Genomes and Genes
leukotriene b4 receptors
Summary: A class of cell surface leukotriene receptors with a preference for leukotriene B4. Leukotriene B4 receptor activation influences chemotaxis, chemokinesis, adherence, enzyme release, oxidative bursts, and degranulation in polymorphonuclear leukocytes. There are at least two subtypes of these receptors. Some actions are mediated through the inositol phosphate and diacylglycerol second messenger systems.
- Chung J, Kim G, Mun Y, Ahn J, Seong C, Kim J. Leukotriene B4 pathway regulates the fate of the hematopoietic stem cells. Exp Mol Med. 2005;37:45-50 pubmed..Our results suggest that LTB4-BLT2 interaction is involved in the cytokine-induced differentiation and ex vivo expansion of hematopoietic stem cells. ..
- Tager A, Bromley S, Medoff B, Islam S, Bercury S, Friedrich E, et al. Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat Immunol. 2003;4:982-90 pubmed..Our findings show that the LTB4-BLT1 pathway is involved in linking early immune system activation and early effector T cell recruitment. ..
- Shin E, Lee H, Bae Y. Leukotriene B4 stimulates human monocyte-derived dendritic cell chemotaxis. Biochem Biophys Res Commun. 2006;348:606-11 pubmed..Thus human myeloid DCs express functional BLT2 but not BLT1, suggesting a physiological role of LTB4 and BLT2 in regulating DC trafficking during induction of immune responses. ..
- Chiang N, Fierro I, Gronert K, Serhan C. Activation of lipoxin A(4) receptors by aspirin-triggered lipoxins and select peptides evokes ligand-specific responses in inflammation. J Exp Med. 2000;191:1197-208 pubmed
- Jala V, Shao W, Haribabu B. Phosphorylation-independent beta-arrestin translocation and internalization of leukotriene B4 receptors. J Biol Chem. 2005;280:4880-7 pubmed..Thus, receptor phosphorylation-dependent mechanisms regulate G-protein-mediated pathways; however, phosphorylation-independent mechanisms regulate beta-arrestin association and internalization of BLT1. ..
- Tong W, Ding X, Hennig R, Witt R, Standop J, Pour P, et al. Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Clin Cancer Res. 2002;8:3232-42 pubmed..LTB4 receptor blockade and inhibition of the downstream signal pathway are likely to be valuable for the treatment of human pancreatic cancer. ..
- Tager A, Dufour J, Goodarzi K, Bercury S, von Andrian U, Luster A. BLTR mediates leukotriene B(4)-induced chemotaxis and adhesion and plays a dominant role in eosinophil accumulation in a murine model of peritonitis. J Exp Med. 2000;192:439-46 pubmed..These studies demonstrate that BLTR is the key receptor that mediates LTB(4)-induced leukocyte activation and establishes a model to decipher the functional roles of BLTR and LTB(4) in vivo. ..
- Hashimoto A, Endo H, Hayashi I, Murakami Y, Kitasato H, Kono S, et al. Differential expression of leukotriene B4 receptor subtypes (BLT1 and BLT2) in human synovial tissues and synovial fluid leukocytes of patients with rheumatoid arthritis. J Rheumatol. 2003;30:1712-8 pubmed..Conclusion. BLT2 is the main receptor mediating the effects of LTB4 in the synovial tissues of patients with RA; this suggests the possibility of developing a new therapy to block LTB4 in inflammatory arthritis. ..
- Luster A, Tager A. T-cell trafficking in asthma: lipid mediators grease the way. Nat Rev Immunol. 2004;4:711-24 pubmed
- Hennig R, Ding X, Tong W, Schneider M, Standop J, Friess H, et al. 5-Lipoxygenase and leukotriene B(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. Am J Pathol. 2002;161:421-8 pubmed..These findings provide further evidence of up-regulation of this pathway in pancreatic cancer and that LOX inhibitors are likely to be valuable in the treatment of this dreadful disease. ..
- Yokomizo T, Kato K, Hagiya H, Izumi T, Shimizu T. Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2. J Biol Chem. 2001;276:12454-9 pubmed..These findings suggest that BLT2 functions as a low affinity receptor, with broader ligand specificity for various eicosanoids, and mediates distinct biological and pathophysiological roles from BLT1. ..
- Jozefowski S, Biedroń R, Bobek M, Marcinkiewicz J. Leukotrienes modulate cytokine release from dendritic cells. Immunology. 2005;116:418-28 pubmed..Our results indicate that both autocrine and paracrine leukotrienes may modulate cytokine release from DCs, in a manner that is consistent with previously reported T helper 2-polarizing effects of leukotrienes. ..
