Endogenous prostaglandin E2amplifies IL-33 production by macrophages through an E prostanoid (EP)2/EP4-cAMP-EPAC-dependent pathway.
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 PGE2synthase 1 (mPGES-1) (1). We demonstrate that IL-33 production by bone marrow-derived murine macrophages (bmMFs) requires the generation of endogenous PGE2and the intrinsic expression of EP2receptors 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 EP2receptors displayed reduced LPS-induced IL-33 levels. A selective EP2agonist and, to a lesser extent, EP4receptor agonist potentiated LPS-induced IL-33 generation from both mPGES-1-null and WT bmMFs, whereas EP1and EP3receptor agonists were inactive. The effects of PGE2depended 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 PGE2generation, and exogenous PGE2partly 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 repetitiveAlternariainhalation challenges. Cumulatively, our data demonstrate that endogenous PGE2, EP2receptors, and EPAC are prerequisites for maximal LPS-induced IL-33 expression and that exogenous PGE2can amplify IL-33 production via EP2and EP4receptors. The ubiquitous induction of mPGES-1-dependent PGE2may be crucial for innate immune system activation during various IL-33 driven pathologic disorders.
Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts 02115; Harvard Medical School, Boston, Massachusetts 02115.
Sachin K
SK
Samuchiwal
Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts 02115; Harvard Medical School, Boston, Massachusetts 02115.
Barbara
B
Balestrieri
Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Hannah
H
Raff
Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts 02115; Harvard Medical School, Boston, Massachusetts 02115. Electronic address: jboyce@rics.bwh.harvard.edu.
Joshua A
JA
Boyce
D000818:Animals; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D000067596:Interleukin-33 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D000071876:Prostaglandin-E Synthases / Q000235:genetics / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000378:metabolism*
C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D008070:Lipopolysaccharides; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
EPAC; IL-33; PGE2; bone marrow macrophages; cAMP; cytokine; innate immunity; mPGES-1; macrophage; prostaglandin