Prostaglandin E2 Suppresses Chemokine Production in Human Macrophages through the EP4 Receptor

Why is this work in the frame?

A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.

No Canadian affiliation. An affiliation-only frame — the usual design — would never have seen this work. It is one of the works that make the case for inverting the frame.

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Teacher spread

0.245 · how far apart the two teachers sit on this one work

Validation status

score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Abstract

Pro-inflammatory pathways participate in the pathogenesis of atherosclerosis. However, the role of endogenous anti-inflammatory pathways in atheroma has received much less attention. Therefore, using cDNA microarrays, we screened for genes regulated by prostaglandin E2 (PGE2), a potential endogenous anti-inflammatory mediator, in lipopolysaccharide (LPS)-treated human macrophages (MΦ). PGE2 (50 nm) attenuated LPS-induced mRNA and protein expression of chemokines including monocyte chemoattractant protein-1, interleukin-8, macrophage inflammatory protein-1α and -1β, and interferon-inducible protein-10. PGE2 also inhibited the tumor necrosis factor-α-, interferon-γ-, and interleukin-1β-mediated expression of these chemokines. In contrast to the case of MΦ, PGE2 did not suppress chemokine expression in human endothelial and smooth muscle cells (SMC) treated with LPS and pro-inflammatory cytokines. To assess the potential paracrine effect of endogenous PGE2 on macrophage-derived chemokine production, we co-cultured MΦ with SMC in the presence of LPS. In these co-cultures, cyclooxygenase-2-dependent PGE2 production exceeded that in the mono-cultures, and MIP-1β declined significantly compared with MΦ cultured without SMC. We further documented prominent expression of the PGE2receptor EP4 in MΦ in both culture and human atheroma. Moreover, a selective EP4 antagonist completely reversed PGE2-mediated suppression of chemokine production. Thus, endogenous PGE2may modulate inflammation during atherogenesis and other inflammatory diseases by suppressing macrophage-derived chemokine production via the EP4 receptor. Pro-inflammatory pathways participate in the pathogenesis of atherosclerosis. However, the role of endogenous anti-inflammatory pathways in atheroma has received much less attention. Therefore, using cDNA microarrays, we screened for genes regulated by prostaglandin E2 (PGE2), a potential endogenous anti-inflammatory mediator, in lipopolysaccharide (LPS)-treated human macrophages (MΦ). PGE2 (50 nm) attenuated LPS-induced mRNA and protein expression of chemokines including monocyte chemoattractant protein-1, interleukin-8, macrophage inflammatory protein-1α and -1β, and interferon-inducible protein-10. PGE2 also inhibited the tumor necrosis factor-α-, interferon-γ-, and interleukin-1β-mediated expression of these chemokines. In contrast to the case of MΦ, PGE2 did not suppress chemokine expression in human endothelial and smooth muscle cells (SMC) treated with LPS and pro-inflammatory cytokines. To assess the potential paracrine effect of endogenous PGE2 on macrophage-derived chemokine production, we co-cultured MΦ with SMC in the presence of LPS. In these co-cultures, cyclooxygenase-2-dependent PGE2 production exceeded that in the mono-cultures, and MIP-1β declined significantly compared with MΦ cultured without SMC. We further documented prominent expression of the PGE2receptor EP4 in MΦ in both culture and human atheroma. Moreover, a selective EP4 antagonist completely reversed PGE2-mediated suppression of chemokine production. Thus, endogenous PGE2may modulate inflammation during atherogenesis and other inflammatory diseases by suppressing macrophage-derived chemokine production via the EP4 receptor. Atherosclerosis involves chronic vascular inflammation mediated by pro-inflammatory molecules such as cytokines, chemokines, adhesion molecules, growth factors, and proteases (1Libby P. Circulation. 