Prostaglandin E2 Inhibits NLRP3 Inflammasome Activation through EP4 Receptor and Intracellular Cyclic AMP in Human Macrophages.
PGE2 is a potent lipid mediator involved in maintaining homeostasis but also promotion of acute inflammation or immune suppression in chronic inflammation and cancer. Nucleotide-binding domain, leucine-rich repeat-containing protein (NLR)P3 inflammasome plays an important role in host defense. Uncontrolled activation of the NLRP3 inflammasome, owing to mutations in the NLRP3 gene, causes cryopyrin-associated periodic syndromes. In this study, we showed that NLRP3 inflammasome activation is inhibited by PGE2 in human primary monocyte-derived macrophages. This effect was mediated through PGE2 receptor subtype 4 (EP4) and an increase in intracellular cAMP, independently of protein kinase A or exchange protein directly activated by cAMP. A specific agonist of EP4 mimicked, whereas its antagonist or EP4 knockdown reversed, PGE2-mediated NLRP3 inhibition. PGE2 caused an increase in intracellular cAMP. Blockade of adenylate cyclase by its inhibitor reversed PGE2-mediated NLRP3 inhibition. Increase of intracellular cAMP by an activator of adenylate cyclase or an analog of cAMP, or a blockade of cAMP degradation by phosphodiesterase inhibitor decreased NLRP3 activation. Protein kinase A or exchange protein directly activated by cAMP agonists did not mimic, and their antagonists did not reverse, PGE2-mediated NLRP3 inhibition. Additionally, constitutive IL-1β secretion from LPS-primed PBMCs of cryopyrin-associated periodic fever syndromes patients was substantially reduced by high doses of PGE2. Moreover, blocking cytosolic phospholipase A2α by its inhibitor or small interfering RNA or inhibiting cyclooxygenase 2, resulting in inhibition of endogenous PGE2 production, caused an increase in NLRP3 inflammasome activation. Our results suggest that PGE2 might play a role in maintaining homeostasis during the resolution phase of inflammation and might serve as an autocrine and paracrine regulator.
Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, USA.
Milena
M
Sokolowska
Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, USA.
Li-Yuan
LY
Chen
Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, USA.
Yueqin
Y
Liu
Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, USA.
Asuncion
A
Martinez-Anton
Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, USA.
Hai-Yan
HY
Qi
Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, USA.
Carolea
C
Logun
Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, USA.
Sara
S
Alsaaty
Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Yong Hwan
YH
Park
Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Daniel L
DL
Kastner
Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Jae Jin
JJ
Chae
Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, USA.
James H
JH
Shelhamer
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000096:biosynthesis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D056587:Cryopyrin-Associated Periodic Syndromes / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology*; D004789:Enzyme Activation; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D058847:Inflammasomes / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D061251:Primary Cell Culture; D034622:RNA Interference; D034741:RNA, Small Interfering; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000378:metabolism*
D000067956:Adenylyl Cyclase Inhibitors; D002352:Carrier Proteins; D052246:Cyclooxygenase 2 Inhibitors; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D010726:Phosphodiesterase Inhibitors; D034741:RNA, Small Interfering; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D054513:Group IV Phospholipases A2; C516389:PLA2G4A protein, human; D000262:Adenylyl Cyclases; D015232:Dinoprostone