IL-33 Induces Eicosanoid Formation in Mast Cells By a Novel COX-1-Dependent Mechanism

Rationale: Mast cells (MCs) are involved in allergic and inflammatory reactions; they release potent mediators such as prostaglandin (PG)D₂, thromboxane (TX)B₂ and cysteinyl leukotrienes (cysLTs) after activation. Interleukin (IL)-33 is an effector molecule of Th2 responses, and an agonist for mast cell activation, though the roles of mast cells and their eicosanoids in IL-33-dependent immune responses are not known.

Methods: Murine Bone Marrow-derived MCs (BMMCs) were stimulated with IL-33 and analyzed for eicosanoid production and level of cyclooxygenase (COX)1 and COX2 transcription over time. Wild type (Wt) mice were challenged intranasally with 4 doses of IL-33 (1 µg/day) and assessed for total (TCC) / differential cell count and lipid content in the bronchoalveolar lavage (BALs).

Results: In BMMCs, IL-33 induces a robust release of PGD₂, TXB₂ and cysLTs. The response peaks within 3 h of stimulation and is accompanied by ERK phosphorylation and a sustained upregulation of COX2 transcript. Interestingly, both COX2 upregulation and eicosanoid production are completely suppressed by the selective COX1 inhibitor SC560. Intranasal IL-33 induces robust generation of PGD₂ and TXB₂, along with increases in eosinophils.   

Conclusions: IL-33-dependent BMMC activation requires both COX1 and COX2. In this system, COX1 acts upstream of COX2 to mediate COX2 transcription, eicosanoids production and MAP Kinase activation. IL-33 is a robust inducer of mast cell-associated eicosanoids in vivo, which may participate in the recruitment of eosinophils.