- Del Prete A, Shao W, Mitola S, Santoro G, Sozzani S, Haribabu B. Regulation of dendritic cell migration and adaptive immune response by leukotriene B4 receptors: a role for LTB4 in up-regulation of CCR7 expression and function. Blood. 2007;109:626-31 pubmed..These results provide strong evidence for a role of LTB4 in regulating DC migration and the induction of adaptive immune responses. ..
- Yoo M, Song H, Woo C, Kim H, Kim J. Role of the BLT2, a leukotriene B4 receptor, in Ras transformation. Oncogene. 2004;23:9259-68 pubmed..Taken together, our results suggest that an LTB4-BLT2-linked cascade plays a crucial mediatory role in the cell transformation induced by oncogenic Ha-Ras(V12), possibly acting downstream of Rac-cPLA2. ..
- Choi J, Kim E, Song H, Kim C, Kim J. Reactive oxygen species are generated through a BLT2-linked cascade in Ras-transformed cells. Free Radic Biol Med. 2008;44:624-34 pubmed
- Kuniyeda K, Okuno T, Terawaki K, Miyano M, Yokomizo T, Shimizu T. Identification of the intracellular region of the leukotriene B4 receptor type 1 that is specifically involved in Gi activation. J Biol Chem. 2007;282:3998-4006 pubmed..From mutational studies and three-dimensional modeling, we propose that the extended cytoplasmic helix connected to the transmembrane helix V of BLT1 might be a key region for selective activation of Gi proteins. ..
- Tong W, Ding X, Talamonti M, Bell R, Adrian T. Leukotriene B4 receptor antagonist LY293111 induces S-phase cell cycle arrest and apoptosis in human pancreatic cancer cells. Anticancer Drugs. 2007;18:535-41 pubmed..LY293111 also induces S-phase arrest with downregulation of CDK2, cyclin A and cyclin E. Blockade of leukotriene B4 metabolic pathway may provide a novel treatment for human pancreatic cancer. ..
- Sousa A, Parikh A, Scadding G, Corrigan C, Lee T. Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N Engl J Med. 2002;347:1493-9 pubmed
- Ott V, Cambier J, Kappler J, Marrack P, Swanson B. Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat Immunol. 2003;4:974-81 pubmed..These studies indicate that LTB4 production by activated peripheral leukocytes could be important for the recruitment of effector CD8+ T cells to sites of inflammation. ..
- Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature. 1997;387:620-4 pubmed..Our findings, together with previous reports, show that LTB4 is a unique lipid mediator that interacts with both cell-surface and nuclear receptors. ..
- Gaudreau R, Le Gouill C, Métaoui S, Lemire S, Stankova J, Rola Pleszczynski M. Signalling through the leukotriene B4 receptor involves both alphai and alpha16, but not alphaq or alpha11 G-protein subunits. Biochem J. 1998;335 ( Pt 1):15-8 pubmed..Co-transfection of BLTR with phospholipase C (PLC) beta2, on the other hand, resulted in efficient IP production and co-transfection of BLTR with both Galpha16 and PLCbeta2 resulted in a greater than additive response. ..
- Okuno T, Ago H, Terawaki K, Miyano M, Shimizu T, Yokomizo T. Helix 8 of the leukotriene B4 receptor is required for the conformational change to the low affinity state after G-protein activation. J Biol Chem. 2003;278:41500-9 pubmed
- Subbarao K, Jala V, Mathis S, Suttles J, Zacharias W, Ahamed J, et al. Role of leukotriene B4 receptors in the development of atherosclerosis: potential mechanisms. Arterioscler Thromb Vasc Biol. 2004;24:369-75 pubmed
- Shao W, Del Prete A, Bock C, Haribabu B. Targeted disruption of leukotriene B4 receptors BLT1 and BLT2: a critical role for BLT1 in collagen-induced arthritis in mice. J Immunol. 2006;176:6254-61 pubmed..Thus, BLT1 may be a useful target for therapies directed at treating inflammation associated with arthritis. ..
- Haribabu B, Verghese M, Steeber D, Sellars D, Bock C, Snyderman R. Targeted disruption of the leukotriene B(4) receptor in mice reveals its role in inflammation and platelet-activating factor-induced anaphylaxis. J Exp Med. 2000;192:433-8 pubmed..002) relative to male (1 of 11) mice of PAF-induced anaphylaxis. These results demonstrate the role of BLTR in leukotriene-mediated acute inflammation and an unexpected sex-related involvement in PAF-induced anaphylaxis. ..
- Chiang N, Gronert K, Clish C, O Brien J, Freeman M, Serhan C. Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion. J Clin Invest. 1999;104:309-16 pubmed..Moreover, LXA4 and ATL counter BLTR-amplified networks, revealing a novel protective role for LX and ATL in stress responses that has applications in perioperative medicine. ..
- Lundeen K, Sun B, Karlsson L, Fourie A. Leukotriene B4 receptors BLT1 and BLT2: expression and function in human and murine mast cells. J Immunol. 2006;177:3439-47 pubmed..These receptors may mediate recruitment and accumulation of MCs in response to LTB4 production in areas of inflammation. ..
