Aspirin induces IL-4 production: augmented IL-4 production in aspirin-exacerbated respiratory disease

Abstract

Aspirin hypersensitivity is a hallmark of aspirin-exacerbated respiratory disease (AERD), a clinical syndrome characterized by the severe inflammation of the respiratory tract after ingestion of cyclooxygenase-1 inhibitors. We investigated the capacity of aspirin to induce interleukin-4 (IL-4) production in inflammatory cells relevant to AERD pathogenesis and examined the associated biochemical and molecular pathways. We also compared IL-4 production in peripheral blood mononuclear cells (PBMCs) from patients with AERD vs aspirin-tolerant asthma (ATA) upon exposure to aspirin. Aspirin induced IL-4 expression and activated the IL-4 promoter in a report assay. The capacity of aspirin to induce IL-4 expression correlated with its activity to activate mitogen-activated protein kinases, to form DNA–protein complexes on P elements in the IL-4 promoter and to synthesize nuclear factor of activated T cells, critical transcription factors for IL-4 transcription. Of clinical importance, aspirin upregulated IL-4 production twice as much in PBMCs from patients with AERD compared with PBMCs from patients with ATA. Our results suggest that IL-4 is an inflammatory component mediating intolerance reactions to aspirin, and thus is crucial for AERD pathogenesis. The cell signaling protein interleukin 4 (IL4) is implicated in the hypersensitivity to aspirin that can worsen the symptoms of asthma. Aspirin-exacerbated respiratory disease (AERD) is characterized by severe inflammation of the respiratory tract after ingestion of aspirin by some people with asthma. Il Yup Chung at Hanyang University, with co-workers in other South Korean centers, looked for a role for IL4 in AERD. Their investigation was prompted by having previously found that aspirin can increase IL4 production in some leukemic cell lines. This was surprising, since aspirin is generally found to inhibit IL4 production. Chung's group reports that blood cells from AERD patients increase their production of IL4 when exposed to aspirin in tissue culture. This finding may help in the diagnosis of AERD, and clarify the causes of aspirin intolerance in general.