Disease relevance of Ltb4r1

• The disease severity correlated well with histopathology, including loss of joint architecture, inflammatory cell infiltration, fibrosis, pannus formation, and bone erosion in joints of BLT1/BLT2(+/+) animals and a total absence of disease pathology in leukotriene receptor-deficient mice [1].
• However, among the 16 HIV/SIV strains tested, the human BLT receptor did not act as a coreceptor for virus entry into CD4-expressing cells based on infection and cell-cell fusion assays [2].
• PURPOSE: To investigate the role of leukotriene B4 (LTB4) and its receptor BLT1 in the pathogenesis of mouse uveitis [3].
• To determine the importance of BLT-1 in atherogenesis, we crossed BLT-1-null mice with apolipoprotein (apo)-E-deficient mice, which develop severe atherosclerosis [4].
• Oral administration of LTB4 receptor antagonists either as a pre-treatment or post-treatment attenuated TPA-induced edema and influx of neutrophils [5].
• We have shown that BLT1 contributes to the frequency and size of abdominal aortic aneurysms in mice and that BLT1 deletion in turn inhibits proinflammatory circuits and enzymes that modulate vessel wall integrity [6].

High impact information on Ltb4r1

• LTB4 elicited BLT1-dependent chemotaxis in effector cells, but not in naive or central memory cells [7].
• Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues [7].
• Leukotriene B4 (LTB4) is a potent chemoattractant for myeloid leukocytes, which express BLT1, the high-affinity receptor for LTB4 [7].
• Intravital microscopy showed that BLT1 signaling induced rapid integrin-mediated arrest of rolling effector and central memory cells in postcapillary venules [7].
• Our findings show that the LTB4-BLT1 pathway is involved in linking early immune system activation and early effector T cell recruitment [8].

Chemical compound and disease context of Ltb4r1

• Neutrophil influx in a peritonitis model and acute ear inflammation in response to arachidonic acid was significantly reduced in BLTR(-/-) mice [9].
• RESULTS: Compared with wild-type mice, BLT1 -/- mice developed significantly lower airway responsiveness to inhaled methacholine, lower goblet cell hyperplasia in the airways, and decreased interleukin (IL)-13 production both in vivo, in the bronchoalveolar lavage fluid, and in vitro, after antigen stimulation of lung cells in culture [10].
• Leukotriene B4 (LTB4) is a rapidly synthesized, early neutrophil chemoattractant that signals via its cell surface receptor, BLT-1, to attract and activate neutrophils during peritonitis [11].
• Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells [12].
• To test the hypothesis that the Hecate-CGbeta conjugate selectively abolishes cells possessing LHR, estrogen dependent and independent human breast cancer cell lines (MCF-7; MDA-MB-231) and a mouse Leydig tumor cell line (BLT-1) were treated in vitro with Hecate-CGbeta conjugate and Hecate alone [13].

Biological context of Ltb4r1

• 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 [14].
• CP-105,696, (+)-1-(3S,4R)-[3-(4-phenylbenzyl)- 4-hydroxychroman-7-yl]cyclopentane carboxylic acid, is an LTB4 receptor antagonist that inhibits LTB4 binding to human neutrophil membranes with an IC50 of 3.7 nM and inhibits LTB4-induced chemotaxis of these cells with an IC50 of 5.2 nM [15].
• BLT1 and BLT2 are high- and low-affinity LTB4 receptors, respectively, and form a gene cluster in human and mouse [16].
• The LTB4 receptor antagonist, LY293111 inhibited tumor growth and induced apoptosis in vitro [17].
• PMN phagocytosis and CD11b levels were decreased in BLT-1(-/-) mice [11].

Anatomical context of Ltb4r1

• Because LXA4 and aspirin-triggered 15-epimeric LXA4 (ATL) selectively regulate leukocyte responses, they were tested in BLTR transgenic mice [18].
• Also, in BLTR transgenic mice, 5-LO expression and product formation were selectively increased in exudates, demonstrating that receptor overexpression amplifies proinflammatory circuits [18].
• In 5-lipoxygenase-deficient mice, the absence of leukotriene B4 biosynthesis did not detectably alter m-BLT receptor binding in membranes obtained from glycogen-elicited neutrophils [2].
• In Xenopus laevis melanophores transiently expressing m-BLTR, LTB4 induced the aggregation of pigment granules, confirming the inhibition of cAMP production induced by LTB4 [2].
• The animals were then treated with and without the BLT1 receptor antagonist, CP105696, at the disease onset after immunization or at day 0 or day 6 after T-cell transfer [3].

