Disease relevance of Ptger4

• The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut [1].
• Thus, PGE2 contributes to disease progression at least in part by binding to the EP4 receptor [2].
• Prostaglandin E receptor EP4 antagonism inhibits breast cancer metastasis [3].
• Bt(2)cAMP greatly stimulated bone resorption similarly in both wild-type and EP4-knockout mice [4].
• Induction of adherent activity in mastocytoma P-815 cells by the cooperation of two prostaglandin E2 receptor subtypes, EP3 and EP4 [5].

High impact information on Ptger4

• Here we show that although Langerhans cells express all four PGE receptor subtypes, their migration to regional lymph nodes was decreased only in EP4-deficient (Ptger4-/-) mice and in wild-type mice treated with an EP4 antagonist [6].
• An EP4 agonist promoted the migration of Langerhans cells, increased their expression of costimulatory molecules and enhanced their ability to stimulate T cells in the mixed lymphocyte reaction in vitro [6].
• Contact hypersensitivity to antigen was impaired in Ptger4-/- mice and in wild-type mice treated with the EP4 antagonist during sensitization [6].
• This requirement is absent in mice lacking the prostaglandin E2 EP4 receptor (EP4(-/-) mice) [7].
• The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth [7].

Chemical compound and disease context of Ptger4

• Our results show for the first time that antagonism of the EP4 receptor with either AH23848 or ONO-AE3-208 reduced metastasis as compared with vehicle-treated controls [3].
• Prostaglandin estradiol (PGE(2)) stimulates bone resorption by a cyclic AMP (cAMP)-dependent mechanism that involves prostaglandin E receptors of the EP2 and EP4 subtypes [8].
• Infusion of higher doses of the EP4 agonist at 3 and 10 microg/kg/h attenuated LPS-induced hypotension and hyporeactivity to norepinephrine [9].
• Impaired bone resorption by lipopolysaccharide in vivo in mice deficient in the prostaglandin E receptor EP4 subtype [10].

Biological context of Ptger4

• We conclude that EP4 maintains intestinal homeostasis by keeping mucosal integrity and downregulating immune response [1].
• Promoter analyses of the EP4 receptor gene promoter in RAW 264.7 cells indicated that there is a constitutive negative regulatory region between -992 and -928 bp, a constitutive positive region between -928 and -554 bp, and an LPS/serum-responsive region between -554 and -116 bp [11].
• To study expression of the EP4 receptor we isolated the mouse EP4 receptor gene; the gene is 10 kilobase pairs (kb) in length and, like other known prostanoid receptor genes, contains three exons and two introns [11].
• Pharmacologic inhibition of EP4 receptors in furosemide-treated WT mice with the specific antagonist ONO-AE3-208 mimicked the changes in renin mRNA expression, plasma renin concentration, diuresis, and sodium excretion seen in EP4-/- mice [12].
• However, 9 h after hCG injection, just before ovulation, the signals for EP4 mRNA were still detectable in both cell types, whereas those for EP2 mRNA were found only in cumulus cells [13].

Anatomical context of Ptger4

• The EP4 deficiency impaired mucosal barrier function and induced epithelial loss, crypt damage, and aggregation of neutrophils and lymphocytes in the colon [1].
• Thus, PGE(2) regulates cellular immune responses through distinct EP receptors on different immune cell populations: EP2 receptors directly inhibit T cell proliferation while EP2 and EP4 receptors regulate antigen presenting cells functions [14].
• Thus the results suggest that PGI(2) and PGE(2) generated simultaneously with cytokines by macrophages treated with zymosan may influence the cytokine production through IP, EP2, and EP4 receptors [15].
• The effect of deletion of cyclooxygenase-2, prostaglandin receptor EP2, or EP4 in bone marrow cells on osteoclasts induced by mouse mammary cancer cell lines [16].
• Disruption of the EP2 gene in bone marrow cells had no effect on OC formation in the cocultures, while disruption of the EP4 gene in bone marrow cells abrogated OC formation in the cocultures [16].

