View source for Leukotriene B4 receptor 2

{{DISPLAYTITLE:Leukotriene B<sub>4</sub> receptor 2}}
{{Infobox_gene}}
'''Leukotriene B4 receptor 2''', also known as '''BLT2''', '''BLT2 receptor''', and '''BLTR2''', is a [[Integral membrane protein]] that is encoded by the '''LTB4R2''' [[gene]] in humans and the Ltbr2 gene in mice.<ref name="entrez">{{cite web | title = Entrez Gene: LTB4R2 leukotriene B4 receptor 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=56413| accessdate = }}</ref><ref name="pmid11006272">{{cite journal | vauthors = Wang S, Gustafson E, Pang L, Qiao X, Behan J, Maguire M, Bayne M, Laz T | title = A novel hepatointestinal leukotriene B4 receptor. Cloning and functional characterization | journal = The Journal of Biological Chemistry | volume = 275 | issue = 52 | pages = 40686–94 | date = Dec 2000 | pmid = 11006272 | pmc =  | doi = 10.1074/jbc.M004512200 }}</ref><ref name="pmid10934229">{{cite journal | vauthors = Kato K, Yokomizo T, Izumi T, Shimizu T | title = Cell-specific transcriptional regulation of human leukotriene B(4) receptor gene | journal = The Journal of Experimental Medicine | volume = 192 | issue = 3 | pages = 413–20 | date = Aug 2000 | pmid = 10934229 | pmc = 2193224 | doi = 10.1084/jem.192.3.413 }}</ref>

Discovered several years after the [[leukotriene B4 receptor]] 1 (BLT1), BLT2 receptor binds [[leukotriene B4]] (LTB4) with far lower affinity than the BLT1 receptor does and therefore has been termed the '''low affinity LTB4 receptor'''.  Sometime after its initial discovery, the BLT2 receptor was shown to bind and become activated by several other arachidonic acid metabolites, one of which, 12-hydroxyheptadecatrienoic acid (12-HHT), has 10- to 100-fold higher affinity for it than does LTB4; 12-HHT fails to bind or activate BLT1 receptors.  While BLT2 receptors have some actions similar to BLT1 receptors, they have other actions which clearly oppose those of BLT1 in regulating inflammation and allergic responses; BLT2 receptors also have actions that extend beyond those of BLT1 receptors.  Laboratory, animal, and other pre-clinical studies suggest that BLT2 receptors may be involved not only in inflammation and allergy but also in human cancer.

== Function ==

BLT2 is a [[Cell surface receptor]] that functions by recognizing, binding, and mediating responses to a particular set of messenger molecules or [[ligand (biochemistry)|ligands]].  These messenger ligands are any one of a range of structurally different [[arachidonic acid]] metabolites made and released by nearby cells to act as [[paracrine]] signals for coordinating responses between cells or [[autocrine]] signals for modulating their parent cells' responses.

== Genes ==

Several years after their identification of a [[Leukotriene B4]] (LTB4) receptor termed BLT1 or BLTR1 and encoded by the LTB4R1 gene,<ref>{{cite journal | vauthors = Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T | title = A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis | journal = Nature | volume = 387 | issue = 6633 | date = Jun 1997 | pmid = 9177352 | doi = 10.1038/42506 | pages=620–4}}</ref> Shimizu and colleagues identified a second LTB4 receptor, BLT2 or BLTR2, encoded by the LTB4R2 gene.<ref name="Kato_2000">{{cite journal | vauthors = Kato K, Yokomizo T, Izumi T, Shimizu T | title = Cell-specific transcriptional regulation of human leukotriene B(4) receptor gene | journal = The Journal of Experimental Medicine | volume = 192 | issue = 3 | date = Aug 2000 | pmid = 10934229 | doi=10.1084/jem.192.3.413 | pmc=2193224 | pages=413–420}}</ref> LTBR1 and LTBR2 encode for proteins with 45% [[amino acid]] identity that belong to the [[G protein–coupled receptor]] superfamily.  The two genes form a cluster on human and mouse chromosome 14; in humans but not mice, this cluster has a very unusual configuration in that LTBR2's [[open reading frame]] overlaps the [[Promoter (genetics)]] and 5' [[Untranslated region]] of LTBR1.<ref name="Kato_2000"/><ref name="Yokomizo_2015">{{cite journal | vauthors = Yokomizo T | title = Two distinct leukotriene B4 receptors, BLT1 and BLT2 | journal = Journal of Biochemistry | volume = 157 | issue = 2 | date = Feb 2015 | pmid = 25480980 | doi = 10.1093/jb/mvu078 | pages=65–71}}</ref>  The significance of this overlap is not known.  Monkeys, rats, and dogs have also be shown to express LTB4R2 [[orthologs]].<ref name="ReferenceC">{{cite journal | vauthors = Okuno T, Ishitani T, Yokomizo T | title = Biochemical Characterization of Three BLT Receptors in Zebrafish | journal = PLOS ONE | volume = 10 | issue = 3 | pmid = 25738285 | doi = 10.1371/journal.pone.0117888 | year=2015 | pages=e0117888 | pmc=4349892}}</ref>

Two BLT2-like receptors, Blt2a and Blt2b, with 49% amino acid identity to each other and 34% and 29%, respectively, amino acid identities to human BLT2 have been cloned from [[Zebrafish]] embryos.<ref name="ReferenceC"/>  The latter citation presents a phylogenic tree on the amino acid relateness of these two receptors as well as those from humans, monkeys, dogs, rats and mice to each other.

== Mechanism of action ==
BLT2 receptors, similar to BLT1 receptors, are [[G protein coupled receptors]] that, when ligand-bound, activate [[G proteins]] that contain either the [[Gi alpha subunit]] and are therefore inhibited by [[pertussis toxin]] or the [[Gq alpha subunit]] and therefore not inhibited by pertussis toxin.  (Pertussis toxin sensitivity is an imported test for G protein receptor linkages.)  BLT2 receptors stimulate cells to transiently elevated cytosolic calcium ion concentrations, thereby activating calcium-activated intracellular signaling molecules; it also stimulates cells to activate [[Extracellular signal-regulated kinases]] (ERKs), [[Protein kinase B]] (also known as Akt), [[c-Jun N-terminal kinases]] (JNKs), [[Janus kinase]] (JAK)-[[STAT protein]] (i.e. signal transducer and activator of transcription, [[NADPH oxidase]] (NOX), and NF-κB pathways.  One prominent cell-activating pathway involves BLT2 receptor activation of NOX2 or NOX1 with the subsequent production of [[reactive oxygen species]] which in turn activate the transcription inducing function of NF-κB.<ref>{{cite journal | vauthors = Cho KJ, Seo JM, Kim JH| date = Jul 2011 | title =  Bioactive lipoxygenase metabolites stimulation of NADPH oxidases and reactive oxygen species| url = | journal = Mol Cells | volume = 32 | issue = 1| pages = 1–5 | doi = 10.1007/s10059-011-1021-7 | pmid=21424583 | pmc=3887656}}</ref><ref>''Am J Cancer Res.'' 2013 Aug 14;3(4):347-55. eCollection 2013</ref><ref>{{cite journal | vauthors = Lee JW, Kim JH| date = Oct 2013 | title =  Activation of the Leukotriene B4 Receptor 2-Reactive Oxygen Species (BLT2-ROS) Cascade following Detachment Confers Anoikis Resistance in Prostate Cancer Cells| journal = J. Biol. Chem. | volume = 288 | issue = 42| pages = 30054–63 | doi = 10.1074/jbc.M113.481283 | pmid=23986446 | pmc=3798474}}</ref>

