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indirect

indirect

indirect

PMID: 16978535,9348319 On the contrary, PGE2 has also been shown to stimulate DC and promote IL-12 production when given in combination with TNF-alpha PMID: 16978535 The fact that PGE2 and IL-10 strongly inhibit the production of IL-12 implies a feedback mechanism at the level of the APC, and may represent an important mean controlling the differentiation of APC from bone marrow progenitors or from circulating monocytes.

indirect

indirect

indirect

PMID: 16978535,7525853,8739216,9464843 Previous studies showed that PGE2 up-regulates the production of IL-10 by macrophages and T cells PMID: 16978535,1940799 In monocytes, IL-10 synthesis was found to be enhanced after LPS exposure, suggesting that IL-10 may regulate the inflammatory response to LPS.

PMID: 16978535 Based on pharmacological and cDNA cloning studies, four subtypes of PGE receptors designated EP receptors (EP1, EP2, EP3 and EP4) have been identified and have been shown to differ in their signal transduction pathways.

PMID: 16978535 Based on pharmacological and cDNA cloning studies, four subtypes of PGE receptors designated EP receptors (EP1, EP2, EP3 and EP4) have been identified and have been shown to differ in their signal transduction pathways.

PMID: 16978535 Based on pharmacological and cDNA cloning studies, four subtypes of PGE receptors designated EP receptors (EP1, EP2, EP3 and EP4) have been identified and have been shown to differ in their signal transduction pathways.

PMID: 16978535 Based on pharmacological and cDNA cloning studies, four subtypes of PGE receptors designated EP receptors (EP1, EP2, EP3 and EP4) have been identified and have been shown to differ in their signal transduction pathways.

indirect

PMID: 16978535 The EP1 receptor activates phospholipase C and phosphatidylinositol turnover and stimulates the release of intracellular calcium

indirect

PMID: 16978535 The EP1 receptor activates phospholipase C and phosphatidylinositol turnover and stimulates the release of intracellular calcium

indirect

PMID: 16978535 The EP1 receptor activates phospholipase C and phosphatidylinositol turnover and stimulates the release of intracellular calcium

indirect

PMID: 16978535 The EP2 and EP4 receptors signal by stimulating adenylate cyclase, which increases the intracellular levels of cAMP.

indirect

PMID: 16978535 The EP2 and EP4 receptors signal by stimulating adenylate cyclase, which increases the intracellular levels of cAMP. PMID: 16978535 The molecular mechanisms by which PGE2 possibly inhibits iNOS expression could be related to its ability to increase intracellular cAMP levels, which in turn inhibit NF-KappaB/DNA binding activity.

indirect

PMID: 16978535 The EP2 and EP4 receptors signal by stimulating adenylate cyclase, which increases the intracellular levels of cAMP.

PMID: 16978535,11859113 Using EP receptor-selective synthetic agonists and dibutyryl cAMP, we demonstrated that PGE2-EP2 and -EP4 signaling stimulate the production of IL-10 by BM-DC

PMID: 16978535,11859113 Using EP receptor-selective synthetic agonists and dibutyryl cAMP, we demonstrated that PGE2-EP2 and -EP4 signaling stimulate the production of IL-10 by BM-DC

indirect

indirect

PMID: 16978535,11859113 Using EP receptor-selective synthetic agonists and dibutyryl cAMP, we demonstrated that PGE2-EP2 and -EP4 signaling stimulate the production of IL-10 by BM-DC

indirect

indirect

indirect

PMID: 16978535,11859113 Using EP receptor-selective synthetic agonists and dibutyryl cAMP, we demonstrated that PGE2-EP2 and -EP4 signaling stimulate the production of IL-10 by BM-DC PMID: 16978535 Agonists of cAMP-elevating receptors, such as butaprost (EP2 receptor), dose-dependently enhanced IL-10 production from LPS-stimulated BM-DC PMID: 16978535,11859113 The enhanced BM-DC release of IL-10 observed after LPS stimulation appears to be closely connected to COX-2 activity as the COX-2-selective inhibitor NS-398 significantly reduced IL-10 levels

PMID: 16978535,11859113 Using EP receptor-selective synthetic agonists and dibutyryl cAMP, we demonstrated that PGE2-EP2 and -EP4 signaling stimulate the production of IL-10 by BM-DC

indirect

indirect

indirect

PMID: 16978535,11859113 Using EP receptor-selective synthetic agonists and dibutyryl cAMP, we demonstrated that PGE2-EP2 and -EP4 signaling stimulate the production of IL-10 by BM-DC PMID: 16978535 Agonists of cAMP-elevating receptors, such as butaprost (EP2 receptor), dose-dependently enhanced IL-10 production from LPS-stimulated BM-DC PMID: 16978535,11859113 The enhanced BM-DC release of IL-10 observed after LPS stimulation appears to be closely connected to COX-2 activity as the COX-2-selective inhibitor NS-398 significantly reduced IL-10 levels

indirect

indirect

PMID: 16978535,11859113 Using EP receptor-selective synthetic agonists and dibutyryl cAMP, we demonstrated that PGE2-EP2 and -EP4 signaling stimulate the production of IL-10 by BM-DC

