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The Leukotriene E4 Puzzle: Finding the Missing Pieces and Revealing the Pathobiologic Implications

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The Leukotriene E4 Puzzle: Finding the Missing Pieces and Revealing the Pathobiologic Implications Mechanisms of allergic diseases (Supported by an educational grant from Merck & Co., Inc.) Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD The leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications K. Frank Austen, MD, Akiko Maekawa, PhD, Yoshihide Kanaoka, MD, PhD, and Joshua A. Boyce, MD Boston, Mass INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review AAAAI designates these educational activities for a maximum of 1 AMA articles in this issue. Please note the following instructions. PRA Category 1 Creditä. Physicians should only claim credit commensu- Method of Physician Participation in Learning Process: The core ma- rate with the extent of their participation in the activity. terial for these activities can be read in this issue of the Journal or online at List of Design Committee Members: Authors: K. Frank Austen, MD, Akiko the JACI Web site: www.jacionline.org. The accompanying tests may only Maekawa, PhD, Yoshihide Kanaoka, MD, PhD, and Joshua A. Boyce, MD be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Activity Objectives Date of Original Release: September 2009. Credit may be obtained for 1. To better understand the biologic activities of leukotriene (LT) E4. these courses until August 31, 2011. 2. To understand the interactions of the cysteinyl leukotrienes (cysLTs) Copyright Statement: Copyright Ó 2009-2011. All rights reserved. with their receptors. Overall Purpose/Goal: To provide excellent reviews on key aspects of 3. To appreciate the key biochemical aspects of the LT pathway. allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic Recognition of Commercial Support: This CME activity is supported disease. by an educational grant from Merck & Co., Inc. Accreditation/Provider Statements and Credit Designation: The Disclosure of Significant Relationships with Relevant Commercial American Academy of Allergy, Asthma & Immunology (AAAAI) is ac- Companies/Organizations: J. A. Boyce has received speaking hono- credited by the Accreditation Council for Continuing Medical Education raria from Merck. The rest of the authors have declared that they have no (ACCME) to provide continuing medical education for physicians. The conflict of interest. The intracellular parent of the cysteinyl leukotrienes (cysLTs), (particularly those that were aspirin sensitive) were selectively leukotriene (LT) C4, is formed by conjugation of LTA4 and hyperresponsive to LTE4, and that a potential distinct LTE4 reduced glutathione by LTC4 synthase in mast cells, eosinophils, receptor was present in guinea pig trachea. Recent studies have basophils, and macrophages. After extracellular export, LTC4 is begun to uncover receptors selective for LTE4: P2Y12,an converted to LTD4 and LTE4 through sequential enzymatic adenosine diphosphate receptor, and CysLTER, which was removal of glutamic acid and then glycine. Only LTE4 is observed functionally in the skin of mice lacking the type 1 and sufficiently stable to be prominent in biologic fluids, such as 2 cysLT receptors. These findings prompt a renewed focus on urine or bronchoalveolar lavage fluid, of asthmatic individuals LTE4 receptors as therapeutic targets that are not currently and at sites of inflammation in animal models. LTE4 has addressed by available receptor antagonists. (J Allergy Clin received little attention because it binds poorly to the classical Immunol 2009;124:406-14.) type 1 and 2 cysLT receptors and is much less active on normal Key words: Leukotriene E4, G protein–coupled receptor, bronchial airways than LTC4 or LTD4. However, early studies indicated asthma, inflammation, knockout mouse that LTE4 caused skin swelling in human subjects as potently as LTC4 and LTD4, that airways of asthmatic subjects Of the 3 cysteinyl leukotrienes (cysLTs; leukotriene [LT] C4, From the Department of Medicine, Harvard Medical School, Division of Rheumatology, LTD4, and LTE4), only LTE4 is sufficiently stable so as to be de- Immunology and Allergy, Brigham and Women’s Hospital. tectable in extracellular fluids. Although widely used as a bio- Received for publication April 10, 2009; revised May 6, 2009; accepted for publication marker of cysLT pathway activity in clinical studies, LTE4 has May 6, 2009. received little attention in recent literature as a mediator of inflam- Available online August 3, 2009. Reprint requests: K. Frank Austen, MD, Department of Medicine, Harvard Medical mation because of its poor activity at the classical cysLT School, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s receptors (type 1 cysteinyl leukotriene receptor [CysLT1R] and Hospital, One Jimmy Fund Way, Boston, MA 02115. E-mail: [email protected]. type 2 cysteinyl leukotriene receptor [CysLT2R]). However, sev- harvard.edu. eral earlier studies clearly demonstrated that LTE4 had biologic 0091-6749/$36.00 Ó 2009 American Academy of Allergy, Asthma & Immunology activity that differed from that of its precursors, predicting (cor- doi:10.1016/j.jaci.2009.05.046 rectly in retrospect) the existence of specific LTE4-reactive recep- Terms in boldface and italics are defined in the glossary on page 407. tors. This review will highlight LTE4 from a historical 406 J ALLERGY CLIN IMMUNOL AUSTEN ET AL 407 VOLUME 124, NUMBER 3 actively sensitized guinea pigs or human lung fragments of aller- Abbreviations used gic patients requiring resection. Its potent constrictor activity on cysLT: Cysteinyl leukotriene guinea pig or human bronchioles in the presence of an antihista- CysLT1R: Type 1 cysteinyl leukotriene receptor mine provided compelling evidence for its potential role in CysLT2R: Type 2 cysteinyl leukotriene receptor asthma. The initial analyses into the physical characteristics and ERK: Extracellular signal-regulated kinase composition of SRS-A from the rat suggested possible sulfur con- GPCR: G protein–coupled receptor tent.2 This led to the identification by Murphy et al3 of LTC , the LT: Leukotriene 4 first component of SRS-A, by loading a mastocytoma cell line LTC4S: Leukotriene C4 synthase 35 MIP-1b: Macrophage inflammatory protein 1b with [ S]cysteine and identifying the radiolabeled component re- PG: Prostaglandin leased in response to activation with calcium ionophore. LTC4 PPAR-g: Peroxisome proliferator-activated receptor g was composed of a metabolite of arachidonic acid (eicosatetrae- SRS-A: Slow-reacting substance of anaphylaxis noic acid) with 3 conjugated double bonds and a peptide adduct WT: Wild-type through a sulfur bridge. The exact stereochemistry of the lipid and the amino acid sequence of the S-linked peptide of LTC4 were obtained by comparing purified natural SRS-A with candi- date synthetic cysLTs prepared by E. J. Corey.4 These synthetic perspective, from its discovery to the identification of its receptors cysLTs showed bioactivity consistent with the functional defini- and mechanisms of action. tion of SRS-A offered by Brocklehurst,1 who noted that a range of activities could contract the guinea pig ileum in the presence DISCOVERY OF LTE4 of an antihistamine. The slow-reacting substance of anaphylaxis (SRS-A), so Because we had anticipated that the activity of SRS-A could be named by Brocklehurst,1 was identified as a substance generated attributed to a single product, we were surprised to find that by in vitro antigen/allergen challenge of perfused lungs of partially purified SRS-A from the peritoneal cavity of rats GLOSSARY ARACHIDONIC ACID: Arachidonic acid is the precursor for both LTs and ‘‘LUKASTS’’: Montelukast, pranlukast, and zafirlukast all block the prostaglandins and is found on the nuclear membrane. Together, LTs CysLT1R, whereas biosynthetic pathway inhibitors, such as zileuton, and prostaglandins are called eicosanoids. block the production of both cysLTs and LTB4. ASPIRIN-EXACERBATED RESPIRATORY DISEASE (AERD): AERD con- MACROPHAGE INFLAMMATORY PROTEIN 1b (MIP-1b): MIP-1 is in- sists of a clinical constellation of nasal polyposis with eosinophilic volved in the chemotaxis and activation of monocytes. CysLTs can sinusitis, asthma, and idiosyncratic sensitivity to nonsteroidal anti- induce MIP-1b and MIP-1a production from monocytes through the inflammatory agents that inhibit COX-1. Treatment of patients with CysLT1R. AERD includes LT inhibitors. PERMEABILITY-ENHANCING ACTIVITY: Activated vascular endothe- COX-2: COX-2 is induced by LPS, IL-1, and IL-2 to produce prostaglandin lium allows leakage of dyes (eg, Evans blue and fluorescein isothiocy- intermediates from arachidonic acid. anate–albumin) into the extravascular space, making tissues appear CYSTEINYL LEUKOTRIENE (cysLT): LTs, so named because of their colored (blue) or fluorescent (fluorescein isothiocyanate). generation from ‘‘leuko’’cytes and conserved 3-double-bond ‘‘trienes,’’ PERTUSSIS TOXIN: Pertussis toxin inhibits the function of GPCRs are generated from arachidonic acid by 5-lipoxygenase/5-lipoxygenase– through adenosine diphosphate ribosylation of Ga. activating protein. Conversion of LTA4 to LTC4 by means of addition of PULMONARY RESISTANCE: Mechanical factors that limit alveolar glutathione is the first step to generating cysLTs. LTA4 hydrolase con- access to air. Pulmonary resistance is calculated by using Ohm’s and verts LTA4 to LTB4. The major sources of LTC4S (and thus cysLTs) are eo- Poiseuille’s laws, which factor in the pressure
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