== Tissue distribution ==

The human BLT2 receptor is expressed in a wide range of tissues including spleen, blood leukocytes, liver, ovary, pancreas, heart, prostate gland, testes, small intestine, kidney, lung, colon, thymus, muscle, and placenta; this contrasts with the BLT1 receptor which appears to have a more limited expression pattern including mainly circulating blood leukocytes and lymphocytes.<ref>{{cite journal | vauthors = Tager AM, Luster AD | title = BLT1 and BLT2: the leukotriene B(4) receptors | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 69 | issue = 2–3 | pmid = 12895595 | doi=10.1016/S0952-3278(03)00073-5 | year=2003 | pages=123–34}}</ref><ref>{{cite journal | vauthors = Pace E, Ferraro M, Di Vincenzo S, Bruno A, Giarratano A, Scafidi V, Lipari L, Di Benedetto DV, Sciarrino S, Gjomarkaj M | title = Cigarette smoke increases BLT2 receptor functions in bronchial epithelial cells: in vitro and ex vivo evidence | journal = Immunology | volume = 139 | issue = 2 | date = Jun 2013 | pmid = 23347335 | doi = 10.1111/imm.12077 | pages=245–55 | pmc=3647190}}</ref><ref name = "pmid24588652">{{cite journal | vauthors = Bäck M, Powell WS, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE | title = Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7 | journal = British Journal of Pharmacology | volume = 171 | issue = 15 | date = Aug 2014 | pmid = 24588652 | doi = 10.1111/bph.12665 | pages=3551–74 | pmc=4128057}}</ref> The mouse Blt2 receptor also shows a more limited distribution pattern than the human BLT2 receptor, showing appreciable expression in the small intestine and skin, and low expression in the colon and spleen.<ref name = "pmid24588652"/><ref name="Watanabe M 2014">{{cite journal | vauthors = Watanabe M, Machida K, Inoue H | title = A turn on and a turn off: BLT1 and BLT2 mechanisms in the lung | journal = Expert Review of Respiratory Medicine | volume = 8 | issue = 4 | date = Aug 2014 | pmid = 24742066 | doi = 10.1586/17476348.2014.908715 | pages=381–3}}</ref>

== Ligands ==

While initially defined as a low affinity receptor for the [[5-lipoxygenase]] product of arachidonic acid metabolism, LTB4, BLT2 binds and is activated by not only LTB4 but also the [[cycloxygenase]]-[[thromboxane synthase]] enzyme pathway of arachidonic acid metabolism, [[12-Hydroxyheptadecatrienoic acid]] (12-HHT) as well as by three products of the [[12-lipoxygenase]] pathway of aracidonic acid metabolism, 12(''S'')-HETE, 12(''S'')-HpETE, and 12(''R'')-HETE (see [[12-Hydroxyeicosatetraenoic acid]], by a member of the [[15-lipoxygenase]] pathway of arachidonic acid metabolism, 15(''S'')-HETE (see [[15-Hydroxyicosatetraenoic acid]]), and by another member of the LTB4 family of arachidonic acid metabolites, 20-hydroxy-LTB4; the relative BLT2 receptor-binding affinities of these 7 metabolites are ~1000, 100, 10, 10, 3, 3, and 1, respectively.<ref>{{cite journal | vauthors = Yokomizo T, Kato K, Hagiya H, Izumi T, Shimizu T | title = Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 15 | date = Apr 2001 | pmid = 11278893 | doi = 10.1074/jbc.M011361200 | pages=12454–9}}</ref><ref name = "Okuno_2008">{{cite journal | vauthors = Okuno T, Iizuka Y, Okazaki H, Yokomizo T, Taguchi R, Shimizu T | title = 12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic acid is a natural ligand for leukotriene B4 receptor 2 | journal = The Journal of Experimental Medicine | volume = 205 | issue = 4 | date = Apr 2008 | pmid = 18378794 | doi = 10.1084/jem.20072329 | pages=759–66 | pmc=2292216}}</ref> Thus, the most recently discovered ligand, 12-HHT, which does not bind to BLT1 receptors, shows by far the highest affinity of all of the tested ligands for BLT2 receptors.  Among these 7 ligand, in contrast, BLT1 binds and is activated by only LTB4 and 20-hydroxy-LTB4.

The two BLT4-like receptors in Zebrafish, Blt2a and Blt2b, when transfected into [[chinese hamster ovary cell]]s, mediate rises in cytosolic calcium responses to both 12-HHT and LTB4 with 12-HHT being about 500- to 1000-fold stronger that LTB4 in doing so; 12-HHT is inactive in this assay in chinese hamster ovary cells made to express the Zebrafish LTB4 receptor-1 (Blt1).<ref name="ReferenceC"/> Thus, BLT1 receptor exhibits exquisite specificity, binding 5(''S''),12(''R'')-dihydroxy-6''Z'',8''E'',10''E'',14''Z''-eicosatetraenoic acid (i.e. LTB4) but not LTB4's 12(''S'') or 6''Z'' isomers whereas the BLT2 receptor exhibits a binding pattern that includes ''S'' and ''R'' [[stereoisomers]], aracidonic acid metabolites composed of 17 and 20 carbons, and metabolites with a [[hydroxyl]] residue at the 5, 12, or 15 position.  BLT2's binding pattern can only be considered as promiscuous.<ref name="Yokomizo_2015"/>  This promiscuous binding pattern complicates determination of which arachidonic acid metabolite and which metabolite-forming oxygenase (i.e. cyclooxygenase or lipoxygenase) is responsible for any given BLT2-dependent response.  These determinations are often critical to defining the full mechanisms involved in, as well as the means for inhibiting or promoting, the functions of BLT2.

