A PPAR-independent pathway to PUFA-induced COX-2 expression
TL;DR: The results demonstrate a pathway to the induction of COX-2 by PUFAs requiring NF-kappaB but not PPAR or PKC, and the PPAR-independent effect of PUFA was mimicked by the PKC activators 4beta-PMA and prostaglandin F(2alpha), but was not blocked by thePKC inhibitor RO318425.
About: This article is published in Molecular and Cellular Endocrinology.The article was published on 2008-06-11 and is currently open access. It has received 15 citations till now. The article focuses on the topics: PPAR agonist & Reporter gene.
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TL;DR: In this article, the role of NF-κB in the pathogenesis of endometriosis has been evaluated using a literature search conducted in PubMed to identify all relevant citations, highlighting the important role of NGF in the pathwayophysiology of Endometria.
135 citations
Cites background from "A PPAR-independent pathway to PUFA-..."
...MG-132 (47, 69, 70) In vitro, EEC Y IL-6 and LIF In vitro, bovine ESC Y PTGS-2 and COX-2 Parthenolide (69) In vitro, bovine ESC Y PTGS-2 SN-50 (33, 47) In vitro, EEC Y IL-6 and LIF In vivo, nude mouse Y Ec lesion development Y ICAM-1 and [ apoptosis Curcumin (53, 54, 67, 168) In vitro, ESC and EcSC Y MIF In vivo, human Unknown, Y symptoms? Sulindac (55) In vitro, ESC Y RANTES Thalidomide (62) In vitro, EcSC Y IL-8 TPCK (59) In vitro, EcSC Y IL-8 GnRH-a (59) In vivo, human/in vitro, EcSC Y IL-8...
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...The most accepted hypothesis on the origin of peritoneal endometriosis postulates that this disease originates from regurgitated menstrual endometrial cells (ECs) able to survive, adhere, invade, and proliferate in the peritoneal cavity (5–9)....
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...In vitro studies in stimulated ECs and EcCs testing different NF-kB inhibitors—including MG132, parthenolide, SN-50, BAY 11-7085, curcumin, sulindac, thalidomide, N-tosyl-l-phenylalanine chloromethyl ketone (TPCK), GnRH agonists, progesterone, progestational compounds, IKK-2 inhibitor, PPAR-g ligand (pioglitazone), IL-10, and NF-kB decoy oligonucleotides (ODNs)—have shown a reduction in proinflammatory, growth, and invasion mediators COX-2, IL-6, leukemia inhibitory factor (LIF), MIF, RANTES, IL-8, MCP-1, GM-CSF, ICAM-1, and MMP-9, have reduced cell proliferation, monocyte chemotactic activity, and cell invasion, and have increased apoptosis as a result of decreased NF-kB activation (33, 47, 53–55, 59, 62–64, 67–70, 87, 88, 159, 160)....
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...Further studies are needed to understand the complex genomic and nongenomic interactions between estrogen and progesterone, their receptors, NF-kB, and other pathways in ECs and EcCs....
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...In vitro studies have revealed constitutive and inducible activation of NF-kB in ECs....
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TL;DR: The current understanding of the effects as well as the underlying mechanisms of ω-3 PUFAs on autoimmune diseases is summarized.
Abstract: The recognition of ω-3 polyunsaturated acids (PUFAs) as essential fatty acids to normal growth and health was realized more than 80 years ago. However, the awareness of the long-term nutritional intake of ω-3 PUFAs in lowering the risk of a variety of chronic human diseases has grown exponentially only since the 1980s (1, 2). Despite the overwhelming epidemiological evidence, many attempts of using fish-oil supplementation to intervene human diseases have generated conflicting and often ambiguous outcomes; null or weak supporting conclusions were sometimes derived in the subsequent META analysis. Different dosages, as well as the sources of fish-oil, may have contributed to the conflicting outcomes of intervention carried out at different clinics. However, over the past decade, mounting evidence generated from genetic mouse models and clinical studies has shed new light on the functions and the underlying mechanisms of ω-3 PUFAs and their metabolites in the prevention and treatment of rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, and type 1 diabetes. In this review, we have summarized the current understanding of the effects as well as the underlying mechanisms of ω-3 PUFAs on autoimmune diseases.
99 citations
TL;DR: The nature and mechanisms of fatty acid-mediated regulation of CREBh, a recently identified transcription factor that appears to be required for hepatic synthesis of C-reactive protein, are examined, establishing a potential molecular link between fatty acids and inflammation.