PMID: 16978535,11859113 Using EP receptor-selective synthetic agonists and dibutyryl cAMP, we demonstrated that PGE2-EP2 and -EP4 signaling stimulate the production of IL-10 by BM-DC

PMID: 16978535 In fact, microbial products such as LPS activate TLR4-derived signaling pathways including NF-KappaB and/or MAPK, which results in the induction of cyclooxygenase (COX)-2 and the production of PGE2 PMID: 16978535 Figure 1

indirect

PMID: 16978535 In fact, microbial products such as LPS activate TLR4-derived signaling pathways including NF-KappaB and/or MAPK, which results in the induction of cyclooxygenase (COX)-2 and the production of PGE2 PMID: 16978535 Figure 1

indirrect

PMID: 16978535 In fact, microbial products such as LPS activate TLR4-derived signaling pathways including NF-KappaB and/or MAPK, which results in the induction of cyclooxygenase (COX)-2 and the production of PGE2 PMID: 16978535 Figure 1

indirect

indirect

PMID: 16978535 In fact, microbial products such as LPS activate TLR4-derived signaling pathways including NF-KappaB and/or MAPK, which results in the induction of cyclooxygenase (COX)-2 and the production of PGE2 PMID: 16978535 Figure 1 PMID: 16978535 Pro-inflammatory cytokines, such as TNF-α are also able to induce COX-2 expression and PGE2 production by cells of immune system, particularly DC. PMID: 16978535,15219461 Moreover, we have recently demonstrated that IL-10 suppresses COX-2 protein expression and PG production in BM-DC PMID: 16978535 Antiinflammatory cytokines, such as IL-4, IL-13, and IL-10 can inhibit COX-2 induction.

indirect

indirect

PMID: 16978535 In fact, microbial products such as LPS activate TLR4-derived signaling pathways including NF-KappaB and/or MAPK, which results in the induction of cyclooxygenase (COX)-2 and the production of PGE2 PMID: 16978535 Figure 1

indirect

PMID: 16978535 In fact, microbial products such as LPS activate TLR4-derived signaling pathways including NF-KappaB and/or MAPK, which results in the induction of cyclooxygenase (COX)-2 and the production of PGE2 PMID: 16978535 Figure 1 PMID: 16978535,15219461 Moreover, we have recently demonstrated that IL-10 suppresses COX-2 protein expression and PG production in BM-DC PMID: 16978535 The COX enzyme exists in two isoforms: COX-1, a constitutive form that is expressed in multiple cell types and is thought to produce PGs central to physiologic homeostasis, and COX-2, an inducible form that is rapidly up-regulated in response to inflammatory stimuli and is responsible for the production of large amounts of PGs at the inflammation site. PMID: 16978535 PGE2 and NO are two pleiotropic mediators produced at inflammatory sites by the inducible enzymes, COX-2 and nitric oxide synthase (iNOS), respectively.

indirect

PMID: 16978535 Pro-inflammatory cytokines, such as TNF-alpha are also able to induce COX-2 expression and PGE2 production by cells of immune system, particularly DC.

PMID: 16978535 Since BM-DC express EP receptors at their surface, they become target to autocrine and paracrine PGE2, which by binding to EP2 and/or EP4 acts on DC and induces the production of endogenous IL-10.

indirect

indirect

PMID: 16978535 Since BM-DC express EP receptors at their surface, they become target to autocrine and paracrine PGE2, which by binding to EP2 and/or EP4 acts on DC and induces the production of endogenous IL-10.

indirect

indirect

PMID: 16978535 Since BM-DC express EP receptors at their surface, they become target to autocrine and paracrine PGE2, which by binding to EP2 and/or EP4 acts on DC and induces the production of endogenous IL-10.

indirect

PMID: 16978535,11859113,7836930 We and other have demonstrated that PGE2 produced by DC is a potent inhibitor of human and murine IL-12 PMID: 16978535 The fact that PGE2 and IL-10 strongly inhibit the production of IL-12 implies a feedback mechanism at the level of the APC, and may represent an important mean controlling the differentiation of APC from bone marrow progenitors or from circulating monocytes.