Based on the rather large structural differences in the known BLT2 receptor ligands, there may be other as yet undefined ligands that bind to and activate this receptor.  For example, the [[Formyl peptide receptor 2]] (FPL2 receptor) was initially suggested to be a second receptor with ~70% amino acid identity to [[Formyl peptide receptor 1]] (FPL1 receptor).  Both receptor types bind and are activated by a series of formylated oligopeptide [[chemotactic factors]] but FLP2 receptor appears to be a promiscuous receptor in that it also binds to and is activated by [[lipoxin]]s and [[resolvin]]s as well as various polypeptides and proteins.  The FLP2 receptor appears to be engaged primarily in dampening and resolving inflammation responses, actions which appear to be diametrically opposite to the pro-inflammatory actions of FLP1 receptors.

== Btr2 Knockout mice ==
The expression of Blt2 receptors in mice appears limited to fewer tissues than the BLT2 receptor in humans; Blt1 is robustly expressed only in mouse small intestine and skin.<ref name="pmid24588652"/><ref name="Watanabe M 2014"/><ref name="url_BLT_UPHAR_BPS">{{cite web | url = http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=268 | title = BLT<sub>2</sub> receptor &#124; Leukotriene receptors &#124; | work = IUPHAR/BPS Guide to PHARMACOLOGY | first1 = Takehiko | last1 = Yokomizo | first2 =  Magnus Bäck | last2 =  Sven-Erik | last3 =  Dahlén | first3 =  Jeffrey | last4 = Drazen | first4 = Jilly F. | last5 = Evans | first5 =  G. Enrico | last6 = Rovati | first6 =  Takao | last7 = Shimizu | first7 =  Charles N.| last8 =  Serhan | name-list-format = vanc }}</ref>  LTB4R2 [[knockout]] mouse studies, therefore, may reveal a more limited role for the BLT2 receptor than that in humans.

BLT2 receptor knockout mice exhibit attenuated ovalbumen-induced allergic airway eosinophilia and [[Interleukin 13]] (IL-13) content in their [[bronchoalveolar lavage]] fluid compared with [[wild type]] mice and CD4-positive T cells isolated from the knockout mice showed a reduction IL-13 production but there was no change in the bronchospasm response to ovalbumin in these mice.<ref>{{cite journal | vauthors = Matsunaga Y, Fukuyama S, Okuno T, Sasaki F, Matsunobu T, Asai Y, Matsumoto K, Saeki K, Oike M, Sadamura Y, Machida K, Nakanishi Y, Kubo M, Yokomizo T, Inoue H | title = Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia | journal = FASEB Journal | volume = 27 | issue = 8 | date = Aug 2013 | pmid = 23603839 | doi = 10.1096/fj.12-217000 | pages=3306–14}}</ref>  The BLT2 receptor ligand(s) and metabolic pathway(s) producing this ligand(s) were not identified.  These results indicate that the Blt2 receptor functions to promote the eosinophilic-base inflammation which accompanies and may contribute to allergic lung disease; this effect may be do in part to its ability to reduce production of the pro-allergic cytokine, IL-13; the receptor does not appear to be responsible for allergen-induced bronchospasm.  BLT2 receptor could play a similar role in human allergic diseases such as [[asthma]].

In response to the oral administration of the [[inflammation]]-inducer [[dextran]] sodium sulfate, Blt2 receptor knockout mice, compared to wild type or Blt1 receptor knockout mice, exhibited: a) more severe colitis inflammation and body weight loss; b) increased [[mRNA]] expression for the pro-inflammatory cytokines [[interferon-γ]], [[IL1B]], and [[Interleukin 6]], two pro-inflammatory [[chemokines]] viz., chemokine ligand 9 (also termed [[chemokine ligand 10]]) and chemokine 19 ([[CCL19]]), and [[metalloproteinases]]-3, -10, and -13 in inflamed colon tissues; c) enhanced accumulation of [[interferon]]-producing macrophages in affected colon tissues; d) increased phosphorylation of signal transducer and activator of transcription 3 (i.e. [[STAT3]]) in the crypts of affected colon tissue; and e) reduced colon [[mucosa]] integrity and barrier function as deduced from the effects of in vitro studies on the impact of BLT2 receptor expression on leakage of FITC-dextran in Madin-Darby canine kidney II cells.  These results suggest that Blt2 receptors normally function to suppress colon inflammation in mice; based on its mass content in affected colon tissues, 12-HHT appears at least partly responsible for maintaining this function by stimulating Blt2 receptors.<ref>{{cite journal | vauthors = Iizuka Y, Okuno T, Saeki K, Uozaki H, Okada S, Misaka T, Sato T, Toh H, Fukayama M, Takeda N, Kita Y, Shimizu T, Nakamura M, Yokomizo T | title = Protective role of the leukotriene B4 receptor BLT2 in murine inflammatory colitis | journal = FASEB Journal | volume = 24 | issue = 12 | date = Dec 2010 | pmid = 20667973 | doi = 10.1096/fj.10-165050 | pages=4678–90}}</ref>  A similar role for the 12-HHT-BLT2 axis could occur in humans and be relevant to diseases such as [[ulcerative colitis]] and [[Crohn's disease]].

LTB4R1 gene knockout provides complete protection from the joint inflammation occurring in a mouse model of rheumatoid arthritis (collagen-induced arthritis); double knockout of LTB4R1 snf LTB4R2 genes did not alter the complete protection afforded by LTB4R1 knockout.<ref name = "Shao_2006">{{cite journal | vauthors = Shao WH, Del Prete A, Bock CB, Haribabu B | title = Targeted disruption of leukotriene B4 receptors BLT1 and BLT2: a critical role for BLT1 in collagen-induced arthritis in mice | journal = Journal of Immunology | volume = 176 | issue = 10 | date = May 2006 | pmid = 16670336 | pages=6254–61 | doi=10.4049/jimmunol.176.10.6254}}</ref> Further evidence for the role of BLT2 in arthritis was seen in a model of serum transfer arthritis where loss of BLT2 led to weakened inflammation and damage to joints.<ref>{{cite journal|last1=Mathis|first1=Steven|title=Nonredundant roles for leukotriene B4 receptors BLT1 and BLT2 in inflammatory arthritis|journal=Journal of Immunology|date=Sep 1, 2010|volume=185|issue=5|pages=3049–3056|doi=10.4049/jimmunol.1001031|pmid=20656922}}</ref>

Thus, the knockout studies available to date assign BLT2 receptors a protective role in dampening certain allergic and inflammatory responses; this role contrasts with the assignment of BLT1 receptors as contributing to both these types of responses.<ref name = "Shao_2006"/><ref>{{cite journal | vauthors = Miyahara N, Takeda K, Miyahara S, Matsubara S, Koya T, Joetham A, Krishnan E, Dakhama A, Haribabu B, Gelfand EW | title = Requirement for leukotriene B4 receptor 1 in allergen-induced airway hyperresponsiveness | journal = American Journal of Respiratory and Critical Care Medicine | volume = 172 | issue = 2 | date = Jul 2005 | pmid = 15849325 | doi = 10.1164/rccm.200502-205OC | pages=161–7 | pmc=2718465}}</ref> More study is needed to determine if BLT2 receptors protect against other allergic and inflammatory responses and if they function similarly in humans.