1995; 91: 2844-2850Crossref PubMed Scopus (1807) Google Scholar, 2Libby P. Ridker P.M. Maseri A. Circulation. 2002; 105: 1135-1143Crossref PubMed Scopus (5792) Google Scholar). During atherogenesis, these factors can act in an autocrine or paracrine manner to regulate cell migration, proliferation, apoptosis, and extracellular matrix metabolism. However, atheroma formation may not occur in a continuous and linear fashion (3Libby P. Braunwald E. Zipes D.P. Libby P. Heart Disease: A Textbook of Cardiovascular Medicine. Harcourt, Philadelphia2001: 995-1009Google Scholar). The balance between persistent pro-inflammatory signals and intrinsic anti-inflammatory pathways likely determines development, progression, and clinical manifestation of atherosclerotic plaques. Several therapeutic strategies may decrease the progression of atherosclerosis through the regulation of the inflammatory response. For example, in addition to its original intended targets, lipid lowering therapy also stabilizes lesions by decreasing the expression of pro-inflammatory molecules including matrix metalloproteinases (MMPs), 1The abbreviations used are: MMP, matrix metalloproteinase; PG, prostaglandin; LPS, lipopolysaccharide; MΦ, macrophage; MCP-1, monocyte chemoattractant protein-1; MIP-1, macrophage inflammatory protein-1; IP-10, interferon-inducible protein-10; EC, endothelial cell(s); SMC, smooth muscle cell(s); COX, cyclooxygenase; Th1, T helper cell type 1; RPA, RNase protection assay; CREB, cAMP response element-binding protein; PKA, cAMP-dependent protein kinase A; TXA2, thromboxane A2; PPAR, peroxisome proliferator-activated receptor; IL, interleukin; RANTES, regulated on activation normal T cell expressed and secreted; 8-Br-cAMP, 8-bromo-cAMP; IFN, interferon; TNF, tumor necrosis factor; ELISA, enzyme-linked immunosorbent assay; RT, reverse transcriptase; PBS, phosphate-buffered saline 1The abbreviations used are: MMP, matrix metalloproteinase; PG, prostaglandin; LPS, lipopolysaccharide; MΦ, macrophage; MCP-1, monocyte chemoattractant protein-1; MIP-1, macrophage inflammatory protein-1; IP-10, interferon-inducible protein-10; EC, endothelial cell(s); SMC, smooth muscle cell(s); COX, cyclooxygenase; Th1, T helper cell type 1; RPA, RNase protection assay; CREB, cAMP response element-binding protein; PKA, cAMP-dependent protein kinase A; TXA2, thromboxane A2; PPAR, peroxisome proliferator-activated receptor; IL, interleukin; RANTES, regulated on activation normal T cell expressed and secreted; 8-Br-cAMP, 8-bromo-cAMP; IFN, interferon; TNF, tumor necrosis factor; ELISA, enzyme-linked immunosorbent assay; RT, reverse transcriptase; PBS, phosphate-buffered salinetissue factor, MCP-1, and CD40 ligand (4Aikawa M. Rabkin E. Okada Y. Voglic S.J. Clinton S.K. Brinckerhoff C.E. Sukhova G.K. Libby P. Circulation. 1998; 97: 2433-2444Crossref PubMed Scopus (529) Google Scholar, 5Aikawa M. Voglic S.J. Sugiyama S. Rabkin E. Taubman M.B. Fallon J.T. Libby P. Circulation. 1999; 100: 1215-1222Crossref PubMed Scopus (146) Google Scholar, 6Bustos C. Hernandez-Presa M.A. Ortego M. Tunon J. Ortega L. Perez F. Diaz C. Hernandez G. Egido J. J. Am. Coll. Cardiol. 1998; 32: 2057-2064Crossref PubMed Scopus (413) Google Scholar). PPARα agonists such as the fibric acid derivatives, beyond effect on the lipid profiles, can exert anti-inflammatory properties by suppression of vascular cell adhesion molecule-1 and tissue factor (7Marx N. Mackman N. Schonbeck U. Yilmaz N. Hombach V., V Libby P. Plutzky J. Circulation. 