Reviews and feature articleThe leukotriene E4 puzzle: Finding the missing pieces and revealing the pathobiologic implications
Section snippets
Discovery of LTE4
The slow-reacting substance of anaphylaxis (SRS-A), so named by Brocklehurst,1 was identified as a substance generated by in vitro antigen/allergen challenge of perfused lungs of actively sensitized guinea pigs or human lung fragments of allergic patients requiring resection. Its potent constrictor activity on guinea pig or human bronchioles in the presence of an antihistamine provided compelling evidence for its potential role in asthma. The initial analyses into the physical characteristics
Early pharmacology of LTE4 in animals
The potency of LTE4 for contraction of guinea pig tracheal spirals in vitro was 10-fold greater than that of either LTC4 or LTD4, whereas for guinea pig parenchymal strips, the potency of LTD4 was 6-fold that of LTE4 and 20-fold that of LTC4. Furthermore, the concentration effect for LTD4 and LTE4 on parenchymal strips observed by Drazen et al12 was biphasic, with the initial low concentration effect (studied only for LTD4) being competitively antagonized by FPL55712. In contrast, LTC4 was the
Early studies of LTE4 metabolism
The products of the granulocyte respiratory burst, which are abundant with inflammation, can alter the stability of each cysLT in vitro and in vivo. Phorbol 12-myristate 13-acetate–activated human neutrophils converted each cysLT to their subclass-specific S-diastereoisomeric sulfoxides, which retained their ability to be detected by cysLT–specific antibodies but lost greater than 95% of function. Each sulfoxide was further processed to identical diastereoisomers of 6-trans LTB4, which were
Early pharmacology of LTE4 in human subjects
Although the early pharmacology of the 3 sequentially generated cysLTs identified LTE4 as the most stable in physiologic and pathobiologic models, clinical attention shifted to LTD4 and LTC4, which on inhalation were up to 1000 times as potent as histamine.21, 22 LTE4 was only 39 times as potent as histamine in reducing maximum expiratory flow at 30% of vital capacity in healthy human subjects.21, 22, 23 Although each cysLT was a potent bronchoconstrictor in patients with bronchial asthma,
Functional and pharmacologic characterization of CysLTER, a cutaneous receptor preferential for LTE4
In addition to addressing the pharmacology of the cysLTs during the 1980s, we began to characterize LTC4S, the integral protein of the outer nuclear membrane responsible for biosynthesis of LTC4, by means of conjugation of glutathione to LTA4.7 After expression cloning of human LTC4S and then homology cloning of murine LTC4S,27, 28 we turned to targeted disruption of murine LTC4S to explore for phenotypic characteristics that might depend on the functions of the cysLTs.29 In a model of passive
Discovery that the P2Y12 receptor mediates mast cell activation and pulmonary inflammation by LTE4
As is the case for many effector cells of bone marrow origin, mast cells express both CysLT1R and CysLT2R.35, 36 LTC4 and LTD4 both induce calcium flux, cytokine and chemokine generation, phosphorylation of extracellular signal-regulated kinase (ERK), and proliferation of human mast cells in vitro.35, 36, 37 These responses, like those of the cutaneous microvasculature, are regulated positively by CysLT1R but negatively regulated by CysLT2R based on experiments in which each receptor is
Epilogue
At this early stage, clinical considerations must be circumspect and limited based on these findings for receptors in naive mice in model systems or with targeted disruption of classical receptors. Nonetheless, the history of cysLT-mediated permeability effects in guinea pigs and human subjects suggests that this important aspect of the inflammatory process is as responsive to LTE4 as to its precursors, LTC4 and LTD4, which are only transiently present during an inflammatory process. The
References (43)
- et al.
Slow reacting substances (SRSs): the structure identification of SRSs from rat basophil leukemia (RBL-1) cells
Prostaglandins
(1980) - et al.
Identification of the C(6)-S-conjugate of leukotriene A with cysteine as a naturally occurring slow reacting substance of anaphylaxis (SRS-A). Importance of the 11-cis-geometry for biological activity
Biochem Biophys Res Commun
(1980) - et al.