== Bltr2 transgenic mice ==
The overexpression of BLT2 receptors in Bltr2 transgenic mice enhances the ability of subcutaneously injected LTB4 and 12-HETE to stimulate new blood vessel formation in skin. Studies indicate that the actions of both ligands were mediated by Blt2 receptors and, that [[Vascular endothelial growth factor]] (VEGF) stimulated BLT2 expression and 12-HETE production in [[Human umbilical vein endothelial cell]]s (HUVEC), and that BLT2 receptor or 12-lipoxygenase knockdown inhibited VEGF-induced angiogenesis in in vitro assays.<ref>{{cite journal | vauthors =  Kim GY, Lee JW, Cho SH, Seo JM, Kim JH| date = Jun 2009 | title =  Role of the Low-Affinity Leukotriene B4 Receptor BLT2 in VEGF-Induced Angiogenesis| url = | journal = Arterioscler Thromb Vasc Biol | volume = 29 | issue = 6| pages = 915–20 | doi = 10.1161/ATVBAHA.109.185793 | pmid=19286633}}</ref>  These results suggest tha BLT2 receptors play critical roles in the development of VEGF-induced neovascularization and are of particular interest to the roles of BLT2 receptors in the growth and spread of cancers and in inflammation (see below).

== Activities and clinical significance ==

=== Allergic airways disesase ===

Mouse bone marrow [[mast cells]] and human [[eosinophils]] exhibit in vitro [[chemotaxis]] responses to 12-HHT.<ref>{{cite journal | vauthors = Okuno T, Iizuka Y, Okazaki H, Yokomizo T, Taguchi R, Shimizu T | title = 12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic acid is a natural ligand for leukotriene B4 receptor 2 | journal = The Journal of Experimental Medicine | volume = 205 | issue = 4 | pages = 759–66 | date = Apr 2008 | pmid = 18378794 | doi = 10.1084/jem.20072329 | pmc=2292216}}</ref><ref name="ReferenceA">{{cite journal | vauthors = Goetzl EJ, Gorman RR | title = Chemotactic and chemokinetic stimulation of human eosinophil and neutrophil polymorphonuclear leukocytes by 12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) | journal = Journal of Immunology | volume = 120 | issue = 2 | pages = 526–31 | date = Feb 1978 | pmid = 621391 }}</ref>  Since both cell types are implicated in allergic reactions, this suggests that BLT2 receptors could contribute to allergic responses in mice and humans.  However, in a mouse model of ovalbumin-induced allergic airway disease: '''a)''' 12-HHT and its companion cyclooxygenase metabolites, [[Prostaglandin E2]] and [[Prostaglandin D2]], but not 12 other lipoxygenase or cyclooxygenase metabolites showed a statistically significantly increase in bronchoalveolar lavage fluid levels after intratracheal ovalbumin challenge; '''b)''' only 12-HHT, among the monitored BLT2 receptor-activating ligands (i.e. LTB4, the 12(''S'') stereoisomer of [[12-HETE]], and 15(''S'')-HETE) rose to a level capable of activating BLT2 receptors; and '''c)''' BLT2 [[knockout]] mice exhibited a greatly ''enhanced'' response to ovalabumin challenge.<ref>{{cite journal | vauthors = Matsunaga Y, Fukuyama S, Okuno T, Sasaki F, Matsunobu T, Asai Y, Matsumoto K, Saeki K, Oike M, Sadamura Y, Machida K, Nakanishi Y, Kubo M, Yokomizo T, Inoue H | title = Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia | journal = FASEB Journal | volume = 27 | issue = 8 | pages = 3306–14 | date = Aug 2013 | pmid = 23603839 | doi = 10.1096/fj.12-217000 }}</ref> This study also found that the expression of BLT2 receptors was significantly reduced in [[CD4+ T cell]]s (which are known to mediate allergy-reactions) taken from asthmatic compared to non-asthmatic human controls.  Thus, BLT2 receptors suppress allergic airways disease in mice and may function similarly in humans. These studies also allow that BLT2 receptors play suppressive functions in other allergic diseases.

=== Inflammation ===
The high affinity BLT2 receptor agonist, 12-HHT, stimulates in vitro chemotactic responses in human [[neutrophil]]s,<ref name="ReferenceA"/> suggesting that this receptor, similar to BLT1 receptors, contributes to inflammation by recruiting circulating blood neutrophils to disturbed tissue sites.<ref name="ReferenceB">{{cite journal | vauthors = Yokomizo T | title = Two distinct leukotriene B4 receptors, BLT1 and BLT2 | journal = Journal of Biochemistry | volume = 157 | issue = 2 | pages = 65–71 | date = Feb 2015 | pmid = 25480980 | doi = 10.1093/jb/mvu078 }}</ref>  Other studies, however, indicate that the role of BLT2 receptors in inflammation is directed toward other cell types than neutrophils and differs very much from that of BLT1 receptors.  Immortalized human skin [[keratinocyte]] [[HaCaT]] cells respond to [[ultraviolet B]] (UVB) radiation by generating toxic [[reactive oxygen species]] which in turn triggers the cells to become [[apoptotic]] and eventually die.  This response is BLT2 receptor-dependent since '''a)''' topical treatment of mouse skin with a BLT2 receptor antagonist, LY255283, protects against UVB radiation-induced apoptosis; '''b)''' BLT2-overexpressing transgenic mice exhibit more extensive skin apoptosis in response to UVB irradiation that [[wild type]] mice;<ref>{{cite journal | vauthors = Ryu HC, Kim C, Kim JY, Chung JH, Kim JH | title = UVB radiation induces apoptosis in keratinocytes by activating a pathway linked to "BLT2-reactive oxygen species" | journal = The Journal of Investigative Dermatology | volume = 130 | issue = 4 | pages = 1095–106 | date = Apr 2010 | pmid = 20090768 | doi = 10.1038/jid.2009.436 }}</ref> and '''c)''' 12-HHT inhibits HaCaT cells from synthesizing the pro-inflammation mediator, [[interleukin-6]] (IL-6), in response to UVB radiation.<ref>{{cite journal | vauthors = Lee JW, Ryu HC, Ng YC, Kim C, Wei JD, Sabaratnam V, Kim JH | title = 12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid suppresses UV-induced IL-6 synthesis in keratinocytes, exerting an anti-inflammatory activity | journal = Experimental & Molecular Medicine | volume = 44 | issue = 6 | pages = 378–86 | date = Jun 2012 | pmid = 22391335 | doi = 10.3858/emm.2012.44.6.043 | pmc=3389076}}</ref>  Furthermore, BLT2 receptor knock-out mice mount of more severe intestinal inflammation response to dextran sodium sulfate than either wild type or BLT1 receptor knockout mice (see Knockout studies).  Thus, BLT2 receptors appear responsible for suppressing UVB-induced skin inflammation and, in contrast to BLT1 receptors, oppose the development and thereby dampen the severity of experimental colitis in mice.

