Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase.

Conrad, Douglas; Kühn, Hartmut; Mulkins, Mary A.; Highland, E.; Sigal, Elliott

doi:10.1073/pnas.89.1.217

Cited by 348 publications

(259 citation statements)

References 33 publications

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“…Alternatively, the enzyme may play a role in the inflammatory reaction in the atherosclerotic lesion. The specific induction of the 15-lipoxygenase in human monocytes by the cytokine IL 4 [42] which is known to be of importance in inflammation [43] is supportive of this hypothesis. Since inflammation may be regarded as defence mechanism against endothelial injury in the early stages of plaque development, the intracellular action of the lipoxygenase might be involved in a repair process.…”

Section: Discussionsupporting

confidence: 64%

Oxygenation of lipoproteins by mammalian lipoxygenases

Belkner

Wiesner

Rathman

et al. 1993

European Journal of Biochemistry

148

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Oxidative modification converts low-density lipoprotein (LDL) into its atherogenic form and appears to be a necessary precondition for LDL uptake by macrophages during foam cell formation. Cellular lipoxygenases have been implicated in this process. We studied the interaction of purified mammalian lipoxygenases with human LDL in v i m and found that the arachidonate 15-lipoxygenases of rabbit and man are capable of oxygenating lipoproteins as indicated by oxygen uptake and by the formation of thiobarbituric-acid-reactive substances. Furthermore, oxygenated polyenoic fatty acids, such as 13-hydro(pero)xy-9Z, 11 E-octadecadienoic acid and 15-hydro(pero)xy-5,8,11,13 (Z,Z, Z,E)-eicosatetraenoic acid were detected in the lipid compartment of various lipoproteins classes after lipoxygenase treatment. More than 90% of the oxygenated polyenoic fatty acids were found in the ester-lipid fraction, particularly in the cholesterol esters, whereas only small amounts of free hydro(pero)xy polyenoic fatty acids were detected. Lipoxygenase-catalyzed oxygenation of LDL is not restricted to the lipid compartment but also leads to a cooxidative modification of the apoproteins as indicated by changes in the electrophoretic mobility and by the formation of carbonyl derivatives of amino acid side chains. The possible biological significance of lipoxygenase-induced oxidative modification of lipoproteins in the pathogenesis of atherosclerosis is discussed.Atherosclerosis is a multifactoral disease, the pathogenesis of which is not fully understood [l-31. It has been shown by morphological studies that the accumulation of lipid-loaded foam cells in the subendothelial space leads to the formation of fatty streaks, which are generally accepted as the early atherosclerotic lesions [l -41. Foam cells develop from monocyte-derived macrophages [5, 61 or from smooth muscle cells [7] by taking up modified low-density lipoproteins (LDL) via scavenger-receptor(s)-mediated pathways. The occurrence of oxidatively modified proteins in atherosclerotic lesions [8, 91 and the fact that oxidatively modified LDL is rapidly taken up by macrophages [lo] suggested an involvement of oxidative processes in the pathogenesis of atherosclerosis. However, the mechanism of oxidative modification in vivo remains unclear. In-vitro studies with cell-free systems indicated that copper-mediated oxidation converts LDL into its atherogenic form [ll] The oxygenation of lipoproteins by mammalian lipoxygenases has not been studied so far. The soybean lipoxygenase which largely differs from mammalian lipoxygenases with respect to its protein chemical and enzymic properties is capable of oxidizing LDL only in the presence of phospholipase A, which provides free polyenoic fatty acids by cleaving lipoprotein phospholipids [20]. This result is not surprising since the soybean lipoxygenase has been shown to effectively oxygenate ester lipids only in the presence of detergents [21]. However, the rabbit reticulocyte lipoxygenase is capable of oxygenating complex ester lipids such ...

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Section: Discussionsupporting

confidence: 64%

Oxygenation of lipoproteins by mammalian lipoxygenases

Belkner

Wiesner

Rathman

et al. 1993

European Journal of Biochemistry

148

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“…CLECSF13 is a lectin that was identified in macrophages, 55 although here it is seen to have significantly higher expression in dendritic cells. ALOX15 protein expression can be induced in monocytes, 56 but this study shows dendritic cell specificity. Specific here to both resting and induced dendritic cells are two chemokines, CCL13 and CCL17, that have been shown to be expressed in different cell types under different conditions.…”