2001; 103: 213-219Crossref PubMed Scopus (154) Google Scholar). However, the roles and molecular mechanisms of endogenous anti-inflammatory pathways in the evolving atherosclerotic plaque remain incompletely understood. Atheroma, like other inflammatory lesions, display increased biosynthesis of eicosanoids such as prostacyclin (PGI2), thromboxane A2 (TXA2), and PGE2(8Rolland P.H. Jouve R. Pellegrin E. Mercier C. Serradimigni A. Arteriosclerosis. 1984; 4: 70-78Crossref PubMed Google Scholar). Previous studies demonstrated that human atheroma contain both cyclooxygenase isoforms (COX-1 and COX-2), the key enzymes of prostanoid synthesis (9Schonbeck U. Sukhova G.K. Graber P. Coulter S. Libby P. Am. J. Pathol. 1999; 155: 1281-1291Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar, 10Belton O. Byrne D. Kearney D. Leahy A. Fitzgerald D.J. Circulation. 2000; 102: 840-845Crossref PubMed Scopus (371) Google Scholar, 11Cipollone F. Prontera C. Pini B. Marini M. Fazia M., De Cesare D. Iezzi A. Ucchino S. Boccoli G. Saba V. Chiarelli F. Cuccurullo F. Mezzetti A. Circulation. 2001; 104: 921-927Crossref PubMed Scopus (353) Google Scholar). Eicosanoids regulate a broad range of physiological functions. In the context of atherosclerosis, PGI2 or PGE2 inhibits platelet activation and also relaxes vascular smooth muscle cells (SMC) by augmenting intracellular cyclic AMP (cAMP), whereas TXA2 activates platelets and contracts SMC by increasing intracellular Ca2+ (12Coleman R.A. Smith W.L. Narumiya S. Pharmacol. Rev. 1994; 46: 205-229PubMed Google Scholar). Furthermore, PGE2 can inhibit SMC proliferation induced by IL-1 (13Libby P. Warner S.J. Friedman G.B. J. Clin. Invest. 1988; 81: 487-498Crossref PubMed Scopus (408) Google Scholar) and augment MMP-2 and MMP-9 expression in macrophages (MΦ), proteolytic enzymes that may promote vulnerability of atheroma (11Cipollone F. Prontera C. Pini B. Marini M. Fazia M., De Cesare D. Iezzi A. Ucchino S. Boccoli G. Saba V. Chiarelli F. Cuccurullo F. Mezzetti A. Circulation. 2001; 104: 921-927Crossref PubMed Scopus (353) Google Scholar). In contrast to the pro-inflammatory properties of PGE2, some recent data show that PGE2 modulates the T helper cell type 1 (Th1) response, impairing the expression of TNF-α, IL-12, and IFN-γ (14van der Pouw Kraan TC Boeije L.C. Smeenk R.J. Wijdenes J. Aarden L.A. J. Exp. Med. 1995; 181: 775-779Crossref PubMed Scopus (631) Google Scholar, 15Hilkens C. Snijders A. Vermeulen H. van der Meide M.P. Wierenga E. Kapsenberg M. Ann. N. Y. Acad. Sci. 1996; 795: 349-350Crossref PubMed Scopus (24) Google Scholar). However, the potential role of PGE2 as an endogenous anti-inflammatory mediator in human atheroma remains undefined. Here we have applied transcriptional profiling using cDNA microarrays to unveil the effects of several prostanoids and other endogenous mediators on LPS-activated human MΦ. Our results indicate that PGE2 selectively suppresses expression of several chemokines in activated MΦ. Furthermore, we identify the EP4 receptor as the predominant PGE2 receptor isoform present in human MΦ both in culture and in human atheroma, and the involvement of EP4 receptor in the signaling of this novel anti-inflammatory effect of PGE2. All prostanoids and anti-human EP4 receptor antiserum were purchased from Cayman Chemical Co. (Ann Arbor, MI). An EP4 receptor-selective antagonist, L-161,982 (EP4A), and a chemically related inactive analog, L-161,983, were kindly provided by Drs. R. N. Young and M. Abromovitz (Merck Frosst Canada & Co., Kirkland, Quebec, Canada). LPS from Escherichia coli O55:B5 (Calbiochem, La Jolla, CA), human recombinant IL-1β, TNF-α, and IFN-γ (Endogen Inc., Cambridge, MA) were used for cell stimulation. Monocytes were isolated by density-gradient centrifugation, employing Lymphocyte Separation Medium (ICN Biomedicals, Aurora, OH) and subsequence adherence to cell culture dishes from leukopacs of healthy donors. Monocytes were cultured in M199 medium (BioWhittaker, Walkersville, MD) containing 5% human serum (ICN Biomedicals) for 7–9 days to obtain MΦ. Forty-eight h before and during the experiments, the MΦ were incubated in M199 medium containing 1% human serum. Human SMC and endothelial cells (EC) were isolated from human saphenous veins and cultured as described previously (9Schonbeck U. Sukhova G.K. Graber P. Coulter S. Libby P. Am. J. Pathol. 1999; 155: 1281-1291Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar). Both cell types were used after three or four passages. SMC were maintained in DMEM supplemented with penicillin/streptomycin, amphotericin B, and 10% fetal bovine serum, and then cultured 24 h before the experiment in serum-free insulin/transferrin media as described previously (13Libby P. Warner S.J. Friedman G.B. J. Clin. Invest. 1988; 81: 487-498Crossref PubMed Scopus (408) Google Scholar). EC were maintained in M199 medium supplemented with penicillin/streptomycin, amphotericin B, heparin (50 μg/ml), endothelial cell growth factor derived from bovine brains, and 5% fetal bovine serum, and then cultured for 12 h before the experiment in M199 medium containing 5% fetal calf serum without endothelial cell growth factor and heparin. Human MΦ were treated with or without PGE2 (50 nm) for 2 h and then cultured with or without LPS (1 ng/ml) for 5 h. After the stimulation, total RNA was isolated by RNeasy (Qiagen, Valencia, CA) and treated with DNase I. The cDNA microarray experiments were performed with GF211 cDNA array (Research Genetics, Huntsville, AL) containing 4324 known genes. One microgram of total RNA from each experimental condition was used to synthesize 33P-labeled probes. The hybridization, the data collection, and the data normalization were performed as described previously (16Garcia-Cardena G. Comander J. Anderson K.R. Blackman B.R. Gimbrone Jr., M.A. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 4478-4485Crossref PubMed Scopus (455) Google Scholar). The data were analyzed with (Research and J. Gimbrone Jr., M.A. G. 2001; PubMed Scopus Google Scholar) and expressed as the the expression between transcriptional was performed and the results of were the mRNA and protein as described for human chemokines was performed using and CA) to the of the After the was to and to the of the using of MCP-1, and were by using the recombinant and purchased from The of PGE2 was using a PGE2 SMC were cultured on 24 in a culture to with the medium described were cultured in a for 7–9 The with SMC were MΦ for and M199 containing 1% human serum with or without or Cayman were After of LPS was a of 5 for 24 h. the culture medium was to MIP-1β and PGE2. of DNase total RNA from human MΦ was by the of cDNA were by in a containing and The condition for was for of and by an for The of and for PGE2 receptor isoforms as and and and and were using and with MΦ were with and on in 1 1% and supplemented with of protein was by and to a The was in containing 5% and After 2 h of with anti-human EP4 receptor antiserum the was with containing and a with was for 1 h. the was and protein was using for cAMP response element-binding protein and was performed using and Human MΦ were cultured in for were in with normal serum, and then incubated with receptor antiserum or serum for After in PBS, the were incubated with a with were with