Abstract: Excess fatty acids are closely associated with metabolic dysfunction. The deleterious effects of fatty acids relate, in part, to their ability to up-regulate pro-inflammatory cytokines and propagate a state of systemic inflammation. CREBh is a recently identified transcription factor that appears to be required for hepatic synthesis of C-reactive protein. Recent data suggest that fatty acids can up-regulate CREBh, thus establishing a potential molecular link between fatty acids and inflammation. The aim of this study was to examine the nature and mechanisms of fatty acid-mediated regulation of CREBh. H4IIE liver cells were incubated in the absence or presence of varying concentrations (50-500 μM) of albumin-bound, long-chain saturated (palmitate, stearate) or unsaturated (oleate, linoleate) fatty acids (1-16 h). All fatty acids significantly increased CREBh gene expression via transcriptional mechanisms, at concentrations as low as 50 μM. Palmitate- or oleate-mediated up-regulation of CREBh was not inhibited by triacsin C, an inhibitor of long-chain fatty acyl CoA synthetase, or by the PPARα antagonist, MK886. Inhibition of proteasome activity with MG132 or lactacystin, or inclusion of insulin reduced palmitate- and oleate-mediated increases in CREBh mRNA. Finally, we examined fatty acid regulation of CREBh in vivo. Male Wistar rats were exposed to a 4-h pancreatic clamp combined with infusion of saline or a mixed lipid emulsion. CREBh mRNA and protein were significantly increased in rats exposed to the lipid infusion compared to the saline group. Collectively, these results may have important implications for metabolic diseases characterized by excess fatty acids, insulin resistance, and inflammation.
37 citations
Cites background from "A PPAR-independent pathway to PUFA-..."
...Recent data suggest that the proteasome inhibitor MG132 prevents fatty acid induction of the pro-inflammatory enzyme cyclooxygenase-2 in endometrial stromal cells [23]....
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TL;DR: This study demonstrated the cross talk between downstream signaling of CLA and important hormone regulators of endocrine system, i.e. FSH and IGF1, on buffalo granulosa cell function (proliferation and steroidogenesis) and found that CLA intervenes the IGF1 signaling by decreasing p-Akt.
Abstract: Conjugated linoleic acid (CLA) has drawn much interest in last two decades in the area ranging from anticancer activity to obesity. A number of research papers have been published recently with regard to CLA's additional biological functions as reproductive benefits. However, not much is known how this mixture of isomeric compounds mediates its beneficial effects particularly on fertility. In this study, we demonstrated the cross talk between downstream signaling of CLA and important hormone regulators of endocrine system, i.e. FSH and IGF1, on buffalo granulosa cell function (proliferation and steroidogenesis). Experiments were performed in primary serum-free buffalo granulosa cell culture, where cells were incubated with CLA in combination with FSH (25 ng/ml) and IGF1 (50 ng/ml). Results showed that 10 μM CLA inhibits FSH- and IGF1-induced granulosa cell proliferation; aromatase, GATA4, and IGF1 mRNA; and estradiol-17β production. Western blot analysis of total cell lysates revealed that CLA intervenes the IGF1 signaling by decreasing p-Akt. In addition, CLA was found to upregulate peroxisome proliferator-activated receptor-gamma (PPARG) and phosphatase and tensin homolog (PTEN) level in granulosa cells. Further study using PPARG- and PTEN-specific inhibitors supports the potential role of CLA in granulosa cell proliferation and steroidogenesis involving PPARG, PTEN, and PI3K/Akt pathway.
30 citations
Cites background from "A PPAR-independent pathway to PUFA-..."
...However, PPARG-independent effects also cannot be denied completely as PUFAs are known to take PPAR-independent pathways (Derecka et al. 2008) and also PPARG inhibitor (GW9662) inhibited the cell growth of human tumor mammary cell line, which supports the existence of PPARG-independent pathways…...
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TL;DR: Angiotensin II induced Cox-2 gene expression by activating the calcineurin/NFAT signaling pathway in endometrial stromal cells of non-pregnant but not of early-p Regnant rats, which might be related to differential roles that COX-2 plays in the endometrium.
Abstract: Cyclooxygenase (COX)-2, the inducible isoform of cyclooxygenase, plays a role in the process of uterine decidualization and blastocyst attachment. On the other hand, overexpression of COX-2 is involved in the proliferation of the endometrial tissue during endometriosis. Deregulation of the renin-angiotensin-system plays a role in the pathophysiology of endometriosis and pre-eclampsia. Angiotensin II increases intracellular Ca2+ concentration by targeting phospholypase C-gamma in endometrial stromal cells (ESC). A key element of the cellular response to Ca2+ signals is the activity of the Ca2+- and calmodulin-dependent phosphatase calcineurin. Our first aim was to study whether angiotensin II stimulated Cox-2 gene expression in rat ESC and to analyze whether calcineurin activity was involved. In cells isolated from non-pregnant uteri, COX-2 expression -both mRNA and protein- was induced by co-stimulation with phorbol ester and calcium ionophore (PIo), as well as by angiotensin II. Pretreatment with the calcineurin inhibitor cyclosporin A inhibited this induction. We further analyzed the role of the calcineurin/NFAT signaling pathway in the induction of Cox-2 gene expression in non-pregnant rat ESC. Cyclosporin A abolished NFATc1 dephosphorylation and translocation to the nucleus. Cyclosporin A also inhibited the transcriptional activity driven by the Cox-2 promoter. Exogenous expression of the peptide VIVIT -specific inhibitor of calcineurin/NFAT binding- blocked the activation of Cox-2 promoter and the up-regulation of COX-2 protein in these cells. Finally we analyzed Cox-2 gene expression in ESC of early-pregnant rats. COX-2 expression -both mRNA and protein- was induced by stimulation with PIo as well as by angiotensin II. This induction appears to be calcineurin independent, since it was not abrogated by cyclosporin A. In conclusion, angiotensin II induced Cox-2 gene expression by activating the calcineurin/NFAT signaling pathway in endometrial stromal cells of non-pregnant but not of early-pregnant rats. These results might be related to differential roles that COX-2 plays in the endometrium.
