Activation of prostaglandin E2-EP4 signaling reduces chemokine production in adipose tissue.

Inflammation of adipose tissue induces metabolic derangements associated with obesity. Thus, determining ways to control or inhibit inflammation in adipose tissue is of clinical interest. The present study tested the hypothesis that in mouse adipose tissue, endogenous prostaglandin E2 (PGE2) negatively regulates inflammation via activation of prostaglandin E receptor 4 (EP4). PGE2 (5-500 nM) attenuated lipopolysaccharide-induced mRNA and protein expression of chemokines, including interferon-γ-inducible protein 10 and macrophage-inflammatory protein-1α in mouse adipose tissue. A selective EP4 antagonist (L161,982) reversed, and two structurally different selective EP4 agonists [CAY10580 and CAY10598] mimicked these actions of PGE2. Adipose tissue derived from EP4-deficient mice did not display this response. These findings establish the involvement of EP4 receptors in this anti-inflammatory response. Experiments performed on adipose tissue from high-fat-fed mice demonstrated EP4-dependent attenuation of chemokine production during diet-induced obesity. The anti-inflammatory actions of EP4 became more important on a high-fat diet, in that EP4 activation suppressed a greater variety of chemokines. Furthermore, adipose tissue and systemic inflammation was enhanced in high-fat-fed EP4-deficient mice compared with wild-type littermates, and in high-fat-fed untreated C57BL/6 mice compared with mice treated with EP4 agonist. These findings provide in vivo evidence that PGE2-EP4 signaling limits inflammation. In conclusion, PGE2, via activation of EP4 receptors, functions as an endogenous anti-inflammatory mediator in mouse adipose tissue, and targeting EP4 may mitigate adipose tissue inflammation.
AuthorsEva H C Tang, Yin Cai, Chi Kin Wong, Viviane Z Rocha, Galina K Sukhova, Koichi Shimizu, Ge Xuan, Paul M Vanhoutte, Peter Libby, Aimin Xu
JournalJournal of lipid research (J Lipid Res) Vol. 56 Issue 2 Pg. 358-68 (Feb 2015) ISSN: 0022-2275 [Print] United States
PMID25510249 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.
Chemical References
  • CAY 10580
  • CAY10598
  • Chemokine CCL3
  • Chemokine CXCL10
  • Chemokines
  • Interleukin-6
  • Interleukin-8
  • L-161982
  • Pyrrolidinones
  • Receptors, Prostaglandin E, EP4 Subtype
  • Serum Amyloid A Protein
  • Tetrazoles
  • Thiophenes
  • Triazoles
  • Interleukin-10
  • Dinoprostone
  • Adipose Tissue (drug effects, metabolism)
  • Animals
  • Chemokine CCL3 (metabolism)
  • Chemokine CXCL10 (metabolism)
  • Chemokines (metabolism)
  • Dinoprostone (analogs & derivatives, pharmacology)
  • In Vitro Techniques
  • Interleukin-10 (metabolism)
  • Interleukin-6 (metabolism)
  • Interleukin-8 (pharmacology)
  • Male
  • Pyrrolidinones (pharmacology)
  • Receptors, Prostaglandin E, EP4 Subtype (agonists, antagonists & inhibitors, metabolism)
  • Serum Amyloid A Protein (metabolism)
  • Signal Transduction (drug effects, physiology)
  • Tetrazoles (pharmacology)
  • Thiophenes (pharmacology)
  • Triazoles (pharmacology)

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