CA) and with from human and and were from and were in for 5 treated with containing and then incubated with receptor or was performed using CA) to the of the was with expressed as was To unveil potential anti-inflammatory pathways mediated by PGE2 in human atherosclerosis, we used cDNA as All experiments used MΦ derived from human After days of MΦ were treated with PGE2 (50 nm) or for 2 h and then treated with 1 LPS. In the LPS the expression of of the genes a LPS PGE2 attenuated the expression of four the genes of LPS four MIP-1β and regulation of of the chemokine genes did not completely the the microarray data that PGE2 selectively chemokine expression in human MΦ with LPS that chemokines potential for the expression between by cDNA microarray in a the expression between by cDNA microarray To the microarray we used a to regulation of potential chemokines in MΦ isolated from donors. LPS induced MCP-1, IP-10, and mRNA expression with the expression of MCP-1, and and as by not the of mRNA Furthermore, addition of PGE2 the of LPS suppression of chemokine expression to not experiments the production by MΦ of the with mRNA the of MCP-1, IP-10, and from MΦ and for in three 2 Moreover, PGE2 inhibited MIP-1β production in a manner with an of display increased biosynthesis of We compared the anti-inflammatory of PGE2 with other prostanoids in atheroma such as and of PGE2 inhibited LPS-induced MIP-1β production, whereas the other prostanoids did not significantly inhibit MIP-1β production or not pro-inflammatory such as TNF-α, IL-1β, and IFN-γ participate in Thus, we the effect of PGE2 on chemokine production induced by pro-inflammatory cytokines. TNF-α, IL-1β, or IFN-γ induced MIP-1β production to a LPS. PGE2 significantly MIP-1β production induced in the presence of pro-inflammatory such as TNF-α, IL-1β, IFN-γ TNF-α, and IFN-γ and for in three as as LPS IFN-γ or production to a LPS. in the case of PGE2 significantly production from activated MΦ In human atheroma, EC and SMC also chemokines. We the cell of the effect of PGE2 in cells in atheroma by TNF-α, LPS, or LPS IFN-γ induced MCP-1, IP-10, and to in both cell types However, in contrast to the case of MΦ, PGE2 or effect on chemokine expression in EC or SMC We that PGE2 chemokine expression in human MΦ. we the effects of endogenous PGE2 in a SMC synthesize PGE2 in response to pro-inflammatory such as and (13Libby P. Warner S.J. Friedman G.B. J. Clin. Invest. 1988; 81: 487-498Crossref PubMed Scopus (408) Google Scholar, M. M. M.A. L. 2000; PubMed Scopus Google both by activated MΦ. Thus, to assess potential anti-inflammatory effects of PGE2, MΦ were co-cultured with SMC in the presence of LPS for 24 h described The culture medium MIP-1β and PGE2 after this LPS ng/ml) did not PGE2 synthesis in MΦ or SMC cultured whereas LPS PGE2 in the In co-cultures, significantly compared with MΦ cultured without SMC for three the we the effect of types of a J. J. D. M. R. E. B. S. C. J. 1994; PubMed Scopus Google or a D. J. Med. 1999; PubMed Scopus Google to the before LPS stimulation, inhibited PGE2 synthesis and increased production of MIP-1β production compared with the without PGE2 receptor isoforms the of PGE2 (12Coleman R.A. Smith W.L. Narumiya S. Pharmacol. Rev. 1994; 46: 205-229PubMed Google Scholar). We human MΦ these demonstrated mRNA the EP4 receptor in MΦ Moreover, human MΦ EP4 receptor as demonstrated by and and After a for receptor mRNA not A antagonist, L-161,982 nm) M. S. G. M. M. S. N. N. D. Young R. Pharmacol. 