Leukotriene B₄ receptor 2

Leukotriene B4 receptor 2, also known as BLT2, BLT2 receptor, and BLTR2, is an Integral membrane protein that is encoded by the LTB4R2 gene in humans and the Ltbr2 gene in mice.^[5][6][7]

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

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.^[11] The latter citation presents a phylogenic tree on the amino acid relatedness 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

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.[15]^[16][17] 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.^[17][18]

Ligands

While initially defined as a low affinity receptor for the

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.[17]^[18][21] 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.^[22] 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

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 and LTB4R2 genes did not alter the complete protection afforded by LTB4R1 knockout.[24] 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.^[25]

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.^[24][26] 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 cells (HUVEC), and that BLT2 receptor or 12-lipoxygenase knockdown inhibited VEGF-induced angiogenesis in in vitro assays.^[27] These results suggest that 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 disease

Mouse bone marrow

Inflammation

The high affinity BLT2 receptor agonist, 12-HHT, stimulates in vitro chemotactic responses in human

LTB4 and 12(S)-HETE stimulate the invasiveness in an in vitro Matrigel invasion assay of highly malignant human 253 J-BV urinary bladder cancer cell; their activity in this assay is completely inhibited by a 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 receptors, reduced their tumor forming ability after injection into mice; intraperitoneal 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.^[46][47] These results suggest that BLT2 receptors contribute to the aggressiveness and progression of human urinary bladder cancer.

Breast cancer

Compared to non-malignant

Since BLT2 receptors are significantly elevated in human breast cancer tissue compared to non-cancerous breast tissue,[48] 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

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.^[54]

Esophageal cancer

Esophagus

The BLT2 receptor mediates the itch scratching behavior induced by intradermal injection of 12-HETE in mice.[56]

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.^[31] 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