=== Cancer ===
The [[Ras subfamily]] of [[small GTPase]]s function as [[Signal transduction]] proteins by transmitting the presence of extracellular stimuli into inducing the expression of genes which regulate cellular survival, proliferation, differention, adherence to [[extracellular matrix]], and motility as well as factors that are released to promote new blood vessel formation (i.e. [[Neovascularization]]) and to alter the extracellular matrix; the three members of this subfamily, [[KRAS]], NRAS (i.e. [[Neuroblastoma RAS viral oncogene homolog]]), and [[HRAS]], develop [[point mutations]] to become [[oncogenes]] that drive the growth and spread of some 20% of all human cancers.<ref>{{cite journal | vauthors = Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D | title = RAS oncogenes: weaving a tumorigenic web | journal = Nature Reviews. Cancer | volume = 11 | issue = 11 | pages = 761–74 | date = Nov 2011 | pmid = 21993244 | doi = 10.1038/nrc3106 | pmc=3632399}}</ref><ref>{{cite journal | vauthors = Downward J | title = RAS Synthetic Lethal Screens Revisited: Still Seeking the Elusive Prize? | journal = Clinical Cancer Research | volume = 21 | issue = 8 | date = Apr 2015 | pmid = 25878361 | doi = 10.1158/1078-0432.CCR-14-2180 | pages=1802–9 | pmc=4413026}}</ref>  The highest levels of Ras mutations are found in adenocarcinoma of the pancreas (90%), colon (50%), and lung (30%)<ref>{{cite journal | vauthors = Bos JL | year = 1989 | title = Ras oncogenes in human cancer: A review | url = | journal = Cancer Res | volume = 49 | issue = | pages = 4682–4689 }}</ref> Bos, 1989).

Race oncogenes can stimulate arachidonic acid metabolitsm: '''a)''' HRAS, in a rat intestinal epithelial cell line, and KRAS, in a rat lung epithelial cell line, up-regulate COX2 expression and prostglandin synthesis;<ref>{{cite journal | vauthors = Sheng H, Williams CS, Shao J, Liang P, DuBois RN, Beauchamp RD | title = Induction of cyclooxygenase-2 by activated Ha-ras oncogene in Rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway | journal = The Journal of Biological Chemistry | volume = 273 | issue = 34 | pages = 22120–7 | date = Aug 1998 | pmid = 9705357 | doi=10.1074/jbc.273.34.22120}}</ref><ref>{{cite journal | vauthors = Backlund MG, Mann JR, Wang D, Dubois RN | title = Ras up-regulation of cyclooxygenase-2 | journal = Methods in Enzymology | volume = 407 | pages = 401–10 | pmid = 16757341 | doi = 10.1016/S0076-6879(05)07033-3 | year=2006}}</ref><ref>{{cite journal | vauthors = Wang XQ, Li H, Van Putten V, Winn RA, Heasley LE, Nemenoff RA | title = Oncogenic K-Ras regulates proliferation and cell junctions in lung epithelial cells through induction of cyclooxygenase-2 and activation of metalloproteinase-9 | journal = Molecular Biology of the Cell | volume = 20 | issue = 3 | pages = 791–800 | date = Feb 2009 | pmid = 19037103 | doi = 10.1091/mbc.E08-07-0732 | pmc=2633382}}</ref> '''b)''' HRAS induces 12-lipoxygenase in the human epidermoid carcinoma [[A431 cells]];<ref>Biochim Biophys Acta. 1997 Feb 18;1344(3):270-7</ref> and '''c)''' HRAS stimulates the expression of 5-lipoxygenase, [[5-lipoxygenase-activating protein]], LTB4, and BLT2 receptors Rat2 and a rat [[fibroblast]] cell lines thereby increasing the tumor-forming ability the latter cell line in athymic mice.<ref name = "Yoo_2004">{{cite journal | vauthors = Yoo MH, Song H, Woo CH, Kim H, Kim JH | title = Role of the BLT2, a leukotriene B4 receptor, in Ras transformation | journal = Oncogene | volume = 23 | issue = 57 | date = Dec 2004 | pmid = 15489890 | doi = 10.1038/sj.onc.1208151 | pages=9259–68}}</ref>  These studies suggest that the metabolites of cyclooxygenase, 5-lipoxygenase, and 12-lipoxygenase, i.e. 12-HHT, LTB4, and 12-HTE, respectively, may act through BLT2 receptors to contribute to the growth and spread of cancers initiated and/or oncogenic Ras and possibly other oncogenes.  This is supported by findings that BLT2 is abnormally expressed in many human cancers that concurrently overexpress these arachidonic acid metabolizing pathways viz., follicular [[thyroid adenoma]], [[Renal cell carcinoma]], urinary bladder [[Transitional cell carcinoma]], esophagus [[squamous cell carcinoma]], [[colon adenocarcinoma]], the [[Serous cystadenocarcinoma]] type of [[ovarian cancer]], and uterine [[cervical carcinoma]].<ref name = "Yoo_2004"/>  Other studies have implicated BLT4 in these and other types of cancer as follows.