PMID: 16978535

PMID: 16978535,11859113,15219461 We have previously reported that PGE2 inhibits the production of IL-6 and TNF-alpha via induction of endogenous IL-10

indirect

PMID: 16978535,1611085,8070901,2651547,11602631 In macrophage, IL-6, a cytokine with critical role in maturation of humoral immune response, is positively regulated by PGE2, whereas TNF-alpha release is inhibited by PGE2 PMID: 16978535,11859113,15219461 We have previously reported that PGE2 inhibits the production of IL-6 and TNF-alpha via induction of endogenous IL-10

indirect

indirect

PMID: 16978535,12496393 We also demonstrated that leucotriene B4 (LTB4), a pro-inflammatory metabolite synthesized by the action of 5-Lipoxygenase (5-LO) enzyme, induces the production of IL-6 without any effect on TNF-alpha PMID: 16978535,12496393 We have previously reported that endogenous IL-10 inhibits the production of pro-inflammatory LTB4, which is synthesized from AA by the action of both 5-LO and Five-Lipoxygenaseactivating protein (FLAP) enzymes

indirect

indirect

PMID: 16978535,12496393 We also demonstrated that leucotriene B4 (LTB4), a pro-inflammatory metabolite synthesized by the action of 5-Lipoxygenase (5-LO) enzyme, induces the production of IL-6 without any effect on TNF-alpha

indirect

PMID: 16978535,9463407 IL-10 exerts its actions through a heterodimeric membrane receptor formed by a binding chain (IL-10R1) and a transducing chain (IL-10R2, also known as a CFR2-4), whose mutual interaction activates a series of intracellular signaling molecules, including STAT protein

PMID: 16978535,9463407 IL-10 exerts its actions through a heterodimeric membrane receptor formed by a binding chain (IL-10R1) and a transducing chain (IL-10R2, also known as a CFR2-4), whose mutual interaction activates a series of intracellular signaling molecules, including STAT protein

indirect

PMID: 16978535,9463407 IL-10 exerts its actions through a heterodimeric membrane receptor formed by a binding chain (IL-10R1) and a transducing chain (IL-10R2, also known as a CFR2-4), whose mutual interaction activates a series of intracellular signaling molecules, including STAT protein

indirect

PMID: 16978535,7780157 For example, it has been reported that exogenous IL-10 may accelerate the degradation of COX-2 mRNA in human monocytes in vitro

indirect

indirect

PMID: 16978535,1827484 In contrast, IL-10 is an important inhibitor of pro-inflammatory cytokine synthesis in LPS-stimulated macrophages

indirect

PMID: 16978535 The COX enzyme exists in two isoforms: COX-1, a constitutive form that is expressed in multiple cell types and is thought to produce PGs central to physiologic homeostasis, and COX-2, an inducible form that is rapidly up-regulated in response to inflammatory stimuli and is responsible for the production of large amounts of PGs at the inflammation site.

indirect

PMID: 16978535 PGE2 and NO are two pleiotropic mediators produced at inflammatory sites by the inducible enzymes, COX-2 and nitric oxide synthase (iNOS), respectively.

indirect

PMID: 16978535,10903767 NO can exert divergent effects on the constitutive and inducible isoforms of COX by activating COX-1 and inactivating COX-2 in murine macrophages

indirect

indirect

PMID: 16978535,10903767 Previous studies reported that PGE2 was able to inhibit the LPS-stimulated production of NO in J774 macrophages and murine peritoneal macrophages

PMID: 16978535 The molecular mechanisms by which PGE2 possibly inhibits iNOS expression could be related to its ability to increase intracellular cAMP levels, which in turn inhibit NF-KappaB/DNA binding activity.

indirect

PMID: 16978535 The molecular mechanisms by which PGE2 possibly inhibits iNOS expression could be related to its ability to increase intracellular cAMP levels, which in turn inhibit NF-KappaB/DNA binding activity.

indirect

PMID: 16978535 The molecular mechanisms by which PGE2 possibly inhibits iNOS expression could be related to its ability to increase intracellular cAMP levels, which in turn inhibit NF-KappaB/DNA binding activity. PMID: 16978535,9862429 It has previously demonstrated that PGE2 potently suppresses macrophage NO production by preventing NF-κB activation

indirect

PMID: 16978535,15219461 Since TNF-alpha has been reported to induce iNOS expression and PGE2 potently suppresses TNF-alpha production, as we have already reported the inhibitory action of PGE2-cAMP system on NO production might be secondary to the inhibition of TNF-alpha generation.

PMID: 16978535 Since BM-DC express EP receptors at their surface, they become target to autocrine and paracrine PGE2, which by binding to EP2 and/or EP4 acts on DC and induces the production of endogenous IL-10.