Associations of Ltb4r1 with chemical compounds

• Isolation of the m-BLTR gene will form the basis of future experiments to elucidate the selective role of LTB4, as opposed to cysteinyl-leukotrienes, in murine models of inflammation [2].
• Membrane fractions of human embryonic kidney 293 cells stably expressing m-BLTR demonstrated a high affinity and specific binding for leukotriene B4 (LTB4, Kd = 0.24 +/- 0.03 nM) [2].
• Several BLT1 antagonists, including U 75302, failed to inhibit LTB(4) binding to BLT2 [14].
• These data are the first to show both a functional and an essential role for BLT1 in allergen-mediated CD8+ T(EFF) recruitment into the lung and development of AHR and airway inflammation [19].
• The LTB4 receptor antagonist, SC-41930, inhibited the inflammatory response to TPA but had little effect on that initiated by AA [20].

Physical interactions of Ltb4r1

• Leukotriene B(4) (LTB(4)) and leukotriene C(4) (LTC(4)) act through G protein-coupled receptors LTB(4) receptor (BLTR) and Cys-LTR, respectively [9].

Regulatory relationships of Ltb4r1

• Here, we developed a novel murine model of acute lung rejection to demonstrate that BLT1 controls effector CD8+ T cell trafficking into the lung and that disruption of BLT1 signaling in CD8+ T cells reduces lung inflammation and mortality in the model [21].
• Neutrophil recruitment by C5a in vivo required amplification via leukotriene B(4), because both C5a-mediated leukocyte recruitment into the peritoneal cavity and tumor regression were suppressed in leukotriene B(4)R-deficient (BLT-1(-/-)) mice [22].

Other interactions of Ltb4r1

• Taken together, these results suggest a role for leukotrienes in acute inflammation induced by TPA and possible utility of this model to test in vivo 5-LO inhibitors and LTB4 receptor antagonists [5].
• Homozygous low-density receptor knockout (LDLr(-/-)) mice and apolipoprotein E deficient (apoE(-/-)) mice were treated with a specific LTB4 receptor antagonist, CP-105,696, for 35 days [23].
• This is the first report that describes a pathologic role for BLT1-mediated T lymphocyte recruitment in disease and identifies BLT1 as a potential therapeutic target after lung transplantation [21].
• A LTB4 receptor antagonist, SC-41930 [7-(3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8- propyl-2H-1-benzopyran-2-carboxylic acid) and an LTD4 receptor antagonist, LY-171883 [1-(2-hydroxy-3-propyl-4-(4-1H-tetrazol-5-yl)butoxy-phenyl) ethanone)] (i.v.) attenuated influx of neutrophils and associated LTB4 biosynthesis [24].
• Attenuated symptoms were accompanied by reduced IgE production, and accumulation of IL-5 and IL-13 in bronchoalveolar lavage fluid, suggesting attenuated Th2-type immune response in BLT1-null mice [25].

Analytical, diagnostic and therapeutic context of Ltb4r1

• Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion [18].
• Despite excessive PMN recruitment in BLTR transgenic mice, intravenous injection of ATL sharply diminished reperfusion-initiated PMN trafficking to remote organs, and topical application of LX was protective in acute dermal inflammation [18].
• In a model of collagen-induced arthritis on the C57BL/6 background, the BLT1/BLT2(-/-) as well as the previously described BLT1(-/-) animals showed complete protection from disease development [1].
• Deletion of BLT-1 significantly reduced the lesion formation in apo-E-/- mice only during initiating stages (4 and 8 weeks) but had no effect on the lesion size in mice fed atherogenic diet for 19 weeks [4].
• BLT1-mediated T cell trafficking is critical for rejection and obliterative bronchiolitis after lung transplantation [21].

References