| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Alsaaty, Sara Chae, Jae Jin Shelhamer, James H. Chen, Li-Yuan Qi, Hai-Yan Kastner, Daniel L. Sokolowska, Milena Liu, Yueqin Logun, Carolea Park, Yong Hwan Martinez-Anton, Asuncion |
| Description |
Author Affiliation: Sokolowska M ( Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892); Chen LY ( Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892); Liu Y ( Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892); Martinez-Anton A ( Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892); Qi HY ( Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892); Logun C ( Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892); Alsaaty S ( Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892); Park YH ( Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.); Kastner DL ( Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.); Chae JJ ( Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.); Shelhamer JH ( Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892) |
| Abstract |
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-1ß secretion from LPS-primed PBMCs of cryopyrin-associated periodic fever syndromes patients was substantially reduced by high doses of PGE2. Moreover, blocking cytosolic phospholipase A2 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. |
| ISSN |
00221767 |
| e-ISSN |
15506606 |
| DOI |
10.4049/jimmunol.1401343 |
| Journal |
The Journal of Immunology |
| Issue Number |
11 |
| Volume Number |
194 |
| Language |
English |
| Publisher |
The American Association of Immunologists |
| Publisher Date |
2015-06-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Carrier Proteins Metabolism Cyclic Amp Dinoprostone Physiology Macrophages Immunology Receptors, Prostaglandin E, Ep4 Subtype Adenylyl Cyclase Inhibitors Adenylate Cyclase Biosynthesis Genetics Cell Line Cryopyrin-associated Periodic Syndromes Cyclic Amp-dependent Protein Kinases Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Pharmacology Enzyme Activation Group Iv Phospholipases A2 Antagonists & Inhibitors Inflammasomes Inflammation Interleukin-1beta Secretion Leukocytes, Mononuclear Lipopolysaccharides Phosphodiesterase Inhibitors Primary Cell Culture Rna Interference Rna, Small Interfering Receptors, Prostaglandin E, Ep2 Subtype Research Support, N.i.h., Intramural Discipline Immunology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