==== Prostate cancer ====

12-HHT stimulates the [[PC3]] human [[prostate cancer]] cell line to activate several pro-growth and/or pro-survival signaling pathways including [[protein kinase B]], [[phosphoinositide 3-kinase]], [[protein kinase C]], [[proto-oncogene tyrosine-protein kinase Src]], and (by inducing the proteolytic cleavage and release of a ligand for the [[Epidermal growth factor receptor]] [EGFR] receptor from [[HB-EGF]]), EGFR.<ref>{{cite journal | vauthors = Li X, Wei J, Tai HH | title = Activation of extracellular signal-regulated kinase by 12-hydroxyheptadecatrienoic acid in prostate cancer PC3 cells | journal = Archives of Biochemistry and Biophysics | volume = 467 | issue = 1 | date = Nov 2007 | pmid = 17880908 | doi = 10.1016/j.abb.2007.08.005 | pages=20–30}}</ref>  When detached from surfaces, cultured non-malignant PWR-1E and PC3 prostate cancer cells die by engaging suicidal [[apoptosis]] pathways, a reaction termed [[anoikis]].  This is accompanied by increased expression of BLT2 receptors, activation of [[NADPH oxidase]] (NOX), increases in NOX-mediated production of [[reactive oxygen species]] (ROS), and ROS-induced activation of the pro-survival transcription factor, [[NF-κB]].  Ectopic expression and stimulation of BLT2 receptors by 12(''S'')-HETE or a synthetic BLT2 receptor agonist, CAY-10583, inhibits whereas [[Gene knockdown]] by [[mRNA]] interference or pharmacological inhibition by LY255283 enhances these cells' anoikis response to surface detachment.<ref name="pmid24588652"/> Unlike PC-3 cells, [[LNCaP]] and CWR22rv-1 human prostate cancer cell lines require exogenous [[androgen]] for their survival; this mimics the androgen dependency exhibited by most human prostate cancers in their early, untreated stages.  Both cell lines overexpress BLT2 receptors compared to the PWR-1E non-malignant human prostate cell line.  Treatment with the BLT2 receptor antagonist, Ly255283, caused both cell lines to become apoptotic; furthermore, BLT2 receptor knockdown using interference mRNA caused LNCaP but not PWR-1E cell apoptosis.  The effect appears due to the loss of BLT2-induced [[NOX4]] generation, consequential reactive oxygen species-induced NF-κB-activation, and NF-κB-stimulated expression of androgen receptors.<ref>{{cite journal | vauthors = Lee JW, Kim GY, Kim JH | title = Androgen receptor is up-regulated by a BLT2-linked pathway to contribute to prostate cancer progression | journal = Biochemical and Biophysical Research Communications | volume = 420 | issue = 2 | date = Apr 2012 | pmid = 22426480 | doi = 10.1016/j.bbrc.2012.03.012 | pages=428–33}}</ref> 12-HETE also increases the survival of PC-3 cells by helping to maintain high levels of phosphorylated Rb [[retinoblastoma protein]], an effect which reduces the ability of retinoblastoma protein to inhibit the synthesis of DNA and thereby cell division.<ref>{{cite journal | vauthors = Yang P, Cartwright C, Chan D, Vijjeswarapu M, Ding J, Newman RA | title = Zyflamend-mediated inhibition of human prostate cancer PC3 cell proliferation: effects on 12-LOX and Rb protein phosphorylation | journal = Cancer Biology & Therapy | volume = 6 | issue = 2 | date = Feb 2007 | pmid = 17218785 | pages=228–36 | doi=10.4161/cbt.6.2.3624}}</ref> Finally, 12-lipoxygenase is overexpressed and the mass of 12-HETE is far higher in human prostate cancer than nearby normal prostate tissue;<ref>{{cite journal | vauthors = Yang P, Cartwright CA, Li J, Wen S, Prokhorova IN, Shureiqi I, Troncoso P, Navone NM, Newman RA, Kim J | title = Arachidonic acid metabolism in human prostate cancer | journal = International Journal of Oncology | volume = 41 | issue = 4 | date = Oct 2012 | pmid = 22895552 | doi = 10.3892/ijo.2012.1588 | pages=1495–503 | pmc=3982713}}</ref> These findings suggest that BLT4 receptors operate to promote the survival, growth, and spread of human prostate cancer It remains unclear which if any of its 12-HHT, LTB4, and/or 12-HETE ligands mediate BLT2 receptor activation in the human disease.

==== Uninary bladder cancer ====

LTB4 and 12(S)-HETE stimulate the invasivenes in an in vitro Matrigel invasion assay of highly malignant human 253 J-BV unirnary bladder cancer cell; their activity in this assay is completely inhibited by an pharmacological inhibition or siRNA knockdown of BLT2 receptors. The expression of 5-lipoxygenase, [[5-lipoxygenase-activating protein]], 12-lipoxygenase (enzymes synthesizing LTB4 and 12(S)-HETE, respectively) as wells as LTB4 and 12(S)-HETE were substantially elevated in these cells.  Pretreatment of these cells with an inhibitor of BLT2 receptos, reduced their tumor forming ability after injection into mice; intraperetoneal injections of LY255283 into the mice also decreased the metastasis-forming ability of the cells after injection in the urinary bladder.  Finally, BLT2 receptor protein was over expressed by the malignant tissues of human urinary bladder cancer and this expression was positively associated with the severity of this cancer.  The action of BLT2 receptors, similar to their actions on prostate cancer cells, appeared to involve the receptors activation of the NOX, reactive species of oxygen, NK-κB pathway.<ref>{{cite journal | vauthors = Kim EY, Seo JM, Kim C, Lee JE, Lee KM, Kim JH | title = BLT2 promotes the invasion and metastasis of aggressive bladder cancer cells through a reactive oxygen species-linked pathway | journal = Free Radical Biology & Medicine | volume = 49 | issue = 6 | date = Sep 2010 | pmid = 20600831 | doi = 10.1016/j.freeradbiomed.2010.06.023 | pages=1072–81}}</ref><ref>{{cite journal | vauthors = Seo JM, Cho KJ, Kim EY, Choi MH, Chung BC, Kim JH | title = Up-regulation of BLT2 is critical for the survival of bladder cancer cells | journal = Experimental & Molecular Medicine | volume = 43 | issue = 3 | date = Mar 2011 | pmid = 21252614 | doi = 10.3858/emm.2011.43.3.014 | pages=129–37 | pmc=3068295}}</ref> These results suggest that BLT2 receptors contribute to the aggressiveness and progression of human urinary bladder cancer.

==== Breast cancer ====

Compared to non-malignant [[IMR-90]] and immortalized but non-malignant [[MCF-10A]] human breast cancer cell lines, [[MCF-7]], [[ZR-75-1]], [[T47-D]], [[MDA-MB-231]], [[MDA-MB-468]], [[MDA-MB-453]], and [[SK-BR-3]] human breast cancer cell lines (see [[list of breast cancer cell lines]]) overexpress BLT2 mRNA and protein but show relatively little expression of BLT1 mRNA; treatment of the malignant but not non-malignant cells with a BLT2 antagonist, LY255283, but not a BLT1 antagonist, U75302, blocked proliferation of the cells in culture.  LY255283 concurrently caused apoptosis in [[estrogen receptor negative]] [[MDA-MB-468]] and [[MDA-MB-453]] but not [[estrogen receptor positive]] [[MCF-7]] and [[T47-D]] malignant cells.  Since LY255283 also inhibits the BLT1 receptor, the apoptosis-inhibiting action of BLT2 receptors was also demonstrated by showing that [[siRNA]]-induced transient [[Gene knockdown]] of BLT2 receptors caused appotosis in the [[MDA-MB-468]] cell line.  BLT2 receptors link to the activation of the [[NADPH oxidase]], [[NOX1]] (a synthesizer of the [[Superoxide]] anion which is a [[reactive oxygen species]] that, when inappropriately overproduced, causes cell death and tissue injury); the attendant increased production of [[reactive oxygen species]] and activation of [[NF-κB]] appeared responsible for these BLT-2 receptor dependent effects.<ref name="Choi JA p203">{{cite journal | vauthors = Choi JA, Lee JW, Kim H, Kim EY, Seo JM, Ko J, Kim JH | title = Pro-survival of estrogen receptor-negative breast cancer cells is regulated by a BLT2-reactive oxygen species-linked signaling pathway | journal = Carcinogenesis | volume = 31 | issue = 4 | date = Apr 2010 | pmid = 19748928 | doi = 10.1093/carcin/bgp203 | pages=543–51}}</ref>  [[Lipopolysaccharide]] (i.e. [[endotoxin]]) stimulates [[MDA-MB-231]] and [[MDA-MB-435]] cells to increase their invasiveness as determined with in vitro Matrigel Invasion Chamber assays; this effect appears due to the its ability to induce the overexpression of BLT2 receptors, the enzymes which produce LTB4 and 12(''S'')-HETEs, and the key metabolites of these enzymes, LTB4 and 12(''S'')-HETE; furthermore, the latter the binding of the latter metabolites to cells overexpressed BLT2 receptors leads to the activation of NF-κB.<ref>{{cite journal | vauthors = Park GS, Kim JH | title = Myeloid differentiation primary response gene 88-leukotriene B4 receptor 2 cascade mediates lipopolysaccharide-potentiated invasiveness of breast cancer cells | journal = Oncotarget | volume = 6 | issue = 8 | date = Mar 2015 | pmid = 25691060 | pages=5749–59 | doi=10.18632/oncotarget.3304 | pmc=4467399}}</ref>  These results indicate that the 12-HETE/BLT2 interaction reduces the survival of cultured human breast cells by stimulating the production of reactive oxygen species and the activation of NF-κB.

