Disease relevance of Alox15

• Here, we provide in vivo evidence for the role of 12/15-lipoxygenase in atherogenesis and demonstrate diminished plasma IgG autoantibodies to oxidized LDL epitopes in 12/15-lipoxygenase knockout mice crossbred with atherosclerosis-prone apo E-deficient mice (apo E-/-/L-12LO-/-) [1].
• At the acute stage of infection, when granuloma formation is usually maximal, 5-LO deficient mice developed smaller granulomas around liver-deposited schistosome eggs compared with wild type or 12-LO deficient mice [2].
• In this report we characterize e-12LO, which was overexpressed in the baculovirus/insect cell expression system [3].
• 12-lipoxygenase (12-lipoxygenase) (12-LOX) was recruited to glycosphingolipid-enriched microdomains (GEM) in a GM3-dependent manner during oxidative glutamate toxicity [4].
• Arachidonic acid is metabolized by 12-LOX to 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], and this biologically active metabolite is involved in prostate cancer progression by modulating cell proliferation in multiple cancer-related pathways inducing angiogenesis and metastasis [5].

Psychiatry related information on Alox15

• Lastly, cocaine-mediated increases in locomotor activity was augmented acutely but not chronically in 12-LO-/- mice [6].

High impact information on Alox15

• Leukocyte 12-lipoxygenase (12-LO) gene expression in pancreatic beta cells is upregulated by cytotoxic cytokines like IL-1beta [7].
• In summary, elimination of leukocyte 12-LO in mice ameliorates low dose streptozotocin-induced diabetes by increasing islet resistance to cytokines and decreasing macrophage production of nitric oxide [7].
• Male homozygous 12-LO KO mice and control C57BL/6 mice received 5 consecutive daily injections of low-dose streptozotocin to induce immune-mediated diabetes [7].
• Furthermore, cytokine-induced 12-hydroxyeicosatetraenoic acid (12-HETE) production was absent in 12-LO KO islets but present in C57/BL6 islets [7].
• Recent studies have demonstrated that 12-LO inhibitors can prevent glutamate-induced neuronal cell death when intracellular glutathione stores are depleted [7].

Biological context of Alox15

• Collectively, these results identify a novel action for the mouse 12/15-LOX (Alox15) and its products, LXA(4) and NPD1, in wound healing that is distinct from their well established anti-inflammatory properties [8].
• Through combined genetic and genomic approaches, we identified the lipoxygenase gene Alox15 as a negative regulator of peak bone mineral density in mice [9].
• Crossbreeding experiments with Alox15 knockout mice confirmed that 12/15-lipoxygenase plays a role in skeletal development [9].
• The epidermal lipoxygenase gene (Aloxe) resides on mouse chromosome 11 closely linked with the two 12-lipoxygenase genes (Alox12p and Alox12l) [10].
• As one example, analysis of a murine genetic model of osteoporosis demonstrated that genetic variation within the 15-lipoxygenase (Alox15) gene affected peak bone mass, and that treatment with inhibitors of this enzyme improved bone mass and quality in rodent models [11].

Anatomical context of Alox15

• More importantly, Alox15-deficient mice exhibited a defect in both corneal re-epithelialization and neutrophil recruitment that correlated with a 43% reduction in endogenous LXA(4) formation [8].
• 12-LO KO macrophages generated 50% less nitrate/nitrite when compared with C57BL/6 macrophages [7].
• L-12LO-deficient mice have no obvious abnormalities in reticulocyte or mature red blood cells, which suggest that in mice this pathway is not functionally important for erythrocytic development [12].
• We have inactivated the L-12LO gene in mice using homologous recombination in embryonic stem cells [12].
• By in situ hybridization we show that the L-12LO gene is expressed abundantly in a subset of peritoneal macrophages but not in elicited leukocytes, alveolar macrophages, or bone marrow-derived macrophages [12].

Associations of Alox15 with chemical compounds

• OBJECTIVES: We have utilized mice with a disruption of the "leukocyte-type" 12-lipoxygenase gene (12-LO-/- mice) to examine a variety of general behavioral responses as well as several specific responses to morphine and cocaine [6].
• Although the antipsoriatic drug, anthralin, predominantly inhibited epidermal 12-LO, the novel derivatives were more selective 5-LO inhibitors [13].
• By contrast, 12-LO, 15-LO, phosphodiesterase activity and histamine release from mast cells and basophils were unaffected by Wy-48,252 [14].
• Moreover, 5,8,11-eicosatriynoic acid (ETI) which inhibits 5- and 12-LO, and 5, 8, 11, 14-eicosatetraynoic acid (ETYA) which inhibits all known LOs did not affect B-lymphocyte proliferation [15].
• Previously published investigations with the nonspecific 5-LO (EC 1.13.11.34) and 12-LO (EC 1.13.11.31) inhibitors such as nordihydroguaiaretic acid (NDGA) and 6,7-dihydroxycoumarin (Esculetin), are misleading in that they suggest lymphocyte LO activity is required for activation and differentiation of these cells [15].

Regulatory relationships of Alox15

• We then evaluated IL-1beta-induced PGE2 production in islets purified from control C57BL/6 mice and 12-LO knockout mice lacking cytokine-inducible 12-HETE [16].
• Overexpression of 12-LO induced p38 MAPK activation [17].
• Leukocyte type 12-lipoxygenase (12-LO) is an enzyme specifically expressed in the beta cells of the pancreas [18].

Other interactions of Alox15

• Addition of 12-HETE to 12-LO knockout islet cells produced a statistically significant rise in PGE2 production [16].
• Inhibition of either COX-2 or 12-LO can prevent cytokine-induced pancreatic beta-cell dysfunction as defined by inhibition of glucose-stimulated insulin secretion [16].
• GnRH nearly doubled the release of 12-hydroeicosatetraenoic acid, a product of the 12-LO enzyme, within 10 min [19].
• LbetaT2 cells represent a potential model to further study the involvement of 12-LO in GnRH receptor signaling [19].
• In summary, diabetes in vivo and exposure of podocytes to HG in vitro stimulated 12-LO, p38 MAPK, and collagen alpha5(IV) mRNA and (activated) protein [20].

Analytical, diagnostic and therapeutic context of Alox15

• Cellular localisation of 12LO was evaluated using immunocytochemistry [21].
• 12LO activity was evaluated and 12LO protein levels were determined using immunoblotting with a selective leucocyte type 12LO antibody [21].
• Additionally, mice +/- isoflurane (24 h previously) were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion in the presence and absence of a 12-LO inhibitor [22].
• We next examined the effect of 12-LO over-expression on mitogen-activated protein kinases (MAPK) by Western blot analyses using antibodies specific for different phospho-MAP kinases [18].
• A specific reverse transcriptase polymerase chain reaction with a set of primers based on the reported sequence of rat brain 12-LO yielded a 170-bp band which showed 100% homology with the expected rat brain 12-LO sequence [19].

References