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1.
The data presented show different effects of prostaglandins on proliferation and cytotoxic effector functions of murine bone-marrow derived mononuclear cells. Colony stimulating factor (CSF)-dependent proliferation of colony forming unit-cells (CFU c) was inhibited by PGE1, PGE2 and PGB2. Lymphokine induced cytotoxicity and antibody mediated cytotoxicity (ADCC) of monocytes and macrophages were also affected by PG. We conclude that PGE2 may regulate macrophage mediated tumorcell-lysis mainly at the induction phase. If these processes function in vivo, one would therefore expect high affinity binding sites for PGE2 on macrophages. The existence of a receptor for PGE2 one murine bone marrow derived macrophages is described.  相似文献   

2.
In this article, a series of 22 triarylpyrazole derivatives were evaluated for in vitro antiinflammatory activity as inhibitors of nitric oxide (NO) and prostaglandin E2 (PGE2) release induced by lipopolysaccharide (LPS) in murine RAW 264.7 macrophages. The synthesized compounds 1a-h, 2a-f and 3a-h were first examined for their cytotoxicity for determination of the non-toxic concentration for antiinflammatory screening, so that the inhibitory effects against NO and PGE2 production were not caused by non-specific cytotoxicity. Compounds 1h and 2f were the most active PGE2 inhibitors with IC50 values of 2.94 μM and 4.21 μM, respectively. Western blotting and cell-free COX-2 screening revealed that their effects were due to inhibition of COX-2 protein expression. Moreover, compound 1h exerted strong inhibitory effect on the expression of COX-2 mRNA in LPS-induced murine RAW 264.7 macrophages.  相似文献   

3.
The expression of macrophage antitumor activity and the production of prostaglandins (PG) by operationally defined macrophage populations differed under varying culture conditions. Culture conditions that caused increased PGE2 production by activated macrophages resulted in an inhibition of their tumoricidal activity. In contrast, production of high levels of PGE2 by resident and elicited macrophages was associated with an increase in antitumor activity. The activation of resident or elicited cells by lipopolysaccharide (LPS) could be blocked by indomethacin. Treatment of these macrophages with PGE2 alone also resulted in their activation and subsequent tumor cell destruction. Activation of resident and elicited macrophages by LPS appears to be mediated by PGE2.  相似文献   

4.
The purpose of this study was to elucidate the role of NO and O-2 on enzymatic components of cyclooxygenase (COX) pathway in peritoneal macrophages. Activation of murine peritoneal macrophages by lipopolysaccharides (LPS) resulted in time-dependent production of nitric oxide (NO) and prostaglandin E2 (PGE2). This stimulation was also accompanied by the production of other reactive oxygen species such as superoxide (O-2), and by increased expression of COX-2. Our results provide evidence that O-2 may be involved in the pathways that result in arachidonate release and PGE2 formation by COX-2 in murine peritoneal macrophages stimulated by LPS. However, we were not able to demonstrate that NO participates in the regulation of PG production under our experimental conditions.  相似文献   

5.
Elevated levels of prostaglandins such as PGE2 in inflamed gingiva play a significant role in the tissue destruction caused by periodontitis, partly by targeting local fibroblasts. Only very few studies have shown that PGE2 inhibits the proliferation of a gingival fibroblast (GF) cell line, and we expanded this research by using primary human GFs (hGFs) and looking into the mechanisms of the PGE2 effect. GFs derived from healthy human gingiva were treated with PGE2 and proliferation was assessed by measuring cell number and DNA synthesis and potential signaling pathways were investigated using selective activators or inhibitors. PGE2 inhibited the proliferation of hGFs dose‐dependently. The effect was mimicked by forskolin (adenylate cyclase stimulator) and augmented by IBMX (a cAMP‐breakdown inhibitor), pointing to involvement of cAMP. Indeed, PGE2 and forskolin induced cAMP generation in these cells. Using selective EP receptor agonists we found that the anti‐proliferative effect of PGE2 is mediated via the EP2 receptor (which is coupled to adenylate cyclase activation). We also found that the effect of PGE2 involved activation of Epac (exchange protein directly activated by cAMP), an intracellular cAMP sensor, and not PKA. While serum increased the amount of phospho‐ERK in hGFs by ~300%, PGE2 decreased it by ~50%. Finally, the PGE2 effect does not require endogenous production of prostaglandins since it was not abrogated by two COX‐inhibitors. In conclusion, in human gingival fibroblasts PGE2 activates the EP2—cAMP—Epac pathway, reducing ERK phosphorylation and inhibiting proliferation. This effect could hamper periodontal healing and provide further insights into the pathogenesis of inflammatory periodontal disease. J. Cell. Biochem. 108: 207–215, 2009. © 2009 Wiley‐Liss, Inc.  相似文献   

