Prostaglandin E Receptor Type 4-associated Protein Interacts Directly with NF- B1 and Attenuates Macrophage Activation
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Journal of Biological Chemistry
(Impact Factor: 4.57).
05/2008; 283(15):9692-703. DOI: 10.1074/jbc.M709663200
Macrophage activation participates pivotally in the pathophysiology of chronic inflammatory diseases, including atherosclerosis. Through the receptor EP4, prostaglandin E(2) (PGE(2)) exerts an anti-inflammatory action in macrophages, suppressing stimulus-induced expression of certain proinflammatory genes, including chemokines. We recently identified a novel EP4 receptor-associated protein (EPRAP), whose function in PGE(2)-mediated anti-inflammation remains undefined. Here we demonstrate that PGE(2) pretreatment selectively inhibits lipopolysaccharide (LPS)-induced nuclear factor kappaB1 (NF-kappaB1) p105 phosphorylation and degradation in mouse bone marrow-derived macrophages through EP4-dependent mechanisms. Similarly, directed EPRAP expression in RAW264.7 cells suppresses LPS-induced p105 phosphorylation and degradation, and subsequent activation of mitogen-activated protein kinase kinase 1/2. Forced expression of EPRAP also inhibits NF-kappaB activation induced by various proinflammatory stimuli in a concentration-dependent manner. In co-transfected cells, EPRAP, which contains multiple ankyrin repeat motifs, directly interacts with NF-kappaB1 p105/p50 and forms a complex with EP4. In EP4-overexpressing cells, PGE(2) enhances the protective action of EPRAP against stimulus-induced p105 phosphorylation, whereas EPRAP silencing in RAW264.7 cells impairs the inhibitory effect of PGE(2)-EP4 signaling on LPS-induced p105 phosphorylation. Additionally, EPRAP knockdown as well as deficiency of NF-kappaB1 in macrophages attenuates the inhibitory effect of PGE(2) on LPS-induced MIP-1beta production. Thus, PGE(2)-EP4 signaling augments NF-kappaB1 p105 protein stability through EPRAP after proinflammatory stimulation, limiting macrophage activation.
Available from: Joyce E Rundhaug
- "Kabashima et al.  reported that edema, inflammatory cell infiltration, and local blood flow were reduced in both EP2 and EP4 null mice. Interestingly, EP4 mediates an anti-inflammatory response in macrophages and does so through an EP4 (but not EP2) interacting protein, EP4 receptor-associated protein (EPRAP); the complex also interacts with NFκB . Whether EPRAP is expressed in other cell types is unknown. "
[Show abstract] [Hide abstract]
ABSTRACT: One of the most common features of exposure of skin to ultraviolet (UV) light is the induction of inflammation, a contributor to tumorigenesis, which is characterized by the synthesis of cytokines, growth factors and arachidonic acid metabolites, including the prostaglandins (PGs). Studies on the role of the PGs in non-melanoma skin cancer (NMSC) have shown that the cyclooxygenase-2 (COX-2) isoform of the cyclooxygenases is responsible for the majority of the pathological effects of PGE(2). In mouse skin models, COX-2 deficiency significantly protects against chemical carcinogen- or UV-induced NMSC while overexpression confers endogenous tumor promoting activity. Current studies are focused on identifying which of the G protein-coupled EP receptors mediate the tumor promotion/progression activities of PGE(2) and the signaling pathways involved. As reviewed here, the EP1, EP2, and EP4 receptors, but not the EP3 receptor, contribute to NMSC development, albeit through different signaling pathways and with somewhat different outcomes. The signaling pathways activated by the specific EP receptors are context specific and likely depend on the level of PGE(2) synthesis, the differential levels of expression of the different EP receptors, as well as the levels of expression of other interacting receptors. Understanding the role and mechanisms of action of the EP receptors potentially offers new targets for the prevention or therapy of NMSCs.
CANCER AND METASTASIS REVIEW 12/2011; 30(3-4):465-80. DOI:10.1007/s10555-011-9317-9 · 7.23 Impact Factor
Available from: Rich Breyer
- "Pretreatment of bone marrow-derived macrophages with PGE 2 prior to activation with LPS, results in a transitory attenuation of the early phase of production of chemokines and inflammatory cytokines(Minami et al., 2008). Interestingly, this anti-inflammatory effect is mediated by a novel EP4 receptor associated protein that inhibits LPS induced activation of NFkB(Minami et al., 2008). In the absence of pre-treatment with PGE 2 , we report that activation of EP4 −/− macrophages with LPS results in significant suppression of NF-κB-responsive genes and proteins, and suggesting that macrophage EP-4 may impact atherosclerosis by its effects on inflammatory cytokines such as IL-6 and MCP-1 (Fig. 6). "
[Show abstract] [Hide abstract]
ABSTRACT: Prostaglandin (PG) E(2), a major product of activated macrophages, has been implicated in atherosclerosis and plaque rupture. The PGE(2) receptors, EP2 and EP4, are expressed in atherosclerotic lesions and are known to inhibit apoptosis in cancer cells. To examine the roles of macrophage EP4 and EP2 in apoptosis and early atherosclerosis, fetal liver cell transplantation was used to generate LDLR(-/-) mice chimeric for EP2(-/-) or EP4(-/-) hematopoietic cells. After 8 weeks on a Western diet, EP4(-/-) --> LDLR(-/-) mice, but not EP2(-/-) --> LDLR(-/-) mice, had significantly reduced aortic atherosclerosis with increased apoptotic cells in the lesions. EP4(-/-) peritoneal macrophages had increased sensitivity to proapoptotic stimuli, including palmitic acid and free cholesterol loading, which was accompanied by suppression of activity of p-Akt, p-Bad, and NF-kappaB-regulated genes. Thus, EP4 deficiency inhibits the PI3K/Akt and NF-kappaB pathways compromising macrophage survival and suppressing early atherosclerosis, identifying macrophage EP4-signaling pathways as molecular targets for modulating the development of atherosclerosis.
Cell metabolism 01/2009; 8(6):492-501. DOI:10.1016/j.cmet.2008.09.005 · 17.57 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: A protocol for shortcut-based QoS provisioning, named QRISP
(QoS-oriented receiver-initiated shortcut path), is explained. It
enables setting-up a QoS guaranteed path in IPOA/ATM heterogeneous
environment with a single shot of signalling. QRISP extends previous
work of RISP so that a short-cut path is established in LAN-WAN-LAN
interworking environment without additional negotiation and extension of
IP routers. Related service provisioning and management issues are
Global Telecommunications Conference, 1998. GLOBECOM 98. The Bridge to Global Integration. IEEE; 02/1998
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.