Absence of 12/15 Lipoxygenase Reduces Brain Oxidative Stress in Apolipoprotein E-Deficient Mice

Chinnici, Cinzia Maria; Yao, Yuemang; Ding, Tao; Funk, Colin D.; Praticò, Domenico

doi:10.1016/s0002-9440(10)61224-2

Cited by 38 publications

(24 citation statements)

References 29 publications

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“…5,6 In addition, 12/15-LOX may contribute to oxidative stress in mouse brains in vivo. 24 For the first time, the results presented here document an increase of 12/15-LOX on the ischemic side of the infarcted brain, in the peri-infarct region of the cortex. This increase is detected predominantly in neurons, consistent with previous studies showing 12/15-LOX involvement in neuronal cell death in vitro.…”

Section: Discussionsupporting

confidence: 57%

Baicalein and 12/15-Lipoxygenase in the Ischemic Brain

Leyen

Kim

Lee

et al. 2006

Stroke

218

186

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Section: Discussionsupporting

confidence: 57%

Baicalein and 12/15-Lipoxygenase in the Ischemic Brain

Leyen

Kim

Lee

et al. 2006

Stroke

218

186

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“…This could possibly be due to the relatively small contribution of leukocytes to total brain tissue, as well as the high basal levels of 12/15-LOX expression found in brain parenchyma (8). Therefore, we investigated whether infiltrating myeloid cells and or microglia in the brain at least expressed 12/15-LOX during chronic toxoplasmosis.…”

Section: Resultsmentioning

confidence: 99%

12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis

et al. 2009

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Interleukin-12 (IL-12) is critical for resistance to Toxoplasma gondii during both the acute and chronic stages of infection. However, the cellular and molecular pathways that regulate IL-12 production during chronic toxoplasmosis are incompletely defined. We recently discovered that 12/15-lipoxygenase (12/15-LOX), which oxidizes unsaturated lipids in macrophages, is a novel and selective regulator of IL-12 production. We now demonstrate the essential role of this enzyme in the chronic phase of toxoplasmosis. Although 12/15-LOXdeficient mice were resistant to acute T. gondii infection, 80% of 12/15-LOX-deficient mice died during chronic toxoplasmosis, compared to no deaths in wild-type controls. The morbidity of chronically infected 12/15-LOX mice was associated with an increase in brain inflammation and parasite burden. These data suggest that the evolution of the immune response to T. gondii is accompanied by an increasing requirement for 12/15-LOXmediated signaling. Consistent with this conclusion, 12/15-LOX activity was enhanced during chronic, but not acute, toxoplasmosis. Furthermore, the enhanced susceptibility of 12/15-LOX-deficient mice to chronic toxoplasmosis was associated with reduced production of IL-12 and gamma interferon (IFN-␥) that was not evident during acute infection. Importantly, ex vivo IFN-␥ production by 12/15-LOX-deficient splenocytes could be rescued by the addition of recombinant IL-12. These data establish that 12/15-LOX is a critical mediator of the chronic type 1 inflammatory response and that immune mediators can be subject to distinct cellular and/or molecular mechanisms of regulation at different stages of inflammation.Lipoxygenase and cyclooxygenase families are critical regulators of chronic inflammation that seem to play little role in acute processes (26, 37). Because of this potential specificity, these lipid-metabolizing enzymes have been targeted for years in the search for pathways that selectively impact chronic inflammatory disease. Several studies demonstrated an important role for cyclooxygenase and lipoxygenase products in regulating interleukin-12 (IL-12) production, and lipoxygenases in particular contribute toward the response to Toxoplasma gondii. Specifically, lipoxin A 4 (LxA 4 ), a product of both 15-lipoxygenase (15-LOX) and 5-lipoxygenase (5-LOX) (45), downregulates IL-12 produced by toxoplasma antigen-activated dendritic cells (DCs), thereby tempering the immune response (3,42,57). Indeed, 5-LOX-deficient mice infected with T.

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“…3, trace C). This enzyme mediates atherosclerosis (58-60), brain oxidative stress (73), and Alzheimer's disease (74), and is a key player in oxidative stress in general. The efficacy of rabbit 15-LO inhibition by LHA far exceeded the reported efficacy of baicalein (IC 50 between 1.6 and 38 mM) (69) and of other tested flavonoids (75).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies

Butovich

Lukyanova

2008

Journal of Lipid Research

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In this first comparative in vitro study, linoleyl hydroxamic acid (LHA), a simple and stable derivative of linoleic acid, was tested as an inhibitor of several enzymes involved in arachidonic acid metabolism in mammals. The tested enzymes were human recombinant 5-lipoxygenase (h5-LO), porcine leukocyte 12-LO, rabbit reticulocyte 15-LO, ovine cyclooxygenases 1/2 (COX1/COX2), and human microsomal prostaglandin E synthase-1 (mPGES-1). Potato tuber and soybean lipoxygenases (ptLOX and sLOX, respectively) were studied for comparative purposes. LHA inhibited most of the tested enzymes with the exception of mPGES-1. The LHA inhibitory activity increased as follows: mPGES-1 (no inhibition),,COX1 5 COX2,h5-LO 5 sLOX 5 ptLOX, 12-LO,,15-LO. The IC 50 values for COX1/COX2, h5-LO, 12-LO, and 15-LO were 60, 7, 0.6, and 0.02 mM, respectively. sLOX was the only tested enzyme that was capable of aerobic oxygenation of LHA, producing 13-hydroperoxy-LHA. The enzyme rapidly inactivated during the reaction. Therefore, LHA could be used as an effective LO/LOX inhibitor without affecting COX1/COX2 and mPGES-1. Possible implications of this observation include treating diseases and pathological states that are caused by (or lead to) hyperproduction of LO-derived metabolites, e.g., inflammation, cardiovascular disorders, cancer, asthma, allergies, psoriasis, and stroke.-Butovich, I. A., and S. M. Lukyanova. Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies.

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Absence of 12/15 Lipoxygenase Reduces Brain Oxidative Stress in Apolipoprotein E-Deficient Mice

Abstract: Lipoxygenases (LOs) are members of a large family of non-heme iron-containing dioxygenases that insert molecular oxygen into polyunsaturated fatty acids.

Cited by 38 publications

References 29 publications

Baicalein and 12/15-Lipoxygenase in the Ischemic Brain

Baicalein and 12/15-Lipoxygenase in the Ischemic Brain

12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis

Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies

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