Journal of Biochemistry Advance Access published December 4, 2014

Two distinct leukotriene B4 receptors, BLT1 and BLT2 Takehiko Yokomizo1, * 1

Department of Biochemistry, Graduate School of Medicine, Juntendo University, Hongo 2-1-1,

Bunkyo-ku, Tokyo 113-8421, Japan

Running title: Leukotriene B4 receptors *

Takehiko Yokomizo, MD, PhD, Department of Biochemistry, Graduate School of Medicine,

Fax: +81 3 5802 5889; Email: [email protected]

Abbreviations: AA, arachidonic acid, 5Z,8Z,11Z,14Z-eicosatetraenoic acid COX, cyclooxygenase 5(S), 12(S)-diHETE, 5(S),12(S)-dihydroxy-6E,8E,10E,14Z-eicosatetraenoic acid GPCR, G protein-coupled receptor 12(S)-HETE, 12(S)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid 12-HHT, 12(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid 12(S)-HPETE, 12(S)-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid LOX, lipoxygenase LTA4, leukotriene A4, 5(S)-trans-5,6-oxido-7E,9E,11Z,14Z-eicosatetraenoic acid LTB4, leukotriene B4, 5(S), 12(R)-dihydroxy-6Z,8E,10E,14Z-eicosatetraenoic acid LTC4, 5(S)-hydroxy-6(R)-(S-glutathionyl), 7E,9E,11Z,14Z-eicosatetraenoic acid LTD4, 5(S)-hydroxy-6(R)-(S-cysteinylglycinyl), 7E,9E,11Z,14Z-eicosatetraenoic acid LTE4, 5(S)-hydroxy-6(R)-(S-cysteinyl), 7E,9E,11Z,14Z-eicosatetraenoic acid MDA, malondialdehyde NSAIDs, nonsteroidal anti-inflammatory drugs PPARα, peroxisome proliferator-activated receptor α SRS-A, slow reactive substance of anaphylaxis Th1, type 1 helper T cells Th2, type 2 helper T cells Th17, type 17 helper T cells TxAS, thromboxane A2 synthase

© The Authors 2014. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. 1

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Juntendo University, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan. Tel.: +81 3 5802 1030;

Keywords: inflammation, immune response, lipid mediator, eicosanoids, aspirin, wound healing

Footnotes: Detailed information on BLT1 and BLT2 is summarized in the International Union of Basic

and

Clinical

Pharmacology

(IUPHAR)

database.

Please

visit

http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=35 for information on these and other leukotriene receptors (1).

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Summary

Leukotriene B4 (LTB4) is a potent inflammatory mediator derived from arachidonic acid. Two G protein-coupled receptors for LTB4 have been identified: a high-affinity receptor, BLT1, and a low-affinity receptor, BLT2. Both receptors mainly couple to pertussis toxin-sensitive Gi-like G proteins and induce cell migration. 12(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (12-HHT) was identified to bind BLT2 with higher affinity than LTB4. Expression of BLT1 was confirmed in type 1 helper T cells (Th1), Th2 cells, Th17 cells, effector CD8+ T cells, dendritic cells, and osteoclasts in addition to granulocytes, eosinophils, and macrophages, and BLT1-deficient mice showed greatly reduced phenotypes in models of various inflammatory diseases, including peritonitis,

is restricted to intestinal epithelial cells and epidermal keratinocytes. BLT2-deficient mice showed enhanced colitis after administration of dextran sulfate, possibly due to reduced intestinal barrier function. An aspirin-dependent reduction in 12-HHT production was responsible for delayed skin wound healing, showing that the 12-HHT/BLT2 axis also plays an important role in skin biology. BLT1 and BLT2 are therefore potential targets for the development of novel drugs.

