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Endogenous prostaglandin E₂ amplifies IL-33 production by macrophages through an E prostanoid (EP)₂/EP₄-cAMP-EPAC-dependent pathway.

ABSTRACT: 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-?B-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-?B 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-?B 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.

SUBMITTER: Samuchiwal SK

PROVIDER: S-EPMC5437228 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Endogenous prostaglandin E2 amplifies IL-33 production by macrophages through an E prostanoid (EP)2/EP4-cAMP-EPAC-dependent pathway.

Samuchiwal Sachin K SK Balestrieri Barbara B Raff Hannah H Boyce Joshua A JA

The Journal of biological chemistry 20170324 20

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 e ...[more]

PMID: 28341741

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Project description:BackgroundThe EP4 prostanoid receptor is one of four GPCRs that mediate the diverse actions of prostaglandin E2 (PGE2). Novel selective EP4 receptor agonists would assist to further elucidate receptor sub-type function and promote development of therapeutics for bone healing, heart failure, and other receptor associated conditions. The rat EP4 (rEP4) receptor has been used as a surrogate for the human EP4 (hEP4) receptor in multiple SAR studies. To better understand the validity of this traditional approach, homology models were generated by threading for both receptors using the RaptorX server. These models were fit to an implicit membrane using the PPM server and OPM database with refinement of intra and extracellular loops by Prime (Schrödinger). To understand the interaction between the receptors and known agonists, induced-fit docking experiments were performed using Glide and Prime (Schrödinger), with both endogenous agonists and receptor sub-type selective, small-molecule agonists. The docking scores and observed interactions were compared with radioligand displacement experiments and receptor (rat & human) activation assays monitoring cAMP.ResultsRank-ordering of in silico compound docking scores aligned well with in vitro activity assay EC50 and radioligand binding Ki. We observed variations between rat and human EP4 binding pockets that have implications in future small-molecule receptor-modulator design and SAR, specifically a S103G mutation within the rEP4 receptor. Additionally, these models helped identify key interactions between the EP4 receptor and ligands including PGE2 and several known sub-type selective agonists while serving as a marked improvement over the previously reported models.ConclusionsThis work has generated a set of novel homology models of the rEP4 and hEP4 receptors. The homology models provide an improvement upon the previously reported model, largely due to improved solvation. The hEP4 docking scores correlates best with the cAMP activation data, where both data sets rank order Rivenprost>CAY10684 > PGE1 ≈ PGE2 > 11-deoxy-PGE1 ≈ 11-dexoy-PGE2 > 8-aza-11-deoxy-PGE1. This rank-ordering matches closely with the rEP4 receptor as well. Species-specific differences were noted for the weak agonists Sulprostone and Misoprostol, which appear to dock more readily within human receptor versus rat receptor.

Dataset Information

Endogenous prostaglandin E₂ amplifies IL-33 production by macrophages through an E prostanoid (EP)₂/EP₄-cAMP-EPAC-dependent pathway.

Publications

Endogenous prostaglandin E<sub>2</sub> amplifies IL-33 production by macrophages through an E prostanoid (EP)<sub>2</sub>/EP<sub>4</sub>-cAMP-EPAC-dependent pathway.

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