Disease relevance of LTB4R

• RESULTS: Both LTB4 receptor types were found to be expressed in human pancreatic cancer cells [1].
• Leukotriene B4 signaling through NF-kappaB-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia [2].
• BLT receptor up-regulation in the intima in vivo, as well as that induced by IL-1beta in vitro, were prevented by transfection with a dominant-negative form of Ikappa kinase beta carried by adenovirus, indicating that BLT(1) receptor expression depends on NF-kappaBeta [2].
• 5. The LTB4-induced 5-LO activation was effectively inhibited by MK-886 (an inhibitor of 5-LO translocation), by pertussis toxin, and by the LTB4 receptor antagonist, LY-223982 [3].
• In contrast, expressions of BLT1 and BLT2, receptors for leukotriene B4, did not change in the endometriosis [4].

High impact information on LTB4R

• Furthermore, CHO cells expressing exogenous BLTR showed marked chemotactic responses towards low concentrations of LTB4 in a pertussis-toxin-sensitive manner [5].
• Here we report the cloning of the complementary DNA encoding a cell-surface LTB4 receptor that is highly expressed in human leukocytes [5].
• A unique requirement for the leukotriene B4 receptor BLT1 for neutrophil recruitment in inflammatory arthritis [6].
• The promoter region of the BLT1 gene is localized within the open reading frame (ORF) of the BLT2 gene, which encodes a low-affinity receptor for LTB(4) (Yokomizo, T., K. Kato, K. Terawaki, T. Izumi, and T. Shimizu. 2000. J. Exp. Med. 192:421-431) [7].
• BLT1, a high-affinity receptor for LTB(4) (originally termed BLT), is expressed exclusively in inflammatory cells and is inducible in macrophages upon activation [7].

Chemical compound and disease context of LTB4R

• LTB(4) induced migration and proliferation of SMC in vitro, and treatment with the BLT receptor antagonist BIIL 284 (10 mg/kg, once daily) for 14 days after carotid artery balloon injury in vivo inhibited intimal hyperplasia in rats [2].
• Cotton-top tamarins (CTTs) with confirmed active colitis were treated with the second generation LTB4 receptor antagonist, SC-53228 ((+)-(S)-7-[3-(2-cyclopropyl-methyl)-3-methoxy-4-[(methylamino) carbonyl]phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2- propanoic acid), 20 mg/kg bodyweight by gavage, twice daily for 56 days [8].
• Leukotriene B4 receptor inhibitor LY293111 induces cell cycle arrest and apoptosis in human anaplastic large-cell lymphoma cells via JNK phosphorylation [9].
• We also discuss briefly a coreceptor role of BLT in HIV infection, and ion channel modification by LTB4 [10].
• Eicosapentaenoic acid modulates neutrophil leukotriene B4 receptor expression in cystic fibrosis [11].

Biological context of LTB4R

• The P2Y7 gene was shown to be localized to human chromosome 14 [12].
• Methods. BLT1 and BLT2 mRNA were detected by reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization in synovial tissues from 40 patients with RA and 10 patients with OA [13].
• Thus, methylation at CpG sites in the promoter region is important for cell-specific transcription of the BLT1 gene [7].
• A reporter gene assay revealed that a region approximately 80 basepair upstream from the initiator sequence is required for the basal transcription of the BLT1 gene [7].
• Recently, BLT1 expression and LTB4-dependent chemotaxis have been reported in immature mast cells (MCs) [14].

Anatomical context of LTB4R

• The P2Y7 receptor is functionally coupled to phospholipase C in COS-7 cells transiently expressing this receptor [12].
• The P2Y7 receptor mRNA is abundantly present in the human heart and the skeletal muscle, moderately in the brain and liver, but not in the other tissues tested [12].
• In contrast, leukocytes infiltrating synovial fluid predominantly expressed BLT1 mRNA in patients with RA [13].
• Furthermore, pretreatment of neutrophils with a LTB4-receptor antagonist, LY 255283, blocked the AA- and LTB4-induced activation of PLA2 but did not influence the action of 5-HETE [15].
• Pretreatment of mBMMCs with stem cell factor significantly down-regulated expression of BLT1 and BLT2 mRNA and inhibited their migration to LTB4 [14].

Associations of LTB4R with chemical compounds

• The P2Y7 cDNA was transiently expressed in COS-7 cells: binding studies thereon showed a very high affinity for ATP (37 +/- 6 nM), much less for UTP and ADP (approximately 1300 nM), and a novel rank order of affinities in the binding series studied of 8 nucleotides and suramin [12].
• Results. BLT2 (the low-affinity receptor for LTB4) showed stronger expression than BLT1 (the high-affinity receptor) in actively inflamed synovial tissue from patients with RA [13].
• The nascent LTB4 is then released to act on the LTB4 receptor and thereby promote further activation of the 85-kDa PLA2 [15].
• Augmented expression of BLT1 by Dex was associated with enhanced functional activities, such as LTB(4)-induced intracellular calcium mobilization and chemotaxis [16].
• BLT1 calcium signalling was sensitive to the activity of protein kinase C (PKC), protein kinase A (PKA) and protein-tyrosine kinases (PTKs), as well as changes in membrane cholesterol levels and treatments that are known to disrupt normal membrane physiology and/or lipid rafts [17].

Regulatory relationships of LTB4R

• Treatment of neutrophils with an inhibitor of 5-lipoxygenase-activating protein (MK886) and thus synthesis of leukotrienes (LTs) or with an antagonist of the LTB4 receptor (LY223982) blocked the release of elastase [18].
• Blockade of BLT1 by the receptor antagonist significantly suppresses the LTB(4)-stimulated extracellular signal-regulated kinase (ERK) activation in colon cancer cells [19].
• The regulation of CD11b integrin levels on human blood leukocytes and leukotriene B4-stimulated skin by a specific leukotriene B4 receptor antagonist (LY293111) [20].
• From the results it is considered that TNF can influence host defence through the modulation of leukotriene B4 receptor affinity [21].

Other interactions of LTB4R

• This receptor, designated P2Y7, has 352 amino acids and shares 23-30% amino acid identity with the P2Y1-P2Y6 purinoceptors [12].
• This induction is mediated through the BLT1 pathway increasing MCP-1 transcription [22].
• Cancer-related increases in methylation of only two studied genes, LTB4R and MTHFR, which were appreciably methylated even in control tissues, were associated with DNMT1 RNA levels [23].
• Flow cytometric analysis of fresh peripheral blood cells revealed that classical (CD14(++)CD16(-)) monocytes express high levels of BLT1 and CCR2 and that both receptors are down-regulated on CD14(+)CD16(+) monocytes [24].
• Our findings thus suggest that Thr(308) is a major residue involved in GRK6-mediated desensitization of BLT1 signaling [25].

Analytical, diagnostic and therapeutic context of LTB4R

• 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 [26].
• Studies on the expression of the high-affinity receptor for LTB(4) (BLT1) by flow cytometry analysis showed that the receptor was expressed, to a varying degree, in all investigated B-CLL clones [27].
• The antibodies were shown to recognize BLTR in cell ELISA and immunocytochemistry [28].
• 2-12 where the BLTR/BLTR2 genes were previously shown to be located, together with (b) sequence analysis of 83 expressed sequence tags (ESTs) from this region [29].
• Remarkable expression of LTB(4) receptor 1 (BLT1) in human colon cancer tissues was detected by immunohistochemistry, and Western blot analysis revealed the BLT1 expression in cultured human colon cancer cell lines, Caco2 and HT29 [19].

References