Chapter Two - The Leukotrienes: Immune-Modulating Lipid Mediators of Disease

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Abstract

The leukotrienes are important lipid mediators with immune modulatory and proinflammatory properties. Classical bioactions of leukotrienes include chemotaxis, endothelial adherence, and activation of leukocytes, chemokine production, as well as contraction of smooth muscles in the microcirculation and respiratory tract. When formed in excess, these compounds play a pathogenic role in several acute and chronic inflammatory diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel disease. An increasing number of diseases have been linked to inflammation implicating the leukotrienes as potential mediators. For example, recent investigations using genetic, morphological, and biochemical approaches have pointed to the involvement of leukotrienes in cardiovascular diseases including atherosclerosis, myocardial infarction, stroke, and abdominal aortic aneurysm. Moreover, new insights have changed our previous notion of leukotrienes as mediators of inflammatory reactions to molecules that can fine-tune the innate and adaptive immune response. Here, we review the most recent understanding of the leukotriene cascade with emphasis on recently identified roles in immune reactions and pathophysiology.

Introduction

The leukotrienes (LTs) belong to a family of lipid mediators derived from arachidonic acid (AA), collectively known as eicosanoids. These molecules are produced by a specific, non-heme iron-containing, dioxygenase called 5-lipoxygenase (5-LO) together with a downstream leukotriene A4 hydrolase (LTA4H) and/or leukotriene C4 synthase (LTC4S; Fig. 2.1). LTs exert potent biological activities during inflammatory reactions and host defense, and when formed in excess under pathological conditions, these substances may induce and sustain several acute and chronic inflammatory diseases. As indicated by their name, LTs are primarily formed in leukocytes, including neutrophils, monocytes/macrophages, mast cells (MCs), and dendritic cells (DCs). Like other eicosanoids, LTs are paracrine mediators exerting their actions in the local cellular milieu at nanomolar concentrations, and their effects vary between target cells.

The LTs are divided into two major classes, the dihydroxy acid leukotriene B4 (LTB4), one of the most potent chemotactic agents known, and the cysteinyl leukotrienes (CysLTs), leukotriene C4 (LTC4,) leukotriene D4 (LTD4), and leukotriene E4 (LTE4), that are powerful spasmogenic agents. In recent years, a new wave of interest has grown around the potential role of LTs in cardiovascular diseases. In this chapter, we provide an overview of the current understanding of the 5-LO pathway of LT biosynthesis. In addition, we emphasize new implications of LTs as inflammatory mediators in diseases, an area that certainly deserves further attention.

Section snippets

The common part of the 5-LO cascade

The 5-LO cascade is a multistep mechanism involving four key enzymes (Fig. 2.1). The first step in LT biosynthesis is the release of AA, which is generally esterified in the sn-2 position of phospholipids. To increase the levels of free fatty acid, a phospholipase, typically phospholipase A2 (PLA2), is required. The PLA2 family comprises > 15 isoforms that can be grouped based on their primary structure, subcellular localization, and Ca2 + requirement (Murakami et al., 2011). Today, it is widely

LT Receptors

To elicit biological responses as paracrine mediators, LTs are exported over the plasma membrane to reach neighboring cells. Target cells are equipped with G protein-coupled 7-transmembrane-spanning receptors (GPCRs) that recognize specific LTs and transduce intracellular signaling with different sets of G-proteins and second messengers in a ligand-receptor and cell-specific manner (Fig. 2.2).

LTs in Immune Responses

As mentioned earlier, leukocytes are the main cells producing LTs. These cells are key players in the cellular component of the innate immune system, and accordingly, LTs have been regarded as lipid mediators during the first phase of inflammation evoked by injury or pathogen invasion. Thus, it is now well known that LTB4 induces and sustains the recruitment of new inflammatory cells to sites of injury by virtue of its powerful chemotactic property. CysLTs provoke other features of an acute

5-LO and LTs in Human Diseases

Ever since their discovery, the LTs have attracted much attention because of their powerful biological effects in vitro and in vivo. The importance of these lipid mediators in disease development has been evident from their detection in inflammatory exudates and the efficacy of pharmacological intervention to abolish or reduce the inflammatory condition. These lipid mediators are active in the low nanomolar range and elicit a plethora of cellular proinflammatory and immune modulatory responses.

Antileukotriene Drugs

Since the discovery of LTs and their potent biological actions, it has been immediately clear that all components of the LT cascade are potential targets for blocking the biological activities of those lipid mediators. In this direction, the pharmaceutical industry has made considerable efforts to produce enzyme inhibitors and receptor antagonists.

Conclusions

Since the discovery of LTs as powerful proinflammatory agents, these lipid mediators and their related enzymatic pathway have been the subject of intense research that has reached a significantly advanced state. All proteins in the LT cascade have been biochemically defined and cloned, their expression and distribution in various human cells and tissues have been defined, and the entire genes and their promoters have been characterized. Nevertheless, the field of LTs continues to generate new

Acknowledgments

Work in the authors’ laboratory was financed by the Swedish Research Council (10350, 20854, Linneus Grant CERIC), CIDaT, EC FP7 (201668), and the Torsten & Ragnar Söderberg Foundation. J. Z. H. is supported by a Distinguished Professor Award from Karolinska Institutet.

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