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bronchial asthma, rheumatoid arthritis, atherosclerosis, and osteoporosis. In mice, BLT2 expression

Leukotrienes Leukotrienes (2, 3) were named because 1) they are mainly generated in leukocytes, and 2) they contain a ‘triene’ group (three conjugated double bonds) as a common chemical structure. Along with prostaglandins, leukotrienes are representative eicosanoids (bioactive compounds with 20 carbons) and are known to function at nanomolar concentrations. Leukotrienes are classified into two groups, dihydroxy leukotriene (LTB4) and the peptide leukotrienes (LTC4, LTD4, and LTE4). LTB4 is well-known as a potent attractant for granulocytes (4, 5), and peptide leukotrienes are collectively called SRS-As (slow reactive substances of anaphylaxis) because they evoke strong and prolonged contraction of bronchial and vascular smooth muscle (6-8). Since their discovery,

several drugs targeting leukotriene pathways are used clinically, mainly as anti-asthma drugs (9).

Biosynthesis and degradation of leukotrienes As is the case for other eicosanoids, leukotrienes are not stored intracellularly as their mature forms; rather, their common precursor, arachidonic acid, is stored within membrane phospholipids in its esterified form (Figure 1). Upon cell activation, various phospholipase A2s (PLA2s) hydrolyze unsaturated fatty acids at the stereospecific numbering position 2 (sn-2). Among various PLA2s, an intracellular calcium-sensitive cytosolic PLA2 α (cPLA2 α, group IV-A PLA2) is important because this enzyme has a property to selectively release arachidonic acid in response to intracellular calcium increase. Arachidonic acid has been estimated to comprise 5–10% of all unsaturated fatty acids, depending on the cell type. Arachidonic acid is converted into prostaglandins (PGs) by cyclooxygenases (COX1 and 2) and into leukotrienes by 5-lipoxygenase (5-LOX), among other terminal mediators. In cells with abundant expression of 5-LOX, such as granulocytes and macrophages, 5-LOX and FLAP (five lipoxygenase activating protein) oxidize arachidonic acid into an unstable intermediate, LTA4, which has no known biological activity. LTA4 is further converted into LTB4 by LTA4 hydrolase (LTA4H) (10) or is conjugated with glutathione by LTC4 synthase (LTC4S) to form LTC4 (11). LTA4H is expressed ubiquitously and has peptidase activity in addition to its hydrolase activity. The peptidase activity of LTA4H was recently reported to limit chronic pulmonary neutrophilic inflammation by degrading the neutrophil chemoattractant proline-glycine-proline (PGP) (12). Some experiments suggest that LTB4 is synthesized in a transcellular manner, where LTA4 produced in inflammatory cells is transferred to surrounding cells that express LTA4 hydrolase. Two major inactivating pathways for LTB4 have been identified: omega oxidation by a LTB4-specific cytochrome P450 enzyme, 4F3 (13), and dehydration of the 12-hydroxy group of LTB4 by a dehydrogenase (14). The latter enzyme is known to inactivate 4

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biosynthetic enzymes and receptors for leukotrienes have been important drug targets, and indeed,

various eicosanoids, including prostaglandins (15) and lipoxins (16), and is therefore known as eicosanoid reductase.

Cloning and tissue distribution of the LTB4 receptors, BLT1 and BLT2 Although numerous studies show that granulocytes and macrophages express a high-affinity LTB4 receptor (17) that couples to Gi-like G proteins, the receptor remained unidentified for a long time. In 1997, our group succeeded in isolating the cDNA of a high-affinity LTB4 receptor whose expression was induced by retinoic acid in the human leukemic cell line HL-60 (18). The cloned LTB4 receptor, designated BLT1, mainly couples with pertussis toxin-sensitive Gi-like G proteins, and with Gq-like proteins in some cells. The affinity of

