Endogenous prostaglandin E2 potentiates anti‐inflammatory phenotype of macrophage through the CREB‐C/EBP‐β cascade

Abstract

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 2 (PGE 2 ) 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 2 production of macrophages and subsequently reduced arg1, IL10 and Mrc1, YmI and FizzI gene expressions. Of note, PGE 2 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 2 ultimately reinforces arg1, IL10 and Mrc1 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 2 .Keywords: C/EBP-β r CREB r Homeostasis r Macrophages r Prostaglandin E 2 Additional supporting information may be found in the online version of this article at the publisher's web-site Macrophages play a pivotal role in the innate immune system by sensing and killing microbes. Moreover, macrophages have important roles in almost every aspect of an organism's biology including development, tissue repair, and homeostasis [1]. TisCorrespondence: Prof. Seung Hyeok Seok e-mail: lamseok@snu.ac.kr sue macrophages are highly heterogenous in terms of their functions and phenotypes as a consequence of adapting to different tissue environments, where they monitor the local environment and maintain homeostasis [2]. * Both authors contributed equally. Eur. J. Immunol. 2015Immunol. . 45: 2661Immunol. -2671 Historically, all tissue macrophages were considered to be derived from circulating monocytes that originate from hematopoietic stem cells [3]. Recent studies revealed that a substantial portion of tissue macrophages arise from the yolk sac during embryogenesis, and are maintained by local proliferation [4]. Regardless of their origin, macrophages acquire unique characteristics depending on their tissue-specific microenvironment [5]. Macrophage colony-stimulating factor (M-CSF) generally differentiates macrophages with homeostatic function in vivo [6]. Likewise, tissue-specific factors such as GM-CSF in lung alveoli and fat-cell-derived adipokines in adipose tissue also affect macrophage phenotypes. Infections greatly change local tissue microenvironments, particularly when blood-derived monocytes infiltrate infected areas and differentiate into macrophag...

eIF4E-Binding Proteins 1 and 2 Limit Macrophage Anti-Inflammatory Responses through Translational Repression of IL-10 and Cyclooxygenase-2

“…PGs are autocrine and paracrine lipid mediators that maintain local homeostasis. Endogenous PGE 2 production potentiates macrophage anti-inflammatory responses via activation of C/EBPb signaling (42). Our data indicated that induction of PGE 2 synthesis in LPS-stimulated cells is augmented in the absence of 4E-BP1/2.…”

“…COX-2 is a rate-limiting enzyme in the production of PGE 2 , a lipid mediator involved in numerous physiological and pathological processes, including inflammation (42). We found that translation efficiency of Cox-2 mRNA is amplified in 4E-BP1/2 DKO as compared with WT BMDM at steady-state (Fig.…”

“…Consistent with the central role of IL-10 and COX-2 in antiinflammatory responses (35,36,42,44), their expression is tightly regulated through transcriptional and posttranscriptional mechanisms, including RNA stability and translational control via RNA-binding proteins, such as T cell intracellular Ag 1 (TIA-1) and tristetraprolin (reviewed in Refs. 67,68).…”

“…C/EBPb is required for transcriptional activation of antiinflammatory genes in macrophages (42,44). We predicted that amplified PGE 2 -C/EBPb signaling would promote this cellular response in 4E-BP1/2 DKO BMDM.…”

E prostanoid receptor 4 expressing macrophages promote the regeneration of the intestinal epithelial barrier upon inflammation

“…However, the specific mode of action of PGE2 on wound 15 healing macrophages in the intestine remains unclear. In our previous study, endogenous PGE2 was found to potentiate the anti-inflammatory phenotype of resident macrophages (19). In addition, inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a PG-degrading enzyme, stimulated tissue regeneration in dextran sodium sulfate (DSS) colitis (20).…”