The anti-inflammatory effects of prostaglandins.
ABSTRACT Long regarded as proinflammatory molecules, prostaglandins (PGs) also have anti-inflammatory effects. Both prostaglandin D2 (PGD2) and its dehydration end product 15-deoxy-Delta-prostaglandin J2 (15d-PGJ2) seem to play important roles in regulating inflammation, via both receptor-dependent (DP1 and DP2 receptors) and receptor-independent mechanisms. Intracellular effects of PGD2 and 15d-PGJ2 that may suppress inflammation include inhibition of nuclear factor-kappaB (NF-kappaB) by multiple mechanisms (IkappaB kinase inhibition and blockade of NF-kappaB nuclear binding) and activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Prostaglandin F2alpha (PGF2alpha) may also have important anti-inflammatory effects, although current data are limited. In animal models, expression of both PGD and PGF synthases declines during acute inflammation, only to rise again during the resolution phase, suggesting their possible role in resolving inflammation. Prostaglandin E2 (PGE2), the classic model of a proinflammatory lipid mediator, also has anti-inflammatory effects that are both potent and context dependent. Thus, accumulating data suggest that PGs not only participate in initiation, but may also actively contribute to the resolution of inflammation. Indeed, classic inhibitors of PG synthesis such as nonselective and cyclooxygenase-2 (COX-2) selective inhibitors (nonsteroidal anti-inflammatory drugs) may actually prolong inflammation when administered during the resolution phase. These effects may regulate not only tissue inflammation but also vascular disease, possibly shedding light on the controversy surrounding nonsteroidal anti-inflammatory drug use and its relation to myocardial infarction. In this review, we summarize the current understanding of PGs as dichotomous molecules in the inflammatory process.
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ABSTRACT: BACKGROUND: The Transient Receptor Potential (TRP) ion channel TRPA1 is a key player in pain pathways. Irritant chemicals activate ion channel TRPA1 via covalent modification of N-terminal cysteines. We and others have shown that 15-Deoxy-Delta12, 14-prostaglandin J2 (15d-PGJ2) similarly activates TRPA1 and causes channel-dependent nociception. Paradoxically, 15d-PGJ2 can also be anti-nociceptive in several pain models. Here we hypothesized that activation and subsequent desensitization of TRPA1 in dorsal root ganglion (DRG) neurons underlies the anti-nociceptive property of 15d-PGJ2. To investigate this, we utilized a battery of behavioral assays and intracellular Ca2+ imaging in DRG neurons to test if pre-treatment with 15d-PGJ2 inhibited TRPA1 to subsequent stimulation. RESULTS: Intraplantar pre-injection of 15d-PGJ2, in contrast to mustard oil (AITC), attenuated acute nocifensive responses to subsequent injections of 15d-PGJ2 and AITC, but not capsaicin (CAP). Intraplantar 15d-PGJ2---administered after the induction of inflammation---reduced mechanical hypersensitivity in the Complete Freund's Adjuvant (CFA) model for up to 2 h post-injection. The 15d-PGJ2-mediated reduction in mechanical hypersensitivity is dependent on TRPA1, as this effect was absent in TRPA1 knockout mice. Ca2+ imaging studies of DRG neurons demonstrated that 15d-PGJ2 pre-exposure reduced the magnitude and number of neuronal responses to AITC, but not CAP. AITC responses were not reduced when neurons were pre-exposed to 15d-PGJ2 combined with HC-030031 (TRPA1 antagonist), demonstrating that inhibitory effects of 15d-PGJ2 depend on TRPA1 activation. Single daily doses of 15d-PGJ2, administered during the course of 4 days in the CFA model, effectively reversed mechanical hypersensitivity without apparent tolerance or toxicity. CONCLUSIONS: Taken together, our data support the hypothesis that 15d-PGJ2 induces activation followed by persistent inhibition of TRPA1 channels in DRG sensory neurons in vitro and in vivo. Moreover, we demonstrate novel evidence that 15d-PGJ2 is analgesic in mouse models of pain via a TRPA1-dependent mechanism. Collectively, our studies support that TRPA1 agonists may be useful as pain therapeutics.Molecular Pain 09/2012; 8(1):75. · 3.77 Impact Factor
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ABSTRACT: Radix platycodi is the root of Platycodon grandiflorus A. DC, which has been widely used as a food material and for the treatment of a number of chronic inflammatory diseases in traditional oriental medicine. In this study, the anti‑inflammatory effects of the saponins isolated from radix platycodi (PGS) on the production of inflammatory mediators and cytokines in lipopolysaccharide (LPS)-stimulated BV2 murine microglial cells were examined. We also investigated the effects of PGS on LPS‑induced nuclear factor‑κB (NF-κB) activation and phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) signaling pathways. Following stimulation with LPS, elevated nitric oxide (NO), prostaglandin E2 (PGE2) and pro-inflammatory cytokine production was detected in the BV2 microglial cells. However, PGS significantly inhibited the excessive production of NO, PGE2 and pro‑inflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in a concentration-dependent manner without causing any cytotoxic effects. In addition, PGS suppressed NF-κB translocation and inhibited the LPS-induced phosphorylation of AKT and MAPKs. Our results indicate that the inhibitory effect of PGS on LPS-stimulated inflammatory response in BV2 microglial cells is associated with the suppression of NF-κB activation and the PI3K/AKT and MAPK signaling pathways. Therefore, these findings suggest that PGS may be useful in the treatment of neurodegenerative diseases by inhibiting inflammatory responses in activated microglial cells.International Journal of Molecular Medicine 04/2013; · 1.96 Impact Factor
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ABSTRACT: Background: Liver fluke infection of livestock causes economic losses of over US$ 3 billion worldwide per annum. The disease is increasing in livestock worldwide and is a re-emerging human disease. There are currently no commercial vaccines, and only one drug with significant efficacy against adult worms and juveniles. A liver fluke vaccine is deemed essential as short-lived chemotherapy, which is prone to resistance, is an unsustainable option in both developed and developing countries. Protein superfamilies have provided a number of leading liver fluke vaccine candidates. A new form of glutathione transferase (GST) family, Sigma class GST, closely related to a leading Schistosome vaccine candidate (Sm28), has previously been revealed by proteomics in the liver fluke but not functionally characterised. Methodology/Principal Findings: In this manuscript we show that a purified recombinant form of the F. hepatica Sigma class GST possesses prostaglandin synthase activity and influences activity of host immune cells. Immunocytochemistry and western blotting have shown the protein is present near the surface of the fluke and expressed in eggs and newly excysted juveniles, and present in the excretory/secretory fraction of adults. We have assessed the potential to use F. hepatica Sigma class GST as a vaccine in a goat-based vaccine trial. No significant reduction of worm burden was found but we show significant reduction in the pathology normally associated with liver fluke infection. Conclusions/Significance: We have shown that F. hepatica Sigma class GST has likely multi-functional roles in the host-parasite interaction from general detoxification and bile acid sequestration to PGD synthase activity. Citation: LaCourse EJ, Perally S, Morphew RM, Moxon JV, Prescott M, et al. (2012) The Sigma Class Glutathione Transferase from the Liver Fluke Fasciola hepatica. PLoS Negl Trop Dis 6(5): e1666. doi:10.1371/journal.pntd.0001666 Copyright: ß 2012 LaCourse et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by the European Union (DELIVER: Grant FOOD-CT-2005-023025) and the BBSRC (grants BBH0092561 and BB/C503638/2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.PLoS Neglected Tropical Diseases 05/2012; 6(5):e1666. doi:10.1371/journal.pntd.0001666. · 4.57 Impact Factor