Molecules in focus
Leukotriene B4

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Abstract

Leukotriene B4 is a pro-inflammatory mediator synthesised in myeloid cells from arachidonic acid. Synthesis is catalysed by 5-lipoxygenase and leukotriene A4 hydrolase and is increased by inflammatory mediators including endotoxin, complement fragments, tumor necrosis factor and interleukins. A nuclear membrane protein, 5-lipoxygenase activating protein, is an essential co-factor for 5-lipoxygenase. Leukotriene B4 induces recruitment and activation of neutrophils, monocytes and eosinophils. It also stimulates the production of a number of proinflammatory cytokines and mediators indicating an ability to augment and prolong tissue inflammation. Elevated levels of leukotriene B4 have been found in a number of inflammatory diseases and levels are related to disease activity in some of these. Initial data from pharmacological inhibition studies support a role for leukotriene B4 in the pathogenesis of neutrophil mediated tissue damage, and treatments which reduce its production or block its effects may prove beneficial in neutrophil mediated inflammatory diseases.

Introduction

The leukotrienes are biologically active fatty acids, originally isolated from leukocytes, which contain a conjugated triene moiety. Leukotriene B4 (LTB4; 5S,12R-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid) was isolated and purified in 1978 from neutrophils[1]. Subsequently it was chemically synthesised and its ability to activate neutrophils was discovered[8]. LTB4 is now known to be a major product of activated neutrophils and macrophages, with the ability to recruit and activate a range of immune effector cells. A key role has therefore been proposed for LTB4 in the pathogenesis of a variety of inflammatory diseases.

Section snippets

Structure

The structures of leukotriene B4 and its precursors are shown in Fig. 1. All leukotrienes have a 20 carbon chain backbone, with the number of double carbon–carbon bonds indicated by the suffixed number. LTB4 lacks the peptide side chain of cysteinyl leukotrienes (LTC4, LTD4 and LTE4) and has an additional hydroxyl group at C12.

Synthesis and degradation

The production of LTB4 is outlined in Fig. 1. A rise in intracellular free calcium in response to a variety of inflammatory stimuli activates phospholipases at the nuclear envelope cleaving arachidonic acid (AA) from phospholipids. AA is converted to the unstable epoxide leukotriene A4 (LTA4) by the stereospecific abstraction of hydrogen at C7 and the insertion of molecular oxygen at C5 to form 5-hydroperoxyeicosatetraenoic acid (5-HPETE), followed by the stereospecific removal of the pro-R C10

Biological effects of LTB4

LTB4 interacts with cells through specific cell surface receptors. In addition LTB4 can bind directly to intracellular molecules such as PPARα (see Section 3.2).

Leukotriene B4 in health and disease

A key proinflammatory role has been postulated for LTB4 in the light of its ability to recruit and activate inflammatory cells[10]In addition, as its production is upregulated by many inflammatory mediators, including LTB4 itself, it has the potential to amplify their actions (Fig. 2). Elevated concentrations of LTB4 have been found in secretions in a wide variety of inflammatory conditions including cystic fibrosis, bronchiectasis, chronic bronchitis, asthma, adult respiratory distress

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