Altered responses of human macrophages to lipopolysaccharide by hydroperoxy eicosatetraenoic acid, hydroxy eicosatetraenoic acid, and arachidonic acid. Inhibition of tumor necrosis factor production.

Ferrante, Judith; Huang, Zhenjun; Nandoskar, M.; Hii, Charles S.; Robinson, B S; Rathjen, Deborah A.; Poulos, A.; Morris, C. Phillip; Fèrrante, Antonio

doi:10.1172/jci119303

Cited by 40 publications

(30 citation statements)

References 33 publications

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“…The effect of GPs on the level of TNF-␣ is most likely mediated by modulation of the level of arachidonic acid metabolites, especially HPETEs, which are efficient inhibitors of TNF-␣ production in macrophages. 28 Increased LPS resistance of GP mice with an elevated level of TNF-␣ may appear to be surprising. However, in the last several years, the role of this cytokine has been under revision.…”

Section: Discussionmentioning

confidence: 99%

Endotoxemia in Transgenic Mice Overexpressing Human Glutathione Peroxidases

Mirochnitchenko

Prokopenko

Palnitkar

et al. 2000

Circulation Research

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Abstract-In response to endotoxemia induced by administration of lipopolysaccharide, a complex series of reactions occurs in mammalian tissues. During this inflammation response, cells produce different mediators, such as reactive oxygen species, a number of arachidonic acid metabolites, and cytokines. The reactive oxygen species thus generated have been suggested to produce tissue injury as a result of macromolecular damage or by interfering with regulatory processes. They may also act as important signaling molecules to induce redox-sensitive genes. We report here that transgenic mice overexpressing 2 major forms of human glutathione peroxidases (GPs), intra-and extracellular GP, are able to modulate host response during endotoxemic conditions. We show that these animals have a decreased hypotension and increased survival rate after administration of a high dosage of lipopolysaccharide. Overexpression of GPs alters vascular permeability and production of cytokines (interleukin-1␤ and tumor necrosis factor-␣) and NO, affects arachidonic acid metabolism, and inhibits leukocyte migration. These results suggest an important role for peroxides in pathogenesis during endotoxemia, and GPs, by regulating their level, may prove to be good candidates for antioxidant therapy to protect against such injury. 2 There is experimental evidence that suggests oxidative damage in pathogenesis of endotoxemia. 3 To evaluate the role of glutathione peroxidase (GP) in protection against endotoxemia in vivo, we have used transgenic mice overexpressing human extracellular (GPxP) and intracellular (GPx1) GP. In the present study, we report that these animals show an increased rate of survival after administration of a large dosage of LPS. Mice with human GPs are able to modulate levels of lipid peroxidation and inflammatory mediators. These transgenic animals represent a new model system for investigation of the role of GPs and reactive oxygen species (ROS) in endotoxemia and other inflammatory disorders. Materials and Methods Animals and TreatmentsHeterozygous transgenic mice 5 to 6 months old in a C57BL/ 6ϫCBA/J background overexpressing human GPxP (strain 17) and human GPx1 (strain 23) and their normal littermates were bred in our facility. We described the generation of these mice previously. 4 For survival studies, the mice were injected with LPS at a dose of 25 mg/kg (Escherichia coli serotype 0111:B4; Sigma). Arterial blood pressure and heart rate were measured using the Kent tail blood pressure system. For characterization of cytokine production and leukocyte distribution, blood was collected from the retro-orbital cavity of a group of animals dosed with LPS (16 mg/kg of body weight). Plasma was analyzed for cytokine (tumor necrosis factor-␣ [TNF-␣] and interleukin-1␤ [IL-1␤]) production with ELISA kits from R&D Systems. Vascular permeability was determined by assessing tissue accrual of Evan's Blue, as described previously. 5 Sixteen hours after PBS or LPS injection, the animals were administered 25 mg/kg Evan's Blue by tail ...

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Section: Discussionmentioning

confidence: 99%

Endotoxemia in Transgenic Mice Overexpressing Human Glutathione Peroxidases

Mirochnitchenko

Prokopenko

Palnitkar

et al. 2000

Circulation Research

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“…On the day of use, fatty acids were prepared in the presence of DL-␣-dipalmitoyl phosphatidylcholine (DPC; Sigma-Aldrich, St. Louis, MO) as the carrier using a weight ratio of 4:1 of DPC to fatty acid, as described (11). Control cells received an equivalent amount of DPC.…”

Section: Presentation Of Fatty Acids To Cellsmentioning

confidence: 99%

The Immunomodulatory Effects of Novel β-Oxa, β-Thia, and γ-Thia Polyunsaturated Fatty Acids on Human T Lymphocyte Proliferation, Cytokine Production, and Activation of Protein Kinase C and MAPKs

