Endogenous prostaglandin E₂ amplifies IL-33 production by macrophages through an E prostanoid...

When activated through toll-like receptors (TLRs), macrophages generate IL-33, an IL-1 family member that induces innate immune responses through ST2 signaling. LPS, a TLR4 ligand, induces macrophages to generate prostaglandin E₂ (PGE₂) through inducible COX-2 and microsomal PGE₂ synthase 1 (mPGES-1) (1). We demonstrate that IL-33 production by bone marrow-derived murine macrophages (bmMFs) requires the generation of endogenous PGE₂ and the intrinsic expression of EP₂ receptors to amplify NF-κB-dependent, LPS-induced IL-33 expression via exchange protein activated by cAMP (EPAC). Compared with WT cells, bmMFs lacking either mPGES-1 or EP₂ receptors displayed reduced LPS-induced IL-33 levels. A selective EP₂ agonist and, to a lesser extent, EP₄ receptor agonist potentiated LPS-induced IL-33 generation from both mPGES-1-null and WT bmMFs, whereas EP₁ and EP₃ receptor agonists were inactive. The effects of PGE₂ depended on cAMP, were mimicked by an EPAC-selective agonist, and were attenuated by EPAC-selective antagonism and knockdown. LPS-induced p38 MAPK and NF-κB activations were necessary for both IL-33 production and PGE₂ generation, and exogenous PGE₂ partly reversed the suppression of IL-33 production caused by p38 MAPK and NF-κB inhibition. Mice lacking mPGES-1 showed lower IL-33 levels and attenuated lung inflammation in response to repetitive Alternaria inhalation challenges. Cumulatively, our data demonstrate that endogenous PGE₂, EP₂ receptors, and EPAC are prerequisites for maximal LPS-induced IL-33 expression and that exogenous PGE₂ can amplify IL-33 production via EP₂ and EP₄ receptors. The ubiquitous induction of mPGES-1-dependent PGE₂ may be crucial for innate immune system activation during various IL-33 driven pathologic disorders.