Home LiteratureArticle Details
PMID: 10934230 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders.

The Journal of experimental medicine ·Vol. 192 ·No. 3 ·2000-08-07 ·Pages 421-32

Yokomizo T, Kato K, Terawaki K, Izumi T, Shimizu T

Abstract

Leukotriene B(4) (LTB(4)) is a potent chemoattractant and activator of both granulocytes and macrophages. The actions of LTB(4) appear to be mediated by a specific G protein-coupled receptor (GPCR) BLT1, originally termed BLT (Yokomizo, T., T. Izumi, K. Chang, Y. Takuwa, and T. Shimizu. 1997. Nature. 387:620-624). Here, we report the molecular cloning of a novel GPCR for LTB(4), designated BLT2, which binds LTB(4) with a Kd value of 23 nM compared with 1.1 nM for BLT1, but still efficiently transduces intracellular signaling. BLT2 is highly homologous to BLT1, with an amino acid identity of 45.2%, and its open reading frame is located in the promoter region of the BLT1 gene. BLT2 is expressed ubiquitously, in contrast to BLT1, which is expressed predominantly in leukocytes. Chinese hamster ovary cells expressing BLT2 exhibit LTB(4)-induced chemotaxis, calcium mobilization, and pertussis toxin-insensitive inhibition of adenylyl cyclase. Several BLT1 antagonists, including U 75302, failed to inhibit LTB(4) binding to BLT2. Thus, BLT2 is a pharmacologically distinct receptor for LTB(4), and may mediate cellular functions in tissues other than leukocytes. BLT2 provides a novel target for antiinflammatory therapy and promises to expand our knowledge of LTB(4) function. The location of the gene suggests shared transcriptional regulation of these two receptors.

MeSH Terms
Amino Acid Sequence Animals Arthritis, Rheumatoid/therapy Asthma/therapy Base Sequence CHO Cells Cell Line Cloning, Molecular Cricetinae DNA, Complementary Humans Inflammatory Bowel Diseases/therapy Leukotriene B4/metabolism Mice Molecular Sequence Data Psoriasis/therapy Receptors, Leukotriene B4/genetics,immunology,metabolism Renal Insufficiency/therapy Sequence Homology, Amino Acid Signal Transduction Tissue Distribution
Chemicals
DNA, Complementary LTB4R2 protein, human Ltb4r2 protein, mouse Receptors, Leukotriene B4 Leukotriene B4
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Yokomizo T
Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Kato K
Terawaki K
Izumi T
Shimizu T
References (73)
73 references, click to expand
  1. Transduction by leukotriene B4 receptors of increases in cytosolic calcium in human polymorphonuclear leukocytes.
    J Immunol. 1985 Jul;135(1):525-30 PMID: 2987349
  2. Cloning of complementary DNA encoding a functional human interleukin-8 receptor.
    Science. 1991 Sep 13;253(5025):1280-3 PMID: 1891716
  3. Modulation of affinity and density of LTB4 receptors on guinea pig lung membranes by divalent cations and guanine nucleotides.
    Eur J Pharmacol. 1991 Apr 25;206(4):333-8 PMID: 1655491
  4. Biological activity of leukotriene B4 analogs: inhibition of guinea pig eosinophil migration in vitro by the 2,6-disubstituted pyridine analogs U-75,302 and U-75,485.
    Prostaglandins. 1991 Sep;42(3):211-24 PMID: 1664113
  5. Cloning of a cDNA encoding a receptor related to the formyl peptide receptor of human neutrophils.
    Gene. 1992 Sep 10;118(2):303-4 PMID: 1511907
  6. Identification on receptors for leukotriene B4 expressed on guinea-pig peritoneal eosinophils.
    Immunology. 1992 Sep;77(1):129-35 PMID: 1328044
  7. Assignment of the genes encoding human interleukin-8 receptor types 1 and 2 and an interleukin-8 receptor pseudogene to chromosome 2q35.