22 citations
Cites background from "A PPAR-independent pathway to PUFA-..."
...It has been found previously that PKC activators, such as PMA, induced COX-2 expression in ESC [57]....
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References
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TL;DR: The data suggest that arachidonic acid antagonizes PGE(2) signalling through cAMP in the bovine endometrium, possibly acting to ensure a rapid return to oestrus in the case of failure of the maternal recognition of pregnancy.
Abstract: Second messenger signalling through cyclic AMP (cAMP) plays an important role in the response of the endometrium to prostaglandin (PG) E2 during early pregnancy. Arachidonic acid, which is a by-product of the luteolytic cascade in ruminants, is a potential paracrine signal from the epithelium to the stroma. We investigated the effects of arachidonic acid on the response of the stroma to PGE2. cAMP was measured in bovine endometrial stromal cells treated with agents known to activate or inhibit adenylyl cyclase, protein kinase C (PKC) or phosphodiesterase (PDE). PGE2increased the intracellularcAMP concentration within 10 min, and this effect was attenuated by arachidonic acid and the PKC activator, 4b-phorbol myristate acetate (PMA). The inhibitory effect of arachidonic acid on PGE2-induced cAMP accumulation was prevented by the PKC inhibitor, RO318425, and was absent in cells in which PKC had been downregulated by exposure to PMA for 24 h. The effect of arachidonic acid was also prevented by the PDE inhibitor, 3-isobutyl-1-methylxanthine. Arachidonic acid was shown by immunoblotting to prevent induction of cyclooxygenase-2 by PGE2, forskolin or dibutyryl cAMP. The results indicate that arachidonic acid activates PDE through a mechanism involving PKC, counteracting a rise in intracellular cAMP in response to PGE2. The data suggest that arachidonic acid antagonizes PGE2 signalling through cAMP in the bovine endometrium, possibly acting to ensure a rapid return to oestrus in the case of failure of the maternal recognition of pregnancy.
14 citations
TL;DR: It is concluded that arachidonic acid up-regulates the expression of PLA2 I and PGHS2 in the uterine stromal cells, independently of prostanoids, and that prostaglandin E2 is capable of down-regulating enzyme expression.
Abstract: It is well known that arachidonic acid, as a substrate of prostaglandin G/H synthase (PGHS), is converted into prostaglandins of the two-series. In this work, we attempted to determine whether arachidonic acid and prostaglandin E2 might regulate the expression of PGHS and the pancreatic-type phospholipase A2(PLA2 I), which may be involved in the liberation of arachidonic acid from membrane phospholipids. For this purpose, we used the uterine stromal cell line U111 which produces prostaglandin E2 and expresses both the constitutive and inducible PGHS enzymes (PGHS1 and PGHS2) and PLA2 I. The results show that PGHS1 which is expressed at a high level in U111 cells, was not modified by arachidonic acid. The expression of PGHS2 and PLA2 I was up-regulated by increasing arachidonate concentrations (10–10 μM). The maximal response was obtained at 24 h, reaching a 2.3-fold and 2.6-fold increase for PGHS2 and PLA2 I expression, respectively, compared to the control level. To discriminate between the effect of arachidonic acid and that of prostaglandins, which are highly increased in the presence of exogenous arachidonic acid, we treated the cells with two inhibitors of PGHS activity, aspirin and meclofenamic acid. Both inhibitors failed to suppress the arachidonate-induced increase of PLA2 I and PGHS2 expression and even enhanced it either in the presence or absence of arachidonic acid. In contrast, the addition of prostaglandin E2 to the culture medium decreased the expression of both enzymes in a dose-dependent manner, the maximal response being reached at 1 μM. We conclude that arachidonic acid up-regulates the expression of PLA2I and PGHS2 in the uterine stromal cells, independently of prostanoids, and that prostaglandin E2 is capable of down-regulating enzyme expression.
11 citations