[[Epithelial–mesenchymal transition]], a process whereby epithelial cells assume a mesenchymal phenotype, is proposed to occur in a subset of cells in various cancer tissues to promote their movement from a tumor site into blood and lymphatic vessels and thereby form distant metastases.  Human breast cancer often expresses and appears promoted by Ras proteins (see [[carcinogenesis]] and the [[Ras subfamily]]).  The forced expression of oncogenic Ras in cultured human [[MCF-10A]] breast cancer cells markedly up-regulates BLT2 receptors and this up-regulation appears essential for the epithelial–mesenchymal transition-promoting ability of [[Transforming growth factor beta]] in these cells; BLT2 receptors in these cells appear to stimulate the production of reactive oxygen species and activation of NF-κB and may thereby contribute to the metastatic ability of breast cancer.<ref>{{cite journal | vauthors = Kim H, Choi JA, Kim JH | title = Ras promotes transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition via a leukotriene B4 receptor-2-linked cascade in mammary epithelial cells | journal = The Journal of Biological Chemistry | volume = 289 | issue = 32 | date = Aug 2014 | pmid = 24990945 | doi = 10.1074/jbc.M114.556126 | pages=22151–60 | pmc=4139228}}</ref>

Since BLT2 receptors are significantly elevated in human breast cancer tissue compared to non-cancerous breast tissue,<ref name="Choi JA p203"/> the cited studies, when taken together, indicate that BLT2 receptors promote the malignant growth, invasiveness, metastasis and possibly anti-cancer drug resistance of not only cultured human breast cancer cells but also of human breast cancer.

==== Ovarian cancer ====

Compared to CAOV-3 human ovarian cancer cells, SKOV-3 and CAOV-3 human ovarian cancer cells over express BLT4 receptors, LTB4 and 12-HETE metabolizing enzymes, two key metabolites of these enzymes, LTB4 and 12-HETE, and activated STAT3 also are far more invasive in animal models.  Inhibition of BLT2 receptors by LY255283 but not of BLT1 receptors by U75302 and suppression of BLT2 receptors by siRNA treatment reduced the expression of [[NOX4]] (i.e. NADPH oxidase 4, the reactive oxygen species made by this enzyme, activated STAT3, the invasion-promoting enzyme, [[MMP 2]], and the in vitro invasiveness (Matrigel invasion assay) of SKOV-3 and CAOV-3 cells.  LY255283 also inhibited the [[peritoneum]] metastasis of intra-peritoneal injected SKOV-3 cells in athymic mice.<ref>{{cite journal | vauthors = Seo JM, Park S, Kim JH | title = Leukotriene B4 receptor-2 promotes invasiveness and metastasis of ovarian cancer cells through signal transducer and activator of transcription 3 (STAT3)-dependent up-regulation of matrix metalloproteinase 2 | journal = The Journal of Biological Chemistry | volume = 287 | issue = 17 | date = Apr 2012 | pmid = 22396544 | doi = 10.1074/jbc.M111.317131 | pages=13840–9 | pmc=3340142}}</ref>  These studies indicate that the stimulation of BLT4 receptors by LTB4 and/or 12-HETE operate through a NOX4-reactive oxygen species-STAT-3-MMP2 pathway to promote the metastasis of SKOV-3 and CAOV-3 cancer cells in mice and may act similarly to promote metastases in human ovarian cancer.

==== Pancreatic cancer ====

BLT2 receptor protein and mRNA was found to be markedly elevated in human advanced pancreatic intraepithelial [[neoplasia]]s in their primary pancreas sites as well as in [[lymph node]] [[metastasis]] sites; mRNA for BLT1 was also elevated in these tissues but to a ~5-fold greater extent.  Both receptors' mRNA were also expressed in a wide range of human pancreas cancer cell lines with BLT1 receptor mRNA ~2-fold greater than that for BLT2.  The stable over expression of BLT2 in AsPC-1, Colo357, and [[PANC-1]] human pancreas cancer cell lines increased these cells' in vitro growth rates; specific BLT2 agonists also stimulated Colo367 and Panc-1 cell growth.<ref>{{cite journal | vauthors = Hennig R, Osman T, Esposito I, Giese N, Rao SM, Ding XZ, Tong WG, Büchler MW, Yokomizo T, Friess H, Adrian TE | title = BLT2 is expressed in PanINs, IPMNs, pancreatic cancer and stimulates tumour cell proliferation | journal = British Journal of Cancer | volume = 99 | issue = 7 | date = Oct 2008 | pmid = 18781173 | doi = 10.1038/sj.bjc.6604655 | pages=1064–73 | pmc=2567081}}</ref> BLT2 receptors mediated the in vitro migration of Panc-1 cells.<ref>{{cite journal | vauthors = Park MK, Park Y, Shim J, Lee HJ, Kim S, Lee CH | title = Novel involvement of leukotriene B₄ receptor 2 through ERK activation by PP2A down-regulation in leukotriene B₄-induced keratin phosphorylation and reorganization of pancreatic cancer cells | journal = Biochimica et Biophysica Acta | volume = 1823 | issue = 12 | pages = 2120–9 | date = Dec 2012 | pmid = 23017243 | doi = 10.1016/j.bbamcr.2012.09.004 }}</ref>   These results allow that BLT2 receptors may contribute to the malignant growth and metastasis of human pancreas cancer.