    Genomics. 1992 Nov;14(3):685-91 PMID: 1427896
  8. ONO-4057, a novel, orally active leukotriene B4 antagonist: effects on LTB4-induced neutrophil functions.
    Prostaglandins. 1992 Oct;44(4):261-75 PMID: 1332129
  9. The high-affinity interleukin 8 receptor gene (IL8RA) maps to the 2q33-q36 region of the human genome: cloning of a pseudogene (IL8RBP) for the low-affinity receptor.
    Genomics. 1993 Apr;16(1):248-51 PMID: 8486366
  10. Molecular evolution of the human interleukin-8 receptor gene cluster.
    Nat Genet. 1992 Sep;2(1):31-6 PMID: 1303245
  11. Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors.
    Int Immunol. 1993 Oct;5(10):1239-49 PMID: 7505609
  12. Appearance of specific leukotriene B4 binding sites in myeloid differentiated HL-60 cells.
    J Biol Chem. 1985 Nov 15;260(26):14208-13 PMID: 2997200
  13. Development of receptors for leukotriene B4 on HL-60 cells induced to differentiate by 1 alpha,25-dihydroxyvitamin D3.
    J Immunol. 1986 Jun 15;136(12):4631-6 PMID: 3011899
  14. Lipopolysaccharide modulates receptors for leukotriene B4, C5a, and formyl-methionyl-leucyl-phenylalanine on rabbit polymorphonuclear leukocytes.
    J Immunol. 1986 Sep 15;137(6):1971-6 PMID: 3018083
  15. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects.
    Science. 1987 Sep 4;237(4819):1171-6 PMID: 2820055
  16. Molecular cloning of a cDNA coding for human leukotriene A4 hydrolase. Complete primary structure of an enzyme involved in eicosanoid synthesis.
    J Biol Chem. 1987 Oct 15;262(29):13873-6 PMID: 3654641
  17. Identification of a GTP-binding protein alpha subunit that lacks an apparent ADP-ribosylation site for pertussis toxin.
    Proc Natl Acad Sci U S A. 1988 May;85(9):3066-70 PMID: 3129724
  18. Chromosomal organization of adrenergic receptor genes.
    Proc Natl Acad Sci U S A. 1990 Feb;87(4):1516-20 PMID: 2154750
  19. Immunological quantitation and immunohistochemical localization of leukotriene A4 hydrolase in guinea pig tissues.
    J Biol Chem. 1990 May 5;265(13):7520-5 PMID: 2332439
  20. Arachidonic acid cascade and signal transduction.
    J Neurochem. 1990 Jul;55(1):1-15 PMID: 2113081
  21. Involvement of leukotriene B4 in ovulation in the rabbit.
    Endocrinology. 1991 Jul;129(1):193-9 PMID: 1647296
  22. Leukotriene B4 receptors on guinea pig alveolar eosinophils.
    J Pharmacol Exp Ther. 1991 Sep;258(3):784-9 PMID: 1653838
  23. Leukotrienes in renal transplant rejection in rats. Distinct roles for leukotriene B4 and peptidoleukotrienes in the pathogenesis of allograft injury.
    J Immunol. 1994 Jan 15;152(2):867-76 PMID: 8283057
  24. The bifunctional enzyme leukotriene-A4 hydrolase is an arginine aminopeptidase of high efficiency and specificity.
    J Biol Chem. 1994 Apr 15;269(15):11269-73 PMID: 8157657
  25. Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor.
    J Exp Med. 1994 Jul 1;180(1):253-60 PMID: 8006586
  26. Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene.
    Nature. 1994 Nov 10;372(6502):179-82 PMID: 7969451
  27. Altered inflammatory responses in leukotriene-deficient mice.
    Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12852-6 PMID: 7809134
  28. Leukotriene B4 plays a critical role in the progression of collagen-induced arthritis.
    Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):517-21 PMID: 7831322
  29. The in vitro and in vivo pharmacologic activity of the potent and selective leukotriene B4 receptor antagonist CP-105696.