Costabile

Hii

Melino

et al. 2005

The Journal of Immunology

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We have recently demonstrated that a novel n-3 long chain polyunsaturated fatty acid (PUFA) (β-oxa 21:3n-3) was a more potent and more selective anti-inflammatory agent than n-3 PUFA. To gain further insights into this technology, we synthesized other novel PUFA consisting of β-oxa, β-thia, and γ-thia compounds. All three types displayed anti-inflammatory activity. Each of the unsaturated β-oxa fatty acids showed similar inhibition of PHA-PMA-induced T cell proliferation with a parallel inhibition of TNF-β production. However, β-oxa 25:6n-3 and β-oxa 21:4n-3 displayed lower inhibitory action on IFN-γ production. Surprisingly, β-oxa 23:4n-6 and β-oxa 21:3n-6 had marginal effect on IL-2 production. Thus, structural variation can generate selectivity for different immunological parameters. The β-thia compounds 23:4n-6, 21:3n-6, and 21:3n-3 were highly effective in inhibiting all immunological responses. Of the two γ-thia PUFA tested, γ-thia 24:4n-6 was a strong inhibitor of all responses apart from IL-2, but γ-thia 22:3n-6 had very little inhibitory effect. Two of the most active compounds, β-thia 23:4n-6 and β-thia 21:3n-6, were studied in more detail and shown to have an IC50 of 1–2 μM under optimal conditions. Thus, these PUFA retain the immunosuppressive properties of the n-3 PUFAs, 20:5n-3 and 22:6n-3, but not the neutrophil-stimulating properties. Their action on T lymphocytes is independent of cyclooxygenase or lipoxygenase activity, and they act at a postreceptor-binding level by inhibiting the activation of protein kinase C and ERK1/ERK2 kinases.

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“…Several families of nonenzymatic PUFA oxidation products were shown to stimulate or inhibit inflammatory reactions. These include PUFA fragmentation species [e.g., hydroxynonenal (1, 2)], hydroxides and hydroperoxides of PUFAs (3)(4)(5), and isoprostanes (6)(7)(8)(9). In addition to free oxidized PUFAs, esterified oxidized residues also demonstrate pro-and anti-inflammatory activities (10)(11)(12).…”

mentioning

confidence: 99%

Oxidized Phospholipids Are More Potent Antagonists of Lipopolysaccharide than Inducers of Inflammation

Oskolkova¹,

Afonyushkin²,

Preinerstorfer

et al. 2010

The Journal of Immunology

111

109

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Polyunsaturated fatty acids are precursors of multiple pro- and anti-inflammatory molecules generated by enzymatic stereospecific and positionally specific insertion of oxygen, which is a prerequisite for recognition of these mediators by cellular receptors. However, nonenzymatically oxidized free and esterified polyunsaturated fatty acids also demonstrate activities relevant to inflammation. In particular, phospholipids containing oxidized fatty acid residues (oxidized phospholipids; OxPLs) were shown to induce proinflammatory changes in endothelial cells but paradoxically also to inhibit inflammation induced via TLR4. In this study, we show that half-maximal inhibition of LPS-induced elevation of E-selectin mRNA in endothelial cells developed at concentrations of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) 10-fold lower than those required to induce proinflammatory response. Similar concentration difference was observed for other classes and molecular species of OxPLs. Upon injection into mice, OxPAPC did not elevate plasma levels of IL-6 and keratinocyte chemoattractant but strongly inhibited LPS-induced upregulation of these inflammatory cytokines. Thus, both in vitro and in vivo, anti-LPS effects of OxPLs are observed at lower concentrations than those required for their proinflammatory action. Quantification of the most abundant oxidized phosphatidylcholines by HPLC/tandem mass spectrometry showed that circulating concentrations of total oxidized phosphatidylcholine species are close to the range where they demonstrate anti-LPS activity but significantly lower than that required for induction of inflammation. We hypothesize that low levels of OxPLs in circulation serve mostly anti-LPS function and protect from excessive systemic response to TLR4 ligands, whereas proinflammatory effects of OxPLs are more likely to develop locally at sites of tissue deposition of OxPLs (e.g., in atherosclerotic vessels).

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Altered responses of human macrophages to lipopolysaccharide by hydroperoxy eicosatetraenoic acid, hydroxy eicosatetraenoic acid, and arachidonic acid. Inhibition of tumor necrosis factor production.

Cited by 40 publications

References 33 publications

Endotoxemia in Transgenic Mice Overexpressing Human Glutathione Peroxidases

Endotoxemia in Transgenic Mice Overexpressing Human Glutathione Peroxidases

The Immunomodulatory Effects of Novel β-Oxa, β-Thia, and γ-Thia Polyunsaturated Fatty Acids on Human T Lymphocyte Proliferation, Cytokine Production, and Activation of Protein Kinase C and MAPKs

Oxidized Phospholipids Are More Potent Antagonists of Lipopolysaccharide than Inducers of Inflammation

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