Sequential conversion of the glutathionyl side chain of slow reacting substance (SRS) to cysteinyl-glycine and cysteinyl-glycine and cysteine in rat basophilic leukemia cells stimulated with A-23187
Prostaglandins
(1980) - et al.
Characterization of the human cysteinyl leukotriene 2 receptor
J Biol Chem
(2000) - et al.
The myeloperoxidase-dependent metabolism of leukotrienes C4, D4 and E4 to 6-trans-leukotriene B4 diastereoisomers and the subclass-specific S-diastereoisomeric sulfoxides
J Biol Chem
(1983) - et al.
Leukotriene E4 elimination and metabolism in normal human subjects
J Biol Chem
(1990) - et al.
Peroxisomal Degradation of leukotrienes by β-oxidation from the ω-end
J Biol Chem
(1991) - et al.
Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4 and LTB4) in human skin
J Invest Dermatol
(1983) - et al.
Attenuated zymosan-induced peritoneal vascular permeability and IgE-dependent passive cutaneous anaphylaxis in mice lacking leukotriene C4 synthase
J Biol Chem
(2001) - et al.
Targeted gene disruption reveals the role of cysteinyl leukotriene 1 receptor in the enhanced vascular permeability of mice undergoing acute inflammatory responses
J Biol Chem
(2002)
Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice
J Biol Chem
CysLT1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors
Biochem Pharmacol
CysLT2 receptors interact with CysLT1 receptors and down-modulate cysteinyl leukotriene-dependent mitogenic responses of mast cells
Blood
Leukotriene E4 activates peroxisome proliferator activated receptor gamma and induces prostaglandin D2 generation by human mast cells
J Biol Chem
Identification of endogenous surrogate ligands for human P2Y12 receptors by in silico and in vitro methods
Biochem Biophys Res Commun
Regulation of cysteinyl leukotriene type 1 receptor internalization and signaling
J Biol Chem
The release of histamine and formation of a slow reacting substance (SRS-A) during anaphylactic shock
J Physiol
The physicochemical characteristics and purification of slow reacting substance of anaphylaxis
J Immunol
a slow-reacting substance from murine mastocytoma cells
Proc Natl Acad Sci U S A
Synthesis and structure elucidation of leukotrienes
Properties of highly purified leukotriene C4 synthase of guinea pig lung
J Clin Invest
Cited by (86)
The Role of Omalizumab in NSAID-Exacerbated Respiratory Disease: A Narrative Review
2022, Journal of Allergy and Clinical Immunology: In PracticeCitation Excerpt :Increased CysLT production results in the formation of leukotriene E4, which binds to CysLT3 receptors, increasing mucin release in respiratory epithelial cells.5,26,27 This entire process ultimately leads to the recruitment of inflammatory cells into the respiratory tissues.26 PGD2 plays an important role in the pathophysiology of N-ERD.
Innate immune cell dysregulation drives inflammation and disease in aspirin-exacerbated respiratory disease
2021, Journal of Allergy and Clinical ImmunologyLeukotriene D<inf>4</inf> paradoxically limits LTC<inf>4</inf>-driven platelet activation and lung immunopathology
2021, Journal of Allergy and Clinical ImmunologyTuft cells in the pathogenesis of chronic rhinosinusitis with nasal polyps and asthma
2021, Annals of Allergy, Asthma and ImmunologyIntegral Membrane Enzymes in Eicosanoid Metabolism: Structures, Mechanisms and Inhibitor Design
2020, Journal of Molecular BiologyRoles of cysteinyl leukotrienes and their receptors in immune cell-related functions
2019, Advances in ImmunologyCitation Excerpt :Inhalation by normal subjects showed that LTC4 and LTD4 were a thousand times and LTE4 ten times as potent as histamine in eliciting bronchoconstriction (Davidson et al., 1987; Griffin et al., 1983; Weiss et al., 1982). Additional references for these findings are available from a review article (Austen, Maekawa, Kanaoka, & Boyce, 2009). Cell-based receptor expression for three ligands generated in sequence from a single biosynthetic step allows for the cys-LT and their receptor (CysLTR) pathways to provide sequential host responses in which individual steps can have either a positive or negative effect on the integrated host response.
(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
Terms in boldface and italics are defined in the glossary on page 407.