6.
7.
Alternative polarization of macrophages regulates multiple biological processes. While M1-polarized macrophages generally mediate rapid immune responses, M2-polarized macrophages induce chronic and mild immune responses. In either case, polyunsaturated fatty acid (PUFA)-derived lipid mediators act as both products and regulators of macrophages. Prostaglandin E3 (PGE3) is an eicosanoid derived from eicosapentaenoic acid, which is converted by cyclooxygenase, followed by prostaglandin E synthase successively. We found that PGE3 played an anti-inflammatory role by inhibiting LPS and interferon-γ-induced M1 polarization and promoting interleukin-4-mediated M2 polarization (M2a). Further, we found that although PGE3 had no direct effect on the growth of prostate cancer cells in vitro, PGE3 could inhibit prostate cancer in vivo in a nude mouse model of neoplasia. Notably, we found that PGE3 significantly inhibited prostate cancer cell growth in a cancer cell-macrophage co-culture system. Experimental results showed that PGE3 inhibited the polarization of tumour-associated M2 macrophages (TAM), consequently producing indirect anti-tumour activity. Mechanistically, we identified that PGE3 regulated the expression and activation of protein kinase A, which is critical for macrophage polarization. In summary, this study indicates that PGE3 can selectively promote M2a polarization, while inhibiting M1 and TAM polarization, thus exerting an anti-inflammatory effect and anti-tumour effect in prostate cancer.  相似文献   

8.
Lipopolysaccharide (LPS) stimulated prostaglandin E2 (PGE2) formation and induction of cyclooxygenase-2 (COX-2) expression without changing the levels of COX-1 protein in rat peritoneal macrophages. Non-steroidal anti-inflammatory drugs (NSAIDs) (nimesulide, indomethacin and ibuprofen) strongly inhibited LPS-stimulated PGE2 production without any effect on COX-2 protein expression, suggesting that NSAIDs are active in inhibiting the ability of COX-2 to convert arachidonic acid (AA) endogenously released in response to LPS stimulation. Exogenous AA can be converted to PGE2 by both COX isoforms even in LPS-stimulated macrophages. NSAIDs inhibited PGE2 production from exogenous AA mediated by both COX-1 and COX-2. However, the two isoforms interacted differentially with different NSAIDs. Furthermore, NSAIDs were distinctly more active in inhibiting PGE2 production from endogenous AA than that from exogenous AA. These data suggest that PGE2 production through COX-2 from exogenous AA may not be subject to the same regulatory processes as that from endogenous AA and the two metabolic processes may be differentially sensitive to different NSAIDs.  相似文献   

9.
Stimulation of murine macrophages with corn silk induced cyclooxygenase (COX)-2 with secretion of PGE2. Expression of COX-2 was inhibited by pyrolidine dithiocarbamate (PDTC), and increased DNA binding by nuclear factor kappa B (NF-κB), indicating that COX-2 induction proceeds also via the NF-κB signaling pathway. A specific inhibitor of COX-2 decreased the expression level of inducible nitric oxide synthase (iNOS) stimulated by corn silk. PGE2 elevated the expression level of iNOS, probably via EP2 and EP4 receptors on the surface of the macrophages.  相似文献   