specifically recognizes the carbon backbone (6Z,8E,10E,14Z) and the hydroxyl groups [5(S) and 12(R)] of LTB4 because neither all-trans LTB4 nor 12(S)-hydroxy LTB4 [5(S), 12(S)-diHETE (dihydroxy-6E,8E,10E,14Z-eicosatetraenoic acid)] activates BLT1. In addition to the classical finding of BLT1 expression in granulocytes and macrophages, BLT1 expression was later shown in eosinophils, differentiated T cells (Th1, Th2, Th17, and effector CD8 T cells) (19-21), dendritic cells (22), and osteoclasts (23). The gene for BLT2, LTB4R2, was identified (24) during a study of the leukocyte-specific expression of BLT1 (25). In humans and mice, the BLT2 gene is located upstream (5’) of the gene for BLT1 (LTB4R) on chromosome 14. BLT2 shares 45% amino acid identity with BLT1, which suggested that the ligand for BLT1, LTB4, could also activate BLT2. Indeed, high concentrations of LTB4 activated BLT2 overexpressed in cultured cells, with a Kd of approximately 20 nM. In addition to LTB4, 12(S)-HETE (hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid) and 12(S)-HPETE (hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid) were shown to activate BLT2, suggesting that BLT2 is a promiscuous receptor (26). BLT2 is expressed relatively ubiquitously in human tissues (24, 27), and in mice, epithelial cells of the small intestine and colon and epidermal keratinocytes express BLT2 (28, 29).

Identification of 12-HHT as an endogenous ligand for BLT2 Given the short half-life of LTB4 in vivo, and the fact that BLT2 can be activated by monohydroxy fatty acids including 12(S)-HPETE and 12(S)-HETE, we hypothesized that a certain fatty acid metabolite other than LTB4 is the primary ligand of BLT2, and we sought to identify BLT2-specific agonistic activity in rat tissues. We identified strong BLT2-specific agonistic activity in the acetone-soluble fatty acid fraction of rat small intestine. After partial purification using high-performance liquid chromatography and elucidation of the structure by MS/MS (tandem mass 5

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recombinant BLT1 for LTB4 is very high, with a Kd of 0.1–2 nM depending on the cell type. BLT1

spectrometry), 12-hydroxyheptadecatrienoic acid (12-HHT) was determined to be a potent agonist for human and mouse BLT2 (30). 12-HHT competed with labeled LTB4 for binding to BLT2 and activated BLT2 at lower doses than LTB4, resulting in calcium mobilization, chemotaxis, and inhibition of adenylate cyclase. This was a surprising finding because 12-HHT had been thought to be a mere byproduct of thromboxane biosynthesis without any biological activity. Because a large amount of 12-HHT is produced by platelets during blood coagulation, 12-HHT is considered to be the primary ligand for BLT2 in vivo.

Physiological roles of LTB4 and BLT1 LTB4 is well-known for its potent chemotactic effect on granulocytes (3, 4, 17). After the 32), Th1 and Th2 cells (21), Th17 cells (33), CD8+ effector T cells (19, 20), dendritic cells (22, 34), and osteoclasts (23) in mice, and in human T cells (35). LTB4-dependent chemotactic activity in these myeloid and lymphoid cells has been confirmed using BLT1-deficient mice. In most cases, LTB4 is important in the early phase of inflammation, which makes sense because LTB4 production does not require transcription or translation and because LTB4 is rapidly inactivated by various enzymes as described above, consistent with its role as an acute inflammatory mediator. BLT1 expression was also shown to activate NF-κB in vascular smooth muscle cells (36), to cause calcium mobilization and contraction in endothelial cells (37), and to enhance proliferation in myoblasts (38) and neural stem cells (39). The biological significance of BLT1 expression in these non-myeloid cell types should be evaluated in future studies. LTB4 and its receptor are thought to play important roles in protecting against invasion by foreign organisms, especially bacteria (40). Indeed, the LTB4-BLT1 axis is required for neutrophil swarming toward infected bacteria in the lymph nodes (41). LTB4-BLT1 signaling is also important in the clearance of nematode infection, where it activates and recruits macrophages (42) and eosinophils (43). Interestingly, LTB4 has been reported to induce itch responses in mice, although the precise cellular and molecular mechanism is unknown (44, 45).

