Review
Inflammation and immune regulation by 12/15-lipoxygenases

https://doi.org/10.1016/j.plipres.2006.02.003Get rights and content

Abstract

12/15-Lipoxygenases (12/15-LOX) are members of the LOX family, which are expressed in mammals by monocytes and macrophages following induction by the T helper type 2 cytokines, interleukins-4 and -13. They oxygenate free polyenoic fatty acids but also ester lipids and even complex lipid-protein assemblies such as biomembranes and lipoproteins. The primary oxidation products are either reduced by glutathione peroxidases to corresponding hydroxy derivatives or metabolized into secondary oxidized lipids including leukotrienes, lipoxins and hepoxilins, which act as lipid mediators. Examination of knockout and transgenic animals revealed important roles for 12/15-LOX in inflammatory diseases, including atherosclerosis, cancer, osteoporosis, angiotension II-dependent hypertension and diabetes. In vitro studies suggested 12/15-LOX products as coactivators of peroxisomal proliferator activating-receptors (PPAR), regulators of cytokine generation, and modulators of gene expression related to inflammation resolution. Despite much work in this area, the biochemical mechanisms by which 12/15-LOX regulates physiological and pathological immune cell function are not fully understood. This review will summarize the biochemistry and tissue expression of 12/15-LOX and will describe the current knowledge regarding its immunobiology and regulation of inflammation.

Section snippets

Lipoxygenases are lipid peroxidizing enzymes with multiple catalytic activities

LOXs catalyze the stereoselective oxygenation of polyunsaturated fatty acids containing at least one (1Z,4Z)-penta-1,4-dienoic system to the corresponding hydroperoxy derivatives [1]. LOX catalysis is a bimolecular reaction that requires the simultaneous presence of lipid substrate and atmospheric oxygen (Fig. 1). If one of the two substrates is limiting (e.g. severe hypoxia) the enzyme alters its catalytic activity and a different set of reaction products is formed (see below). Lipoxygenation

Tissue specific expression and expression regulation of 12/15-LOXs

In early years of eicosanoid research, conversion of exogenous arachidonic acid to 15-HETE was considered a proof for the presence of 12/15-LOX in a biological sample and in most cases the chirality of the reaction product was not investigated. Today we know that 15-HETE can be formed via alternative metabolic routes (non-enzymatic reactions, two human 15-LOXs, aspirin treated COX2) and thus, the classical activity assay is sufficient any more to prove 12/15-LOX expression. In state of the art

Regulation of immune cell function by 12/15-LOX expression

Induction of murine and human 12/15-LOX in monocytic cells by the TH2 cytokines, interleukins-4 (IL-4) and -13 (IL-13), and its suppression by interferon-γ (IFNγ) were early findings that hinted at a central role for this enzyme in immune regulation [48], [49], [88]. This has been extended by in vitro studies showing that peritoneal macrophages from mice lacking 12/15-LOX show a number of immune defects when compared with wild type. These include (i) decreased IL-4 induction of the scavenger

Pathophysiological role for 12/15-LOX in inflammatory vascular diseases

Inflammatory vascular disease encompasses a spectrum of disorders that includes atherosclerosis, diabetes and hypertension. A central involvement of the immune system in the pathophysiology of these diseases is well recognized. For example, leukocyte recruitment and activation as well as upregulation of both innate and acquired immunity, is a central feature. A role for 12/15-LOX in mediating pathogenic lipid peroxidation associated with inflammatory vascular disease has been discussed for many

What is the physiological role of 12/15-LOX in immune and inflammatory responses

12/15-LOXs are conserved in mammalian species indicating that they play an important physiological role. Without challenge, mice lacking 12/15-LOX appear normal without breeding problems or spontaneous pathophysiology. However, colonies are housed in microbiologically-regulated facilities and so will not be exposed to the same inflammatory and immune challenges experienced by free-living mammals. 12/15-LOX products interact with several inflammation-related signalling pathways often with

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