Section: Nk Cellscontrasting

confidence: 49%

Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data

Abbas¹,

Baldwin²,

Ma³

et al. 2005

Genes Immun

360

356

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Immune cell-specific expression is one indication of the importance of a gene's role in the immune response. We have compiled a compendium of microarray expression data for virtually all human genes from six key immune cell types and their activated and differentiated states. Immune Response In Silico (IRIS) is a collection of genes that have been selected for specific expression in immune cells. The expression pattern of IRIS genes recapitulates the phylogeny of immune cells in terms of the lineages of their differentiation. Gene Ontology assignments for IRIS genes reveal significant involvement in inflammation and immunity. Genes encoding CD antigens, cytokines, integrins and many other gene families playing key roles in the immune response are highly represented. IRIS also includes proteins of unknown function and expressed sequence tags that may not represent genes. The predicted cellular localization of IRIS proteins is evenly distributed between cell surface and intracellular compartments, indicating that immune specificity is important at many points in the signaling pathways of the immune response. IRIS provides a resource for further investigation into the function of the immune system and immune diseases.

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“…Regulation of 15-LOa activity in a variety of cell types has been suggested to be mediated by the Ca 2+ -dependent membrane association of the enzyme with the membrane fraction of cells [16,43]. In monocytes treated with interleukin-4, large amounts of 15-LOa are expressed in the cytosol and the intracellular activity of the enzyme with endogenous substrates is limited [44]. In contrast, in mature reticulocytes the intracellular calcium concentration is in the micromolar range [45,46] and a significant proportion of the enzyme is membrane bound, leading to the detection of specific lipoxygenase products in the membrane lipids [16].…”

Section: Discussionmentioning

confidence: 99%

Differential characteristics of human 15‐lipoxygenase isozymes and a novel splice variant of 15S‐lipoxygenase

Kilty

Logan

Vickers

1999

European Journal of Biochemistry

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The lipoxygenases (LOs) are a family of nonheme iron dioxygenases that catalyse the insertion of molecular oxygen into polyunsaturated fatty acids. Five members of this gene family have been described in man, 5-LO, 12S-LO, 12R-LO, 15-LO and 15S-LO. Using partially purified recombinant 15S-LO enzyme and cells constitutively expressing this protein, we have compared the activity, substrate specificity, kinetic characteristics and regulation of this enzyme to that previously reported for 15-LO. 15S-LO has a threefold higher K m , similar V max and increased specificity of oxygenation for arachidonic acid, and a similar K m but decreased V max for linoleic acid in comparison to 15-LO. Unlike 15-LO, 15S-LO is not suicide inactivated by the products of fatty acid oxygenation. However, in common with other LOs, 15S-LO activity is regulated through calcium-dependent association of the enzyme with the membrane fraction of cells.In addition, whilst independently cloning the recently described 15S-LO, we identified a splice variant containing an in-frame 87-bp deletion corresponding to amino acids 401±429 inclusive. Modelling of the 15S-LO and subsequent studies with partially purified recombinant protein suggest that the deleted region comprises a complete a-helix flanking the active site of the enzyme resulting in decreased specificity of oxygenation and affinity for fatty acid substrates.Alternative splicing of 15S-LO would therefore provide a further level of regulation of fatty acid metabolism. These results demonstrate that there are substantial differences in the enzyme characteristics and regulation of the 15-LO isozymes which may reflect differing roles for the proteins in vivo. Although the LOs produce specific hydroxyeicosatetraenoic (HETE) enantiomers, the enzymes do not all display absolute positional specificity with respect to oxygenation of AA. For example, while 15-LOb exclusively oxygenates C15 of AA [8], 15-LOa oxygenates AA at both C15 and C12 [9]. In addition, the degree of homology between members of the LO family does not define the product profile. For example, amino acid sequence alignments demonstrate that 15-LOb is more closely related to 12R-LO than 15-LOa, suggesting complex evolutionary paths in the LO family.The LOs are responsible for the synthesis of a number of inflammatory mediators, including leukotrienes and lipoxins, which are implicated in inflammatory disorders such as bronchial asthma [10]. Lipoxygenase metabolites have also been implicated in a number of noninflammatory biological processes. For example, 12-HETE and 15-HETE have been implicated in tumour metastases and the formation of atherosclerotic plaques, respectively [11,12]. The important biological roles of these LO metabolites and the complexity of substrate utilization by members of the LO family emphasize the importance of understanding factors which affect the activity and regulation of these enzymes.Overexpression and characterization of recombinant 5-LO, 12-LO and 15-LOa have been carried out allowing kinetic analysis...

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Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase.

Cited by 348 publications

References 33 publications

Oxygenation of lipoproteins by mammalian lipoxygenases

Oxygenation of lipoproteins by mammalian lipoxygenases

Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data

Differential characteristics of human 15‐lipoxygenase isozymes and a novel splice variant of 15S‐lipoxygenase

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