Pathological roles of LTB4 and BLT1 In addition to its beneficial roles in protecting against invasion by foreign organisms, numerous studies have suggested pathological roles for the LTB4/BLT1 axis in inflammatory and immunological diseases. Peritonitis induced by intraperitoneal injection of casein or thioglycollate was attenuated in BLT1-deficient mice, with greatly reduced accumulation of inflammatory cells, particularly eosinophils and macrophages, in the peritoneal cavity (32, 46). In a murine model of bronchial asthma, BLT1-deficient mice showed attenuated asthmatic symptoms, with reduced 6

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molecular identification of BLT1, LTB4 was shown to also induce chemotaxis of eosinophils (31,

eosinophils and Th2 cells in the airway (19, 21, 47). In addition to Th2 cells, the numbers of IL-13+ CD8+ cells in the lung were also reduced in asthmatic BLT1-deficient mice (48). These data suggested that LTB4 functions not only as an attractant for eosinophils and lymphocytes but also as an activator of a Th2 type immune response, and that blockade of BLT1 might be beneficial for asthmatic patients. In addition, LTB4 stimulation caused the migration of vascular smooth muscle cells through BLT1, and a BLT1 antagonist markedly reduced the intimal hyperplasia caused by high-fat diet in rats, suggesting that the LTB4/BLT1 axis may promote atherogenesis (36). BLT1 expressed in mouse macrophages also accelerated atherogenesis by activating NF-κB and inducing the subsequent production of inflammatory cytokines (49). The LTB4/BLT1 axis plays an additional role in bone homeostasis. Osteoclasts express the enzymes required for LTB4 biosynthesis and

bone resorption after ovariectomy in mice (23). Furthermore, the relationship between LTB4 and arthritis is documented in many reports (50). A BLT1 antagonist was shown to reduce the severity of collagen-induced arthritis (51, 52), and BLT1-deficient mice exhibited a much milder phenotype in an inflammatory arthritis model, with reduced production of inflammatory chemokines and cytokines (53). Several pharmaceutical companies are interested in developing BLT1 antagonists as novel drugs for rheumatoid and osteoclastic arthritis (50). Finally, in atopic dermatitis, scratching is known to trigger skin flares by attracting neutrophils, but the responsible chemoattractant has not been determined. In mouse and human skins, mechanical skin injury induced the production of LTB4 and the accumulation of neutrophils in the skin. In addition, BLT1 deficiency and a BLT1 antagonist each attenuated skin inflammation in a murine model of atopic dermatitis (54) and psoriasis (55). Thus, the LTB4/BLT1 axis seems to be involved in most inflammatory diseases that accompany neutrophil accumulation in the lesion.

Physiological and pathophysiological roles of BLT2 In contrast to the well-defined roles of LTB4 in inflammation and immunity, few studies have addressed the physiological and pathophysiological roles of BLT2. BLT2-deficient mice were more sensitive to dextran sulfate-induced colitis, with greatly enhanced inflammation in the colon (56). An in vitro transfection study suggested that BLT2 expression enhanced barrier function in epithelial cells by increasing electric resistance, and the precise mechanism should be examined. BLT2 is also expressed in human and mouse epidermal keratinocytes and enhances wound healing by accelerating keratinocyte migration through the upregulation of tumor necrosis factor α and metalloproteinases (Figure 2) (29). NSAIDs, including aspirin, delay skin wound healing in wild-type mice, and this delay was not observed in BLT2-deficient mice, showing that inhibited production of the BLT2 ligand 12-HHT is responsible for NSAID-dependent delayed wound 7

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produce LTB4, which activates BLT1 expressed on osteoclasts in an autocrine manner and enhances

healing. BLT2 negatively regulates allergic airway inflammation by inhibiting the production of Th2 cytokines (57). Several reports suggest that the BLT2-dependent generation of reactive oxygen species is involved in epithelial-mesenchymal transition and cancer progression (58, 59), but the use of BLT2 antagonists in some of these experiments is problematic (see below). Indeed, BLT2 expression was enhanced in some pancreatic cancer tissues (60); however, the relationship between BLT2 and cancer has yet to be thoroughly evaluated.