10.
Cytosolic phospholipase A2α (cPLA2α) up-regulation has been reported in human colorectal cancer cells, thus we aimed to elucidate its role in the proliferation of the human colorectal cancer cell line, HT-29. EGF caused a rapid activation of cPLA2α which coincided with a significant increase in cell proliferation. The inhibition of cPLA2α activity by pyrrophenone or by antisense oligonucleotide against cPLA2α (AS) or inhibition of prostaglandin E2 (PGE2) production by indomethacin resulted with inhibition of cell proliferation, that was restored by addition of PGE2. The secreted PGE2 activated both protein kinase A (PKA) and PKB/Akt pathways via the EP2 and EP4 receptors. Either, the PKA inhibitor (H-89) or the PKB/Akt inhibitor (Ly294002) caused a partial inhibition of cell proliferation which was restored by PGE2. But, inhibited proliferation in the presence of both inhibitors could not be restored by addition of PGE2. AS or H-89, but not Ly294002, inhibited CREB activation, suggesting that CREB activation is mediated by PKA. AS or Ly294002, but not H-89, decreased PKB/Akt activation as well as the nuclear localization of β-catenin and cyclin D1 and increased the plasma membrane localization of β-catenin with E-cadherin, suggesting that these processes are regulated by the PKB pathway. Similarly, Caco-2 cells exhibited cPLA2α dependent proliferation via activation of both PKA and PKB/Akt pathways. In conclusion, our findings suggest that the regulation of HT-29 proliferation is mediated by cPLA2α-dependent PGE2 production. PGE2via EP induces CREB phosphorylation by the PKA pathway and regulates β-catenin and cyclin D1 cellular localization by PKB/Akt pathway.  相似文献   

11.
Mouse resident peritoneal macrophages stimulated by purified bacterial lipopolysaccharide (LPS) produced both prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2), the latter detected as its stable metabolite, 6-keto PGF. Maximum production, induced in each case by 1 ng/ml purified LPS, was in the range of 10−7M for PGI2 and 3 × 10−8M for PGE2. A quantitatively similar increase in intracellular levels of macrophage cyclic AMP (measured on a whole cell basis), with a similar duration of effect, was stimulated by PGE2 and PGI2; however, only PGE2 had a negative regulatory effect on macrophage activation for tumor cell killing. These data confirm that more than a whole cell increase in the concentration of cyclic AMP is needed to shut off nonspecific tumor cell killing mediated by LPS-activated resident peritoneal macrophages.  相似文献   

12.
13.
Although many previous reports have examined the function of prostaglandin E2 (PGE2) in the migration and proliferation of various cell types, the role of the actin cytoskeleton in human mesenchymal stem cells (hMSCs) migration and proliferation has not been reported. The present study examined the involvement of profilin‐1 (Pfn‐1) and filamentous‐actin (F‐actin) in PGE2‐induced hMSC migration and proliferation and its related signal pathways. PGE2 (10?6 M) increased both cell migration and proliferation, and also increased E‐type prostaglandin receptor 2 (EP2) mRNA expression, β‐arrestin‐1 phosphorylation, and c‐Jun N‐terminal kinase (JNK) phosphorylation. Small interfering RNA (siRNA)‐mediated knockdown of β‐arrestin‐1 and JNK (‐1, ‐2, ‐3) inhibited PGE2‐induced growth of hMSCs. PGE2 also activated Pfn‐1, which was blocked by JNK siRNA, and induced F‐actin level and organization. Downregulation of Pfn‐1 by siRNA decreased the level and organization of F‐actin. In addition, specific siRNA for TRIO and F‐actin‐binding protein (TRIOBP) reduced the PGE2‐induced increase in hMSC migration and proliferation. Together, these experimental data demonstrate that PGE2 partially stimulates hMSCs migration and proliferation by interaction of Pfn‐1 and F‐actin via EP2 receptor‐dependent β‐arrestin‐1/JNK signaling pathways. J. Cell. Physiol. 226: 559–571, 2011. © 2010 Wiley‐Liss, Inc.  相似文献   

14.
Summary Bone cultures exposed to prostaglandin E2 (PGE2) revealed an increase in 45Ca release from bone to medium and an increase in osteoclast number compared to control bones. In addition, PGE2-treated osteoclasts contained a more extensive ruffled border region than control osteoclasts. These data suggest that PGE2 activates existing osteoclasts and causes proliferation and differentiation of osteoclast precursor cells. The existence of macrophages in resorbing fetal bone explants was documented. These macrophages contain numerous phagolysosomes and lipid vacuoles and are often located adjacent to osteoclasts or closely apposed to calcified tissue surfaces. PGE2 caused an early increase in the number of macrophages. It is postulated that fetal bone macrophages are primarily engaged in phagocytosis and digestion of cellular debris, but also play a role in the process of bone resorption.This study was supported by Grant DE-04443 from USPHS  相似文献   