Associations of Ptger4 with chemical compounds

• Prostanoid receptors of murine NIH 3T3 and RAW 264.7 cells. Structure and expression of the murine prostaglandin EP4 receptor gene [11].
• The response to endogenous PGE2 was blunted in EP4-receptor-deficient mice only and especially after prolonged incubation [17].
• Similar expression patterns of EP3 and EP4 in the Day 4 pseudopregnant mouse uterus or in the ovariectomized uterus under combined treatment with estrogen and progesterone suggest that these genes are regulated by ovarian steroids rather than by the embryo during the preimplantation period (Days 1-4) [18].
• Crucial involvement of the EP4 subtype of prostaglandin E receptor in osteoclast formation by proinflammatory cytokines and lipopolysaccharide [19].
• The furosemide-induced increase in plasma renin concentration was significantly decreased in EP4-/- mice and to a lesser degree also in IP-/- mice [12].
• Whereas treatment with PGE(2) or the EP4 selective agonists PGE(1)-OH and ONO-AE1-329 induced migration, tubulogenesis, ERK activation and cAMP production in control adenovirus-transduced endothelial EP4(flox/flox) cells, no effects were seen in adenoCre-transduced EP4(flox/flox) cells [20].

Physical interactions of Ptger4

• Among them, EP2 and EP4 couple to Gs and EP3 to Gi [21].
• High levels of expression of functional EP4 receptors coupled with Gs-protein was confirmed in C3L5 cells by biochemical assay showing a dose-dependent increase of intracellular cAMP synthesis in response to PGE2 [22].

Regulatory relationships of Ptger4

• Intracellular TNF-alpha staining was inhibited 20% by EP4/2 agonists [23].
• Furthermore, EP4 RA suppressed OC formation and prevented the increase in receptor activator of nuclear factor kappaB ligand (RANKL) mRNA levels in the cocultures [16].
• These results indicate that PGE2 enhances osteoclast formation through its EP4 subtype on osteoblasts [19].
• In contrast, the EP4 agonist (PGE1-OH) stimulated macrophage MMP-9 expression, which was inhibited by the EP4 antagonist ONO-AE3-208 [24].
• Alkaline phosphatase-positive nodule formation in the absence or presence of XT-611 was inhibited by an antagonist of EP4 receptor, AH23848B, and synergistically potentiated by 11-deoxy-PGE1, but it was not influenced by other EP antagonists and agonists examined [25].

Other interactions of Ptger4

• There are four receptors for PGE(2) (EP1-EP4) with unique patterns of expression and different coupling to intracellular signaling pathways [14].
• In conclusion, our data indicate that LPS activates airway epithelial TLR4 to cause release of PGE(2) and subsequent EP2 and EP4 receptor-dependent smooth muscle relaxation [26].
• We have investigated the role of COX-2, EP2 receptor, and EP4 receptor in marrow cells for osteoclastogenesis in cocultures of cancer cells and bone marrow cells [16].
• TNF-alpha production was inhibited 50-70% at 2-24 h by EP4/2 agonists, whereas IL-6 was enhanced up to approximately 220% [23].
• Because EP4RA partially inhibited osteoclastogenesis not only in response to PGE(2) but also in response to 1,25D and PTH, these results suggest that activation of the EP4 receptor may play a general role in osteoclastic bone resorption [8].

Analytical, diagnostic and therapeutic context of Ptger4

• DNA microarray analysis revealed elevated expression of genes associated with immune response and reduced expression of genes with mucosal repair and remodeling in the colon of EP4-deficient mice [1].
• In addition, an EP4 receptor antagonist (EP4 RA) was added in some cocultures [16].
• In situ hybridization (ISH) showed that EP4 messenger RNA (mRNA) was expressed on osteoblastic cells but not on multinucleated cells (MNCs) in w/t mice [19].
• Finally, Western blot analysis of the levels of the EP4 receptor protein in control vs. NS-398-treated cells revealed an induction in protein levels in these cells, correlating with the induction in EP4 mRNA [27].
• Using a semiquantitative titration analysis method, we show that following the addition of the COX-2-specific inhibitor NS-398, E-prostanoid receptor subtype (EP3 and EP4) mRNA expression was found to increase threefold each vs. the vehicle-treated control [27].

References