    J Pharmacol Exp Ther. 1995 Apr;273(1):176-84 PMID: 7714764
  30. Metabolism of leukotriene B4 in cultured hepatoma cells.
    Arch Biochem Biophys. 1995 Aug 20;321(2):381-9 PMID: 7646063
  31. In vitro and in vivo effects of leukotriene B4 antagonism in a primate model of asthma.
    J Clin Invest. 1996 Jan 15;97(2):381-7 PMID: 8567958
  32. cDNA cloning, expression, and mutagenesis study of leukotriene B4 12-hydroxydehydrogenase.
    J Biol Chem. 1996 Feb 2;271(5):2844-50 PMID: 8576264
  33. Lipid mediator networks in cell signaling: update and impact of cytokines.
    FASEB J. 1996 Aug;10(10):1147-58 PMID: 8751717
  34. Characterization of the pharmacological profile of the potent LTB4 antagonist CP-105,696 on murine LTB4 receptors in vitro.
    Br J Pharmacol. 1996 Mar;117(6):1127-32 PMID: 8882606
  35. The PPARalpha-leukotriene B4 pathway to inflammation control.
    Nature. 1996 Nov 7;384(6604):39-43 PMID: 8900274
  36. Cloning of cDNA encoding a putative chemoattractant receptor.
    Genomics. 1996 Oct 15;37(2):187-94 PMID: 8921391
  37. Discovery of a novel human G protein-coupled receptor gene (GPR25) located on chromosome 1.
    Biochem Biophys Res Commun. 1997 Jan 3;230(1):69-72 PMID: 9020062
  38. Signalling functions and biochemical properties of pertussis toxin-resistant G-proteins.
    Biochem J. 1997 Feb 1;321 ( Pt 3):561-71 PMID: 9032437
  39. Role of the 5-lipoxygenase-activating protein (FLAP) in murine acute inflammatory responses.
    J Exp Med. 1997 Mar 17;185(6):1065-75 PMID: 9091580
  40. Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice.
    J Exp Med. 1997 Mar 17;185(6):1123-9 PMID: 9091585
  41. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis.
    Nature. 1997 Jun 5;387(6633):620-4 PMID: 9177352
  42. Role of cytosolic phospholipase A2 in allergic response and parturition.
    Nature. 1997 Dec 11;390(6660):618-22 PMID: 9403692
  43. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2.
    Nature. 1997 Dec 11;390(6660):622-5 PMID: 9403693
  44. Significance of leukotriene-A4 hydrolase in the pathogenesis of psoriasis.
    Skin Pharmacol. 1997;10(4):169-77 PMID: 9413890
  45. The lipoxygenase inhibitor, nordihydroguaiaretic acid, inhibits ovulation and reduces leukotriene and prostaglandin levels in the rat ovary.
    Biol Reprod. 1998 May;58(5):1211-6 PMID: 9603255
  46. The preclinical pharmacological profile of the potent and selective leukotriene B4 antagonist CP-195543.
    J Pharmacol Exp Ther. 1998 Jun;285(3):946-54 PMID: 9618393
  47. G protein-coupled receptors. II. Mechanism of agonist activation.
    J Biol Chem. 1998 Jul 17;273(29):17979-82 PMID: 9660746
  48. Signalling through the leukotriene B4 receptor involves both alphai and alpha16, but not alphaq or alpha11 G-protein subunits.
    Biochem J. 1998 Oct 1;335 ( Pt 1):15-8 PMID: 9742207
  49. Molecular and biological characterization of the murine leukotriene B4 receptor expressed on eosinophils.
    J Exp Med. 1998 Sep 21;188(6):1063-74 PMID: 9743525
  50. Pharmacologic actions of the second-generation leukotriene B4 receptor antagonist LY293111: in vitro studies.
    J Pharmacol Exp Ther. 1999 Jan;288(1):286-94 PMID: 9862783
  51. A seven-transmembrane, G protein-coupled receptor, FPRL1, mediates the chemotactic activity of serum amyloid A for human phagocytic cells.
    J Exp Med. 1999 Jan 18;189(2):395-402 PMID: 9892621
  52. Selective expression of a novel surface molecule by human Th2 cells in vivo.
    J Immunol. 1999 Feb 1;162(3):1278-86 PMID: 9973380
  53. Discovery of three novel orphan G-protein-coupled receptors.
    Genomics. 1999 Feb 15;56(1):12-21 PMID: 10036181
  54. Leukotriene binding, signaling, and analysis of HIV coreceptor function in mouse and human leukotriene B4 receptor-transfected cells.