15.
The COX-2 product prostaglandin E2 (PGE2) contributes to the high metastatic capacity of breast tumors. Our published data indicate that inhibiting either PGE2 production or PGE2-mediated signaling through the PGE2 receptor EP4 reduces metastasis by a mechanism that requires natural killer (NK) cells. It is known that NK cell function is compromised by PGE2, but very little is known about the mechanism by which PGE2 affects NK effector activity. We now report the direct effects of PGE2 on the NK cell. Endogenous murine splenic NK cells express all four PGE2 receptors (EP1-4). We examined the role of EP receptors in three NK cell functions: migration, cytotoxicity, and cytokine release. Like PGE2, the EP4 agonist PGE1-OH blocked NK cell migration to FBS and to four chemokines (ITAC, MIP-1α, SDF-1α, and CCL21). The EP2 agonist, Butaprost, inhibited migration to specific chemokines but not in response to FBS. In contrast to the inhibitory actions of PGE2, the EP1/EP3 agonist Sulprostone increased migration. Unlike the opposing effects of EP4 vs. EP1/EP3 on migration, agonists of each EP receptor were uniformly inhibiting to NK-mediated cytotoxicity. The EP4 agonist, PGE1-OH, inhibited IFNγ production from NK cells. Agonists for EP1, EP2, and EP3 were not as effective at inhibiting IFNγ. Agonists of EP1, EP2, and EP4 all inhibited TNFα; EP4 agonists were the most potent. Thus, the EP4 receptor consistently contributed to loss of function. These results, taken together, support a mechanism whereby inhibiting PGE2 production or preventing signaling through the EP4 receptor may prevent suppression of NK functions that are critical to the control of breast cancer metastasis.  相似文献   

16.
Prostaglandin E2 (PGE2) is well known to regulate cell functions through cAMP; however, the role of exchange protein directly activated by cAMP (Epac1) and protein kinase A (PKA) in modulating such functions is unknown in human umbilical cord blood‐derived mesenchymal stem cells (hUCB‐MSCs). Therefore, we investigated the relationship between Epac1 and PKA during PGE2‐induced hUCB‐MSC proliferation and its related signaling pathways. PGE2 increased cell proliferation, and E‐type prostaglandin (EP) 2 receptor mRNA expression level and activated cAMP generation, which were blocked by EP2 receptor selective antagonist AH 6809. PGE2 increased Epac1 expression, Ras‐related protein 1 (Rap1) activation level, and Akt phosphorylation, which were inhibited by AH 6809, adenylyl cyclase inhibitor SQ 22536, and Epac1/Rap1‐specific siRNA. Also, PGE2 increased PKA activity, which was inhibited by AH 6809, SQ 22536, and PKA inhibitor PKI. HUCB‐MSCs were incubated with the Epac agonist 8‐pCPT‐cAMP or the PKA agonist 6‐phe‐cAMP to examine whether Epac1/Rap1/Akt activation was independent of PKA activation. 8‐pCPT‐cAMP increased Akt phosphorylation but not PKA activity. 6‐Phe‐cAMP increased PKA activity, but not Akt phosphorylation. Additionally, an Akt inhibitor or PKA inhibitor (PKI) did not block the PGE2‐induced increase in PKA activity or Akt phosphorylation, respectively. Moreover, PGE2 increased glycogen synthase kinase (GSK)‐3β phosphorylation and nuclear translocation of active‐β‐catenin, which were inhibited by Akt inhibitor or/and PKI. PGE2 increased c‐Myc and vascular endothelial growth factor (VEGF) expression levels, which were blocked by β‐catenin siRNA. In conclusion, PGE2 stimulated hUCB‐MSC proliferation through β‐catenin‐mediated c‐Myc and VEGF expression via Epac/Rap1/Akt and PKA cooperation. J. Cell. Physiol. 227: 3756–3767, 2012. © 2012 Wiley Periodicals, Inc.  相似文献   

