Endogenous prostaglandin E2 potentiates anti‐inflammatory phenotype of macrophage through the CREB‐C/EBP‐β cascade. Issue 9 (20th July 2015)

• Record Type: Journal Article
• Authors: Na, Yi Rang; Jung, Daun; Yoon, Bo Ruem; Lee, Won Woo; Seok, Seung Hyeok
• Is Part Of: European journal of immunology. Volume 45:Issue 9(2015:Sep.)
• Page Start: 2661
• Page End: 2671
• Publication Date: 2015-07-20
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201545471
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Macrophages have important functions in tissue homeostasis, but the exact mechanisms regarding wide spectrum of macrophage phenotype remain unresolved. In this study, we report that mouse bone marrow derived naïve macrophages produce prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) endogenously, resulting in anti‐inflammatory gene expression upon differentiation induced by macrophage colony stimulating factor (M‐CSF). Cyclooxygenase (COX) inhibition by indomethacin reduced endogenous PGE<sub>2</sub> production of macrophages and subsequently reduced <italic>arg1</italic>, <italic>IL10</italic> and <italic>Mrc1, YmI</italic> and <italic>FizzI</italic> gene expressions. Of note, PGE<sub>2</sub> phosphorylates CREB via EP2 and EP4 receptor ligation, thereby transcriptionally increasing C/EBP‐β expression in BALB/c bone marrow derived macrophages. Activated CREB directly binds to the CREB‐responsive element of the C/EBP‐β promoter, such that PGE<sub>2</sub> ultimately reinforces <italic>arg1</italic>, <italic>IL10</italic> and <italic>Mrc1</italic> gene expression. Cyclic AMP activator forskolin also phosphorylated CREB and induced the C/EBP‐β cascade, but this was completely blocked by the PKA inhibitor, H89. Consequently, M‐CSF grown macrophages inhibited T‐cell proliferation but the inhibition ability was reduced when the COX is inhibited by indomethacin or macrophage C/EBP‐β expression was decreased by siRNA transduction. Our results collectively describe the molecular basis for homeostatic macrophage differentiation by endogenous PGE<sub>2</sub>.</p> </abstract>