    J Biol Chem. 1999 Mar 26;274(13):8597-603 PMID: 10085095
  55. Antagonizing leukotriene B4 receptors delays cardiac allograft rejection in mice.
    Transplantation. 1999 Mar 27;67(6):808-15 PMID: 10199727
  56. Characterization of the human cysteinyl leukotriene CysLT1 receptor.
    Nature. 1999 Jun 24;399(6738):789-93 PMID: 10391245
  57. Expression of the CYP4F3 gene. tissue-specific splicing and alternative promoters generate high and low K(m) forms of leukotriene B(4) omega-hydroxylase.
    J Biol Chem. 1999 Jul 23;274(30):21191-9 PMID: 10409674
  58. cDNA cloning and characterization of guinea-pig leukotriene B4 receptor.
    Biochem J. 1999 Aug 15;342 ( Pt 1):79-85 PMID: 10432303
  59. Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion.
    J Clin Invest. 1999 Aug;104(3):309-16 PMID: 10430612
  60. Chemical probes that differentially modulate peroxisome proliferator-activated receptor alpha and BLTR, nuclear and cell surface receptors for leukotriene B(4).
    J Biol Chem. 1999 Aug 13;274(33):23341-8 PMID: 10438511
  61. Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor.
    Mol Pharmacol. 1999 Sep;56(3):657-63 PMID: 10462554
  62. Cloning and characterization of rat leukotriene B(4) receptor.
    Biochem Biophys Res Commun. 1999 Sep 7;262(3):806-12 PMID: 10471406
  63. Expression and molecular cloning of human liver leukotriene B4 omega-hydroxylase (CYP4F2) gene.
    DNA Cell Biol. 1999 Sep;18(9):723-30 PMID: 10492403
  64. Characterization of the cloned guinea pig leukotriene B4 receptor: comparison to its human orthologue.
    Eur J Pharmacol. 1999 Sep 10;380(2-3):203-13 PMID: 10513580
  65. Immunosuppressive effect of leukotriene B(4) receptor antagonist in vitro.
    Biochem Biophys Res Commun. 1999 Oct 22;264(2):321-6 PMID: 10529362
  66. An in vivo approach showing the chemotactic activity of leukotriene B(4) in acute renal ischemic-reperfusion injury.
    Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):823-8 PMID: 10639164
  67. Leukotriene B4 receptor. Cloning and intracellular signaling.
    Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 2):S51-5 PMID: 10673227
  68. Activation of lipoxin A(4) receptors by aspirin-triggered lipoxins and select peptides evokes ligand-specific responses in inflammation.
    J Exp Med. 2000 Apr 3;191(7):1197-208 PMID: 10748237
  69. Cell-specific transcriptional regulation of human leukotriene B(4) receptor gene.
    J Exp Med. 2000 Aug 7;192(3):413-20 PMID: 10934229
  70. Site-specific recombination functions of bacteriophage lambda: DNA sequence of regulatory regions and overlapping structural genes for Int and Xis.
    Proc Natl Acad Sci U S A. 1980 May;77(5):2482-6 PMID: 6446713
  71. Overlap between ampC and frd operons on the Escherichia coli chromosome.
    Proc Natl Acad Sci U S A. 1982 Feb;79(4):1111-5 PMID: 7041115
  72. Enhanced synthesis of leukotriene B4 by colonic mucosa in inflammatory bowel disease.
    Gastroenterology. 1984 Mar;86(3):453-60 PMID: 6319219
  73. Leukotriene B4 binding to human neutrophils.
    Prostaglandins. 1984 Dec;28(6):837-49 PMID: 6097945
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.192.3.421
Published
2000-08-07
Pages
421-32
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193217
Subset
IM
Databases
GENBANK
AB029892, AB029893
Corrections
CommentIn
PMID: 10934235
External Links
PubMed source DOI: 10.1084/jem.192.3.421 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2