Cytokine-Dependent Expression regulation of ALOX15

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Cytokine-Dependent Expression regulation of ALOX15

Introduction

According to the IUPAC recommendations lipoxygenases (LOXs) are classified as fatty acid dioxygenases since they introduce one molecule of atmospheric oxygen into the hydrocarbon tail of fatty acids [1,2]. LOXs are widely distributed in plants and mammals but they only occur sporadically in bacteria, fungi and lower marine organisms [3]. The first mammalian LOXs have been described in the mid 1970 in human blood platelets [4,5] and rabbit reticulocytes [6]. Since then a large number of LOX-isoforms have been described in various animal species. Complete sequencing of the human genome indicated the existence of six different LOX genes (ALOX5, ALOX12, ALOX12B, ALOX15, ALOX15B, ALOXE3), which encode for functionally distinct LOX-isoforms [7]. In addition, a corrupted pseudogene (7) has been detected in the human genome (ALOXE12 ). Free polyenoic fatty acids, such as linoleic acid (9,12-octadecadienoic acid), alpha- (9,12,15-octadecatrienoic acid) and gamma- (6,9,12- octadecatrienoic acid) linolenic acid, arachidonic acid (5,8,11,14- eicosatetraenoic acid), 5,8,11,14,17-eicosapentaenoic acid and 4,7,10,13,16,19-docosahexaenoic acid are preferred substrates of mammalian LOXs. Since free fatty acids do not abundantly occur in most mammalian cells the LOX-pathway is initiated by enzymatic hydrolysis of membrane ester lipids [1]. The primary products of the LOX reaction, the hydroperoxy fatty acids, are subsequently converted to a large array of bioactive mediators, which include leukotrienes [1], lipoxins [8], hepoxilins [9], eoxins [10], resolvins [11], protectins [12] and others. However, LOXs exhibit their biological functions not only by producing bioactive mediators. As oxidizing enzymes they are also involved in the regulation of the cellular redox homeostasis, which strongly impacts the gene expression pattern. Moreover, since ALOX15 orthologs are capable of oxidizing complex ester lipids such as phospholipids [13] and cholesterol esters [14] they modify the functional characteristics of biomembranes and lipoproteins.

The expression of LOX-isoforms in general and of ALOX15 in particular is highly regulated on transcriptional and translational levels [15]. In 1992 it was first reported that expression of ALOX15 can be specifically induced in isolated human monocytes by the Th2-cytokine interleukin-4 (IL4) [16]. Two years later [17] another classical Th2 cytokine, interleukin 13 (IL13), was shown to upregulate ALOX15 expression. Although the mechanistic basis for the IL4/IL13- dependent expression regulation has not extensively been studied in these early reports these papers mark the beginning of a new chapter in LOX research. A quick PubMed search with the key words “lipoxygenase” and “interleukin” revealed some 720 entries over the past 25 years. This review is aimed at summarizing the current knowledge on the cytokine-dependent expression regulation of ALOX15 with particular emphasis on the Th2 cytokines IL4 and IL13. We will also critically evaluate the suggested mechanistic scenarios and the applicability of the robust in vitro effects for the in vivo situation.

Best Regards:
Veronica Thompson

Journal Manager
Journal of Cytokine Biology
Email:  cytokinebiol@oajoirnal.org