- Terawaki K, Yokomizo T, Nagase T, Toda A, Taniguchi M, Hashizume K, et al. Absence of leukotriene B4 receptor 1 confers resistance to airway hyperresponsiveness and Th2-type immune responses. J Immunol. 2005;175:4217-25 pubmed
- Goodarzi K, Goodarzi M, Tager A, Luster A, von Andrian U. Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues. Nat Immunol. 2003;4:965-73 pubmed..These results identify LTB4-BLT1 as a potent nonchemokine pathway for cytotoxic effector cell traffic. ..
- Toda A, Yokomizo T, Masuda K, Nakao A, Izumi T, Shimizu T. Cloning and characterization of rat leukotriene B(4) receptor. Biochem Biophys Res Commun. 1999;262:806-12 pubmed..The present results suggest important roles of LTB(4) in macrophage recruitment and activation. ..
- Haribabu B, Zhelev D, Pridgen B, Richardson R, Ali H, Snyderman R. Chemoattractant receptors activate distinct pathways for chemotaxis and secretion. Role of G-protein usage. J Biol Chem. 1999;274:37087-92 pubmed..Chemotaxis, however, had an absolute requirement for a G(i)-mediated pathway. ..
- Matsukawa A, Hogaboam C, Lukacs N, Lincoln P, Strieter R, Kunkel S. Endogenous monocyte chemoattractant protein-1 (MCP-1) protects mice in a model of acute septic peritonitis: cross-talk between MCP-1 and leukotriene B4. J Immunol. 1999;163:6148-54 pubmed
- Yokomizo T, Kato K, Terawaki K, Izumi T, Shimizu T. A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J Exp Med. 2000;192:421-32 pubmed..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. ..
- Ito S, Ito Y, Katagiri H, Suzuki T, Hoka S, Yokomizo T, et al. Leukotriene B4/leukotriene B4 receptor pathway is involved in hepatic microcirculatory dysfunction elicited by endotoxin. Shock. 2008;30:87-91 pubmed..These findings suggest that the LTB4/BLT1 pathway mediates hepatic microcirculatory dysfunction by enhanced expression of ICAM-1 and TNF-[alpha] in a murine model of endotoxemia. ..
- Mizuno K, Okamoto H, Horio T. Heightened ability of monocytes from sarcoidosis patients to form multi-nucleated giant cells in vitro by supernatants of concanavalin A-stimulated mononuclear cells. Clin Exp Immunol. 2001;126:151-6 pubmed..These findings suggest that the ability of monocytes to form MGC through P2x7 receptors is enhanced in sarcoidosis patients. ..
- Cho K, Seo J, Shin Y, Yoo M, Park C, Lee S, et al. Blockade of airway inflammation and hyperresponsiveness by inhibition of BLT2, a low-affinity leukotriene B4 receptor. Am J Respir Cell Mol Biol. 2010;42:294-303 pubmed publisher..Together, our results suggest that BLT2 plays a pivotal, mediatory role in the pathogenesis of asthma, acting through a "reactive oxygen species-NF-kappaB"-linked inflammatory signaling pathway. ..
- Iwamoto S, Koga T, Ohba M, Okuno T, Koike M, Murakami A, et al. Non-steroidal anti-inflammatory drug delays corneal wound healing by reducing production of 12-hydroxyheptadecatrienoic acid, a ligand for leukotriene B4 receptor 2. Sci Rep. 2017;7:13267 pubmed publisher..Thus, our results reveal that NSAIDs delay corneal wound healing by inhibiting 12-HHT production, and suggest that stimulation of the 12-HHT/BLT2 axis represents a novel therapeutic approach to corneal wound healing. ..
- Kim D, Kim H, Sung K, Kim H, Cho S, Kim K, et al. 12(S)-HPETE induces itch-associated scratchings in mice. Eur J Pharmacol. 2007;554:30-3 pubmed..The scratching induced by 12(S)-HPETE was inhibited by capsaicin, naltrexon, and LY255283. These results suggest the possibility that 12-lipoxygenase product can be added to a new member of an endogenous itch mediator in the skin. ..
- Pettersson A, Sabirsh A, Bristulf J, Kidd Ljunggren K, Ljungberg B, Owman C, et al. Pro- and anti-inflammatory substances modulate expression of the leukotriene B4 receptor, BLT1, in human monocytes. J Leukoc Biol. 2005;77:1018-25 pubmed
- Casillan A, Gonzalez N, Johnson J, Steiner D, Wood J. Mesenteric microvascular inflammatory responses to systemic hypoxia are mediated by PAF and LTB4. J Appl Physiol (1985). 2003;94:2313-22 pubmed
- Tager A, Luster A. BLT1 and BLT2: the leukotriene B(4) receptors. Prostaglandins Leukot Essent Fatty Acids. 2003;69:123-34 pubmed..Reduced disease severity in animal inflammatory models seen with LTB(4) receptor antagonists and in mice with targeted deletion of BLT1 have revealed important roles for LTB(4) and its receptors in regulating pathologic inflammation. ..