2001; PubMed Scopus (146) Google completely reversed the anti-inflammatory of PGE2 in LPS-activated human In three experiments, the of MIP-1β production was antagonist and An inactive of the antagonist did not significantly the anti-inflammatory effect of PGE2. nm) induced MIP-1β production in human a role for the EP4 receptor in the anti-inflammatory of PGE2 in human The EP4 receptor D. Rev. 2000; PubMed Scopus Google Scholar). Several that the signaling for the EP4 receptor involves cAMP-dependent protein kinase A and its such as We the role of of this signaling in the effect of PGE2 on MIP-1β production by using a cell of and a and the between the anti-inflammatory of PGE2 and the of to PGE2, with MIP-1β production in LPS-activated MΦ inhibited PGE2 or of However, did not reverse the effect of MIP-1β production in MΦ in three experiments was for PGE2 for that and not participate in this To to human we the expression of the EP4 receptor in human atherosclerotic lesions by of human atheroma with and smooth muscle The EP4 receptor in lesions to a in smooth muscle cells In or EP4 receptor Human atheroma contain chemokines including MCP-1, IP-10, and D. J. Clin. Invest. PubMed Google Scholar, F. A. Sukhova G.K. Libby P. J. Clin. Invest. 1999; 104: PubMed Scopus Google Scholar, Fallon J.T. M. G. Taubman M.B. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J. P. 1996; PubMed Scopus Google Scholar). of the for MCP-1, its receptor or the of significantly atherogenesis in L. J. M. 1998; PubMed Scopus Google Scholar, L. Okada Y. Clinton S.K. C. Sukhova G.K. Libby P. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, R. R.A. J. Clin. Invest. 1998; PubMed Scopus Google Scholar). chemokine expression of and T cells in the atherosclerotic that MIP-1β and the response that by tissue factor expression on SMC or platelet Fallon J.T. M. G. Taubman M.B. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. F. Sukhova G.K. Libby P. 2000; PubMed Scopus Google Scholar). Thus, chemokines a role in the and of atheroma. and pro-inflammatory such as IL-1β, or CD40 ligand chemokine expression in cells in atheroma, such as EC, SMC, and MΦ A. G. S. Libby P. M. I. F. A. PubMed Google Scholar, Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, R. J. D. 1994; PubMed Google Scholar). However, of potential endogenous mechanisms has of pro-inflammatory that PGE2 selectively and suppresses the expression of MCP-1, and in LPS-activated human MΦ. PGE2 inhibits chemokine production by MΦ. we did not suppression by PGE2 of chemokine expression in activated EC and SMC in the of the effects of PGE2 for MΦ. cell in the molecular mechanisms of the anti-inflammatory of PGE2. endogenous agonists such as or PPARα can inflammatory of other cells in atherogenesis, such as EC and SMC as as MΦ F. A. Sukhova G.K. Libby P. J. Clin. Invest. 1999; 104: PubMed Scopus Google Scholar, R. Libby P. Am. J. Clin. 2000; PubMed Google Scholar, R. Libby P. Gimbrone Jr., M.A. J. Clin. Invest. 1995; PubMed Scopus Google Scholar). Our data show that PGE2 may the of inflammation by MΦ. for MIP-1β and R. G. D. R. A. S. P. A. F. J. Exp. Med. 1998; PubMed Scopus Google Scholar). of cells and increased production of IFN-γ in atheroma can plaque by suppressing synthesis and expression of pro-inflammatory mediators by EC, SMC, and MΦ (3Libby P. Braunwald E. Zipes D.P. Libby P. Heart Disease: A Textbook of Cardiovascular Medicine. Harcourt, Philadelphia2001: 995-1009Google Scholar, S. N. C. J. Clin. Invest. PubMed Scopus Google Scholar). PGE2 may IFN-γ expression in atheroma by suppressing chemokines such as or PGE2 synthesis from acid involves isoforms of (COX-1 and cells types PubMed Scopus Google Scholar). In expression of to pro-inflammatory such as TNF-α, IL-1β, CD40 or LPS (9Schonbeck U. Sukhova G.K. Graber P. Coulter S. Libby P. Am. J. Pathol. 