Nonsteroidal anti-inflammatory–induced inhibition of signal transducer and activator of transcription 6 (STAT-6) phosphorylation in aspirin-exacerbated respiratory disease

• Published in: Journal of allergy and clinical immunology Vol. 138; no. 2; pp. 579 - 585
• Main Authors: Katial, Rohit K., Martucci, Michael, Burnett, Trever, Faino, Anna, Finkas, Lindsay, Liu, Sucai, Alam, Rafeul
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2016; Elsevier Limited
• Subjects: Allergy and Immunology; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Aspirin; Aspirin - adverse effects; Aspirin-exacerbated respiratory disease; Asthma; Asthma - etiology; Asthma - metabolism; Case-Control Studies; Cytokines; Cytokines - biosynthesis; Drug Hypersensitivity - immunology; Drug Hypersensitivity - metabolism; Ethanol; Experiments; Flow cytometry; Humans; IL-4 signaling inhibition; Lymphocytes; mechanism of aspirin desensitization; Nonsteroidal anti-inflammatory drugs; Phosphorylation; pSTAT6 inhibition; Respiratory diseases; Respiratory Tract Diseases - etiology; Respiratory Tract Diseases - metabolism; Signal Transduction - drug effects; STAT6 Transcription Factor - metabolism; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Urine; MFI; LTE4; pSTAT6; Aspirin-exacerbated respiratory disease; NSAID; AERD; STAT4; IL-4 signaling inhibition; STAT6; mechanism of aspirin desensitization; Jak1; pSTAT6 inhibition; Mean fluorescence intensity; LTE 4; Janus kinase 1; Leukotriene E4; Signal transducers and activators of transcription 4; Signal transducers and activators of transcription 6; Nonsteroidal anti-inflammatory drug; Phosphorylated signal transducers and activators of transcription 6
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2015.11.038

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.