BLT antagonists Before the molecular identification of BLT1 and BLT2, many BLT antagonists had been developed and evaluated in vitro and in vivo with the aim of controlling inflammation. I would like

classical BLT antagonist, U75302, was designed based on the structure of LTB4 and was used as a BLT1 antagonist in many studies, but in fact it is only a weak agonist for BLT1 (61). Another BLT antagonist, CP105696, has similar activity on BLT1. The more problematic antagonist is LY255283. Although this compound is sold by various suppliers as a BLT2 antagonist, it was originally developed to inhibit the LTB4 receptor on neutrophils, BLT1 (62). Competitive binding assays using recombinant BLT1 and BLT2 revealed that LY255283 is a non-competitive antagonist for BLT1 and a competitive antagonist for BLT2 (26), and that it inhibits both BLT1- and BLT2-dependent calcium mobilization (57). Currently, there are no BLT2-specific antagonists, and thus it is misleading to draw conclusions about BLT2 functions using only antagonists.

Conclusions It has been 35 years since the discovery of leukotrienes and 17 years since the identification of BLT1. Many studies have demonstrated that BLT1 is a potent chemotactic receptor for inflammatory cells, and BLT1 blockade will be beneficial for the treatment of various inflammatory diseases, including bronchial asthma, inflammatory bowel diseases, rheumatoid arthritis, atopic dermatitis, and postmenopausal osteoporosis. More potent and specific BLT1 antagonists will effectively limit inflammation, especially in the early phase. By contrast, the physiological and pathophysiological roles of BLT2 should be carefully examined. At present, BLT2 agonists are candidates to accelerate wound healing in patients with intractable skin ulcers.

Acknowledgments I thank all our group’s collaborators and apologize for not being able to cite all the relevant literature due to space limitations. References 8

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to briefly discuss the efficacy and specificity of some commonly used BLT antagonists. The

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Figure legends

Figure 1. Production of leukotrienes and 12-HHT from membrane phospholipids. Arachidonic acid cleaved from membrane phospholipids is converted into leukotrienes, prostaglandins, or 12-HHT. We recently identified thromboxane A2 synthase (TxAS)-independent production of 12-HHT from PGH2 (63). Please see the main text for abbreviations.

Figure 2 12-HHT/BLT2 axis accelerates skin wound healing After skin injury, activated platelets in the blood clots produces 12-HHT that activates BLT2

upregulates transcription of TNFα and various metalloproteinases (MMPs). TNFα and MMPs cooperatively activate keratinocyte migration and accelerate wound healing (29).

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expressed on the keratinocytes. BLT2 stimulation activates a transcription factor NF-κB p65 and

OO

COOH

PLA2

O

Arachidonic acid

OH

X

O P O

Membrane phospholipids

O

5-LOX+FLAP

COX1,2

OOH

O

COOH

O

5-HPETE

COX1,2

5-LOX+FLAP COOH O

O

LTA4

O

LTC4S LTA4H

H

OH

O

S Cys Gly Glu

LTC4

OH

COOH

O

COOH

LTB4

TxAS

OH

H

OH

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O

H

OH

S Cys Gly

BLT1 ligand

OOH

PGG2

COOH

PGH2 OH

TxAS or nonenzymic COOH

O

O OH

H

COOH

OH

TXA2

OH

12-HHT

LTD4

BLT2 ligand H H

OH

O OH

S Cys

LTE4

Downloaded from http://jb.oxfordjournals.org/ at Laurentian University on December 8, 2014

Blood clot 12-HHT Epidermis

BL T2

TNFα, IL-1β

MMPs, Chemokine

Dermis Keratinocyte migration & wound healing

Two distinct leukotriene B4 receptors, BLT1 and BLT2.

Leukotriene B4 (LTB4) is a potent inflammatory mediator derived from arachidonic acid. Two G protein-coupled receptors for LTB4 have been identified: ...
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