17.
The interaction between interleukin IL-1α and PGE2 on P388D2 on cells has been investigated. Preincubation of murine macrophage-like cells, P388D1, with IL-1α (0–73 pM) reduced the binding of PGE2 to these cells in a concentration-dependent manner. Scatchard analysis showed that IL-1α decreased the PGE2 binding by lowering both the high and low affinity receptor binding capacities (from 0.31 ± 0.02 to 0.12 ± 0.01 fmol/106 cells for the high affinity receptor binding sites and from 2.41 ± 0.12 to 1.51 ± 0.21 fmol/106 cells for the low affinity receptor binding sites). However, the dissociation constants of the receptor of the IL-1α-treated cells remained unchanged. Inhibition of PGE2 binding IL-1α did not involve changes in either protein phosphorylation or intracellular cyclic AMP levels. Our data clearly show that IL-1α inhibits the binding of PGE2 to monocytes/macrophages and may thereby counter the immunosuppressive actions of PGE2.  相似文献   

18.
Prostaglandins regulate macrophage function by their action on membrane-associated adenyl cyclase. In order to define more directly macrophage-prostaglandin interactions, a binding assay has been developed for macrophage receptors using (3H)-PGI2 as ligand. (3H)-PGI2 binding was specific, saturable and reversible. Moreover, specific binding showed to be enriched in a membrane-enriched fraction of the cells. The assay conditions ensured stability of (3H)-PGI2 during incubations and should exclude intracellular accumulation of the ligand in macrophages. Unlabelled PGE2 and PGI2 competed for (3H)-PGI2 specific binding in both macrophages and membrane preparations. PGE2 showed to be more potent in this respect than PGI2, a phenomena which was also observed for prostaglandin activation of cAMP production in macrophages.The data suggest an interaction at receptor level of endogenously released PGE2 and PGI2 by peritoneal macrophages in vivo and provide support for a previously proposed mechanism of action of low concentrations of PGE2, counteracting stimulation of cAMP production by PGI2 in macrophages.  相似文献   

19.
The serum-free spent medium of lipopolysaccharide-activated rabbit peritoneal macrophages contains a proteinaceous factor that stimulates the synthesis of PGE2 in rabbit articular chondrocytes. Synthesis of this factor by macrophages is inhibited by cycloheximide. Stimulation of PGE2 in chondrocytes is detected after a four-hour exposure to the macrophage factor and is completely abolished by the addition of either cycloheximide or indomethacin to the chondrocyte cultures. The macrophage derived factor has an apparent molecular weight of 30,000, is heat stable and not inactivated upon reductive alkylation or on treatment with phenylglyoxal. Activity is partially destroyed upon treatment with acid (pH 2.0) and upon trypsin treatment.  相似文献   

20.
《ImmunoMethods》1993,2(3):203-210
The regulation of receptors for prostaglandin E2 (PGE2) in monocyte/macrophage-like cells, P388D1, by interleukin-1α (IL-1α) and insulin has been investigated. Many of the effects of IL-1, such as fever and other inflammatory activities, are linked to the stimulation of PGE2 synthesis. On the other hand, PGE2 exhibits suppressive effects on many steps in the immune response, including IL-1 production. The binding of PGE2 to monocytes is reported to be essential for the inhibition of IL-1 production and activity. This inhibition occurs through the stimulation of cyclic AMP synthesis by the activation of PGE2 receptor-linked adenylate cyclase. Although IL-1α stimulates PGE2 synthesis in monocytes/macrophages during immunoactivation, it inhibits the binding of PGE2 to these cells and may thereby exert a countervailing effect on the immunosuppressive action of this prostanoid. By contrast, insulin at physiological concentrations enhances the PGE2 binding to these cells. This suggests that insulin at physiological concentrations may enhance the immunosuppressive action of PGE2. Since the stimulation of cAMP synthesis in cells is regulated by PGE2 binding, it is possible that these hormonal factors may control the immune response by modulating the PGE2 receptor activity of monocytes/macrophages. This article focuses on the interactions of insulin and IL-1 with PGE2 receptors of monocytes/macrophages.  相似文献   

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