The evidence points toward a role

The evidence points toward a role for 12/15-LO activity in WAT in modulating chronic local inflammation and subsequent systemic metabolic decline in the obese state. However, little is known as to the role of 12- and 15-LOs in BAT. Indeed, in addition to WAT, platelet- and leukocyte-type 12-LO are expressed in BAT [19]. Unpublished observations from our lab also reveal that 12/15-LO expression is not increased in BAT when mice are fed a high-fat diet. Therefore, deciphering the mechanism of 12/15-LO activation in WAT and BAT as well as products generated in these fat depots by 12/15-LO will reveal insights into 12/15-LO function.
Contributions
Acknowledgments We would like to thank Swarup K. Chakrabarti for collaborative studies pertaining to the role of leukocyte-type 12-LO in rodent and human adipocytes. We would also like to acknowledge that the National Institutes of HealthP01 HL55798 and R01 HL112605 grants and a National Institutes of Health NRSA Postdoctoral Research FellowshipF32 DK085716 supported many studies from our lab referenced in this manuscript.
Introduction Allergic asthma is a chronic inflammatory disease [1]. Eicosanoids are a family of arachidonic acid-derived lipid mediators which play a key role in the regulation of inflammatory response [2]. There is a large evidence indicating that eicosanoids are essential in the pathogenesis of asthma/allergic inflammation [2,3]. Synthesis of eicosanoids requires arachidonic CCG 203971 to be released from cell membrane phospholipids by phospholipases A2 (PLA2) [4]. Although all PLA2s can release arachidonic acid from phospholipids, only group IVA PLA2 shows selectivity toward phospholipids containing arachidonic acid [5]. It has been shown that this group of IVA cytosolic PLA2 (cPLA2) is crucial for the development of allergic asthma in mice [6]. Moreover, in humans, group IVA PLA2 is overexpressed in severe asthmatic patients indicating the role of arachidonic acid metabolites in the pathogenesis of asthma [7]. Arachidonic acid released by cPLA2 in response to cell activation is subsequently metabolized by cyclooxygenases (COXs) or lipoxygenases (LOXs) to prostaglandins (PGs) or hydroxyeicosatetraenoic acids (HETEs), respectively [5]. Further metabolism of HETEs leads to generation of leukotrienes (LTs) and/or lipoxins (LXs) [2,3]. Important role of COX- and LOX-derived metabolites has been demonstrated in allergic asthma patients and in allergic asthma model in mice [2,8]. However, the role of arachidonic acid-derived eicosanoids in asthma appears complex and still requires further research. Some PGs, such as PGD2 and PGF2α, have pro-inflammatory and pro-asthmatic functions while other PGs, such as PGE2, exert anti-inflammatory and anti-asthmatic functions in both human and mice [3,9]. Similarly, leukotrienes, including leukotriene B4 (LTB4) and cysteinyl LTs (cysLTs), exert pro-inflammatory and pro-asthmatic functions, while LXs, which originate after arachidonate metabolism with both 5-LOX and 15-LOX, attenuate airway inflammation and suppress asthma development [10,11]. Imbalance between synthesis of pro-inflammatory and anti-inflammatory/pro-resolving mediators has been demonstrated in other chronic inflammatory lung diseases and may lead to irreversible lung damage [12,13]. Interactions between the effects of arachidonic acid metabolites are complex and occur on several levels including competition of individual enzymes for a substrate, specific receptor-mediated different effects of individual eicosanoids at cellular level and also via effect of individual eicosanoids on expression of cyclooxygenases and lipoxygenases [13–15]. For instance, PGE2 which is a major product of COX-2, inhibits expression of 5-LOX and up-regulates expression of 15-LOX [14]. On the other hand, 15-HPETE and 15-HETE, which are major products of 15-LOX, inhibit COX-2-dependent PGE2 synthesis [15]. It has already been reported that in 12/15-LOX knockout mice allergen induced airway inflammation is greatly attenuated [16,17]. However, the molecular effects responsible for decrease in inflammatory response after 12/15-knockout are not fully understood. It was therefore of interest to investigate the role of 12/15-LOX in metabolism of eicosanoids in a model of allergic airway inflammation in mice.