aspirin and indomethacin and minimally by sodium salicylate. This inhibition was strongest in aspirin-sensitive patients. Two-group comparisons showed significant differences in pSTAT6 inhibition by all concentrations of indomethacin and aspirin: between aspirin-sensitive and aspirin-tolerant groups and between aspirin-sensitive and control groups. No differences were found between aspirin-tolerant and control groups at all 3 concentrations. The inhibition of pSTAT6 was associated with reduced IL-4 expression.
  
  
  
  NSAIDs inhibited signal transducers and activators of transcription 6 signaling in CD4 T cells. This inhibition was significantly higher in aspirin-sensitive patients than in aspirin-tolerant subjects and was associated with reduced expression of IL-4. These findings have implications for clinical benefits of aspirin desensitization in aspirin-sensitive patients with asthma.
authors.affiliation: National Jewish Health, Denver, Colo. Electronic address: katialr@njhealth.org.
authors.forename: Rohit K
authors.initials: RK
authors.lastname: Katial
authors.affiliation: National Jewish Health, Denver, Colo.
authors.forename: Michael
authors.initials: M
authors.lastname: Martucci
authors.affiliation: National Jewish Health, Denver, Colo.
authors.forename: Trever
authors.initials: T
authors.lastname: Burnett
authors.affiliation: National Jewish Health, Denver, Colo.
authors.forename: Anna
authors.initials: A
authors.lastname: Faino
authors.affiliation: National Jewish Health, Denver, Colo.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Finkas
authors.affiliation: National Jewish Health, Denver, Colo.
authors.forename: Sucai
authors.initials: S
authors.lastname: Liu
authors.affiliation: National Jewish Health, Denver, Colo.
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000009:adverse effects*; D001249:Asthma / Q000209:etiology / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis; D004342:Drug Hypersensitivity / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D012140:Respiratory Tract Diseases / Q000209:etiology / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D050800:STAT6 Transcription Factor; D001241:Aspirin
keywords: Aspirin-exacerbated respiratory disease; IL-4 signaling inhibition; mechanism of aspirin desensitization; pSTAT6 inhibition