Prostaglandin E2-EP4 signaling reduces inflammation in mouse adipose tissue

Abstract

Inflammation of adipose tissue plays a causative role in inducing metabolic syndrome associated with obesity. Thus examining ways to control or inhibit adipose tissue inflammation is of clinical interest. In the present study, we were interested to see if endogenous prostaglandin E2 (PGE2) modulates inflammation via activation of EP4 receptors in mouse adipose tissue. PGE2 (5-500nM) attenuated lipopolysaccharide (LPS)-induced mRNA and protein expression of chemokines in mouse adipose tissue, including interferon-γ-inducible protein 10 (IP10) and macrophage-inflammatory protein (MIP)-1α. Such response was reversed with L161,982 (100nM, a selective EP4 antagonist), mimicked with two structurally different selective EP4 agonists [CAY10580 (10μM) and CAY10598 (10μM)], and was absence in adipose tissue derived from EP4-deficient mice. These findings consolidated the requirement of EP4 in the response. PGE2 significantly reduced LPS-induced chemokines in mature adipocytes, rather than in stromal vascular cells. Antiinflammatory effect of PGE2 in adipose tissue was mimicked with 8-bromo-cyclic adenosine monophosphoate (cAMP) but was insensitive to H98 (a protein kinase A inhibitor). The use of adipose tissue from high-fat fed mice confirmed that EP4-dependent anti-inflammatory response is sustained during diet-induced obesity. Furthermore, adipose tissue and systemic inflammation is enhanced in high-fat fed EP4 deficient mice as compared to wild-type littermates, providing in vivo evidences that PGE2-EP4 signaling modulates inflammation. Our work illustrated that PGE2 via activation of EP4 is a potential endogenous anti-inflammatory mediator in mouse adipose tissue and targeting EP4 could be a strategy to mitigate adipose tissue inflammation.