1999; 155: 1281-1291Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, D.P. J. Full Text PDF PubMed Google Scholar). cells in atheroma, SMC PGE2 in response to pro-inflammatory by the of protein (13Libby P. Warner S.J. Friedman G.B. J. Clin. Invest. 1988; 81: 487-498Crossref PubMed Scopus (408) Google Scholar, M. M. M.A. L. 2000; PubMed Scopus Google Scholar, D. R. PubMed Scopus Google Scholar). MΦ co-cultured with SMC, we demonstrated that MIP-1β production in MΦ. In this LPS ng/ml) did not PGE2 synthesis in SMC of LPS can production of pro-inflammatory such as and by MΦ not macrophage-derived can then augment from SMC in a paracrine A PGE2 production and the production of MIP-1β in the a pro-inflammatory recent that may of inflammation D. J. Med. 1999; PubMed Scopus Google Scholar). Our that can also exert an anti-inflammatory in human atheroma through suppression of chemokine and exert via cell or such as the and can act as agonists for PPARα and J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google these (50 nm) did not inhibit chemokine expression in MΦ not that activation not likely for the anti-inflammatory of PGE2 described The of cell its anti-inflammatory (12Coleman R.A. Smith W.L. Narumiya S. Pharmacol. Rev. 1994; 46: 205-229PubMed Google Scholar, D. Rev. 2000; PubMed Scopus Google Scholar). We demonstrated that human MΦ the EP4 receptor. The experiment using a EP4 receptor-selective antagonist a role for the EP4 receptor in the anti-inflammatory of PGE2 in human MΦ. We the expression of EP4 receptor protein human atheroma. The EP4 receptor in lesions, with a role in inflammation during recent demonstrated that of the for EP4 PGE2-mediated of and in LPS-activated macrophages C. R. J. Clin. Invest. 2001; PubMed Scopus Google the role of the EP4 receptor in the anti-inflammatory in The of PGE2 with the EP4 receptor intracellular cAMP activates PKA, such as D. Rev. 2000; PubMed Scopus Google Scholar). in some PGE2 mediated by the EP4 receptor. In this a cAMP analog, 8-Br-cAMP, inhibited MIP-1β production. However, experiments did not involvement of the and in chemokine suppression by PGE2 in MΦ. In may by a of mechanisms Mackman N. J. Google Scholar). expression of the genes MCP-1, IP-10, and A. S. A. J. S. Y. J. 1994; Google Scholar, U. K.R. A. B. J. Google Scholar, S. J. Med. 1999; Google Scholar). However, involvement of the signaling in MIP-1β expression U. K.R. A. B. J. Google Scholar, R.J. J. Google Scholar). Our cDNA microarray demonstrated that PGE2 selectively a of genes induced by LPS. For example, PGE2 did not suppress expression of RANTES, a H. M. J. Google Scholar). results indicate that the suppression of not for the mediated anti-inflammatory of PGE2. of the by EP4 receptor suppresses chemokine production in MΦ further In these results a novel role of PGE2 as an endogenous of a of potential to atherosclerosis and other chronic inflammatory a this the that of receptor signaling a therapeutic for these clinical data have the that may in some D. 2001; PubMed Scopus Google Scholar). Therefore, of anti-inflammatory pathways by may have and clinical in addition to We Drs. R. N. Young and M. Abromovitz of Frosst Canada & Co. for the of the EP4 receptor antagonist and related inactive We E. A. S. and E. for and for

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

The record

Venue

Journal of Biological Chemistry

Topic

Inflammatory mediators and NSAID effects

Field

Medicine

Canadian institutions

—

Funders

National Heart, Lung, and Blood Institute

Keywords

Prostaglandin E2 receptorProstaglandin E2ChemokineChemistryCell biologyReceptorCCL21Production (economics)Chemokine receptorBiologyEndocrinologyBiochemistryAgonistEconomics

Has abstract in OpenAlex

yes

API

/api/v1/works/W2138877935