==== Colon cancer ====

The proliferation of [[Caco-2]] human epithelial colorectal adenocarcinoma cells in culture was stimulated by 12-HETE and inhibited by a somewhat selective inhibitor of 12-lipoxygenase, [[baicalein]]; the stimulatory effect of 12-HETE appeared due to its interaction with BLT2 receptors based on the effects of pharmacological inhibitors.<ref>{{cite journal | vauthors = Cabral M, Martín-Venegas R, Moreno JJ | title = Role of arachidonic acid metabolites on the control of non-differentiated intestinal epithelial cell growth | journal = The International Journal of Biochemistry & Cell Biology | volume = 45 | issue = 8 | pages = 1620–8 | date = Aug 2013 | pmid = 23685077 | doi = 10.1016/j.biocel.2013.05.009 }}</ref>

==== Esophageal cancer ====

Esophagus [[squamous cell carcinoma]] overexpresses BLT2 receptors.<ref name="pmid15489890">{{cite journal | vauthors = Yoo MH, Song H, Woo CH, Kim H, Kim JH | title = Role of the BLT2, a leukotriene B4 receptor, in Ras transformation | journal = Oncogene | volume = 23 | issue = 57 | pages = 9259–68 | year = 2004 | pmid = 15489890 | doi = 10.1038/sj.onc.1208151 }}</ref>

=== Other activities ===
The BLT2 receptor mediates the itch scratching behavior induced by intradermal injection of 12-HETE in mice.<ref>{{cite journal | vauthors = Kim HJ, Kim DK, Kim H, Koh JY, Kim KM, Noh MS, Lee S, Kim S, Park SH, Kim JJ, Kim SY, Lee CH | title = Involvement of the BLT2 receptor in the itch-associated scratching induced by 12-(S)-lipoxygenase products in ICR mice | journal = British Journal of Pharmacology | volume = 154 | issue = 5 | pages = 1073–8 | date = Jul 2008 | pmid = 18536755 | doi = 10.1038/bjp.2008.220 | pmc=2451041}}</ref>

== Antagonist ==
LY255283 has been presented as a "selective" BLT2 receptor antagonist.  However, this compound is also a BLT1 receptor agonists and therefore cannot be used to discriminate between these two receptor types.<ref name="ReferenceB"/>  In all of the studies using LY255283 quoted above, other methods, such as siRNA knockdown, were used in conjunction with LY255283 to identify BLT2-dependency.  Currently, there are no reports on selective BLT2 receptor antagonists.

== See also ==
* [[Eicosanoid receptor]]
* [[12-Hydroxyheptadecatrienoic acid]]
* [[12-Hydroxyeicosatetraenoic acid]]
* [[15-Hydroxyicosatetraenoic acid]]

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Tager AM, Luster AD | title = BLT1 and BLT2: the leukotriene B(4) receptors | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 69 | issue = 2–3 | pages = 123–34 | year = 2004 | pmid = 12895595 | doi = 10.1016/S0952-3278(03)00073-5 }}
* {{cite journal | vauthors = Kamohara M, Takasaki J, Matsumoto M, Saito T, Ohishi T, Ishii H, Furuichi K | title = Molecular cloning and characterization of another leukotriene B4 receptor | journal = The Journal of Biological Chemistry | volume = 275 | issue = 35 | pages = 27000–4 | date = Sep 2000 | pmid = 10889186 | doi = 10.1074/jbc.C000382200 }}
* {{cite journal | vauthors = Tryselius Y, Nilsson NE, Kotarsky K, Olde B, Owman C | title = Cloning and characterization of cDNA encoding a novel human leukotriene B(4) receptor | journal = Biochemical and Biophysical Research Communications | volume = 274 | issue = 2 | pages = 377–82 | date = Aug 2000 | pmid = 10913346 | doi = 10.1006/bbrc.2000.3152 }}
* {{cite journal | vauthors = Nilsson NE, Tryselius Y, Owman C | title = Genomic organization of the leukotriene B(4) receptor locus of human chromosome 14 | journal = Biochemical and Biophysical Research Communications | volume = 274 | issue = 2 | pages = 383–8 | date = Aug 2000 | pmid = 10913347 | doi = 10.1006/bbrc.2000.3153 }}
* {{cite journal | vauthors = Yokomizo T, Kato K, Terawaki K, Izumi T, Shimizu T | title = A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders | journal = The Journal of Experimental Medicine | volume = 192 | issue = 3 | pages = 421–32 | date = Aug 2000 | pmid = 10934230 | pmc = 2193217 | doi = 10.1084/jem.192.3.421 }}
* {{cite journal | vauthors = Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S | title = Identification of G protein-coupled receptor genes from the human genome sequence | journal = FEBS Letters | volume = 520 | issue = 1–3 | pages = 97–101 | date = Jun 2002 | pmid = 12044878 | doi = 10.1016/S0014-5793(02)02775-8 }}
* {{cite journal | vauthors = Hashimoto A, Endo H, Hayashi I, Murakami Y, Kitasato H, Kono S, Matsui T, Tanaka S, Nishimura A, Urabe K, Itoman M, Kondo H | title = Differential expression of leukotriene B4 receptor subtypes (BLT1 and BLT2) in human synovial tissues and synovial fluid leukocytes of patients with rheumatoid arthritis | journal = The Journal of Rheumatology | volume = 30 | issue = 8 | pages = 1712–8 | date = Aug 2003 | pmid = 12913925 | doi =  }}
* {{cite journal | vauthors = Yoo MH, Song H, Woo CH, Kim H, Kim JH | title = Role of the BLT2, a leukotriene B4 receptor, in Ras transformation | journal = Oncogene | volume = 23 | issue = 57 | pages = 9259–68 | date = Dec 2004 | pmid = 15489890 | doi = 10.1038/sj.onc.1208151 }}
* {{cite journal | vauthors = Qiu H, Johansson AS, Sjöström M, Wan M, Schröder O, Palmblad J, Haeggström JZ | title = Differential induction of BLT receptor expression on human endothelial cells by lipopolysaccharide, cytokines, and leukotriene B4 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 18 | pages = 6913–8 | date = May 2006 | pmid = 16624877 | pmc = 1440767 | doi = 10.1073/pnas.0602208103 }}
* {{cite journal | vauthors = Cho NK, Joo YC, Wei JD, Park JI, Kim JH | title = BLT2 is a pro-tumorigenic mediator during cancer progression and a therapeutic target for anti-cancer drug development | journal = American Journal of Cancer Research | volume = 3 | issue = 4 | pages = 347–55 | year = 2013 | pmid = 23977445 | pmc = 3744015 | doi =  }}
{{refend}}

== External links ==
* {{MeshName|LTB4R2+protein,+human}}
* {{MeshName|Receptors,+Leukotriene+B4}}

{{NLM content}}

{{G protein-coupled receptors}}
{{Prostanoidergics}}

[[Category:G protein-coupled receptors]]