- Serezani C, Aronoff D, Jancar S, Peters Golden M. Leukotriene B4 mediates p47phox phosphorylation and membrane translocation in polyunsaturated fatty acid-stimulated neutrophils. J Leukoc Biol. 2005;78:976-84 pubmed..These results identify a heretofore unrecognized role for activation of 5-LO and subsequent production of LTB(4) in stimulation of PMN NADPH oxidase activation by PUFAs. ..
- Svensson L, Redvall E, Björn C, Karlsson J, Bergin A, Rabiet M, et al. House dust mite allergen activates human eosinophils via formyl peptide receptor and formyl peptide receptor-like 1. Eur J Immunol. 2007;37:1966-77 pubmed..This study indicates that FPR and FPRL1 mediate the activation of eosinophils by HDM, whereas birch pollen employs other pathways shared with FPR to activate human eosinophils. ..
- Brouwers A, Laverman P, Boerman O, Oyen W, Barrett J, Harris T, et al. A 99Tcm-labelled leukotriene B4 receptor antagonist for scintigraphic detection of infection in rabbits. Nucl Med Commun. 2000;21:1043-50 pubmed..The development of a more hydrophilic analogue of 99Tcm-RP517 could improve the clinical applicability of this agent. ..
- Jeon S, Moon H, Kim Y, Choi J, Shin T, Hong S, et al. 15-lipoxygenase metabolites play an important role in the development of a T-helper type 1 allergic inflammation induced by double-stranded RNA. Clin Exp Allergy. 2009;39:908-17 pubmed publisher..Our findings suggest that the 15-LO pathway is a novel therapeutic target for the treatment of virus-associated asthma characterized by Th1 inflammation. ..
- Eriksson E. Mechanisms of leukocyte recruitment to atherosclerotic lesions: future prospects. Curr Opin Lipidol. 2004;15:553-8 pubmed..Detailed study of certain subclasses of leukocytes in the recruitment process will be important in future studies in this field. ..
- Sarau H, Foley J, Schmidt D, Martin L, Webb E, Tzimas M, et al. In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB4 receptor antagonist with anti-inflammatory activity. Prostaglandins Leukot Essent Fatty Acids. 1999;61:55-64 pubmed..These results indicate that SB 201993 blocks the actions of LTB4 and 12-(R)-HETE and inhibits a variety of inflammatory responses; and thus may be a useful compound to evaluate the role of these mediators in disease models. ..
- Huang F, Galemmo R, Johnson W, Poli G, Morrissette M, Mencel J, et al. Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene D4 receptor antagonists. 2. Effects of an additional phenyl ring on receptor affinity. J Med Chem. 1990;33:1194-200 pubmed
- Junek R, Brůnová B, Kverka M, Panajotova V, Jandera A, Kuchar M. Antileukotrienic N-arylethyl-2-arylacetamides in the treatment of ulcerative colitis. Eur J Med Chem. 2007;42:1084-94 pubmed..The importance of antileukotrienic activities for the anti-inflammatory effect, especially in the model of UC was discussed, but further experiments are necessary to confirm the respective relations. ..
- Kim G, Lee J, Cho S, Seo J, Kim J. Role of the low-affinity leukotriene B4 receptor BLT2 in VEGF-induced angiogenesis. Arterioscler Thromb Vasc Biol. 2009;29:915-20 pubmed publisher..The activation of BLT2 itself by either 12(S)-HETE or LTB(4) evoked significant angiogenic phenotypes, both in vitro and in vivo. Our findings indicate that BLT2 plays an essential role in mediating VEGF-induced angiogenesis. ..
- Saif M, Oettle H, Vervenne W, Thomas J, Spitzer G, Visseren Grul C, et al. Randomized double-blind phase II trial comparing gemcitabine plus LY293111 versus gemcitabine plus placebo in advanced adenocarcinoma of the pancreas. Cancer J. 2009;15:339-43 pubmed publisher..These results do not demonstrate any benefit to adding LY to gemcitabine in unpretreated patients with advanced pancreatic carcinoma. ..
- Zhang S, Deng Y, Zhu Y, Dong X, Jiang J, Xie Q. Intracerebroventricular injection of leukotriene B4 attenuates antigen-induced asthmatic response via BLT1 receptor stimulating HPA-axis in sensitized rats. Respir Res. 2010;11:39 pubmed publisher..Here, we investigated how the increased LTB4 level in brain interacts with HPA axis in regulating antigen-induced asthmatic response in sensitized rats...