Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia.

Leukotriene B4 (LTB4) has been implicated in the pathogenesis of allergic diseases. BLT2, a low-affinity LTB4 receptor, is activated by LTB4 and 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT). Although the high-affinity LTB4 receptor BLT1 has been shown to exert proinflammatory roles, the role of BLT2 in allergic inflammation has not been clarified. To study the function of BLT2 in development of asthma, we used mice model of ovalbumin (OVA)-induced allergic airway disease. The 12-HHT levels were elevated in bronchoalveolar lavage (BAL) fluids of OVA-sensitized/challenged wild-type mice. BLT2-deficient mice exhibited enhanced eosinophilia in BAL fluids after OVA exposure. Interleukin (IL)-13 levels in BAL fluids and IL-13-producing CD4(+) T cells in the lungs were elevated in BLT2-deficient mice compared to wild-type mice, whereas the levels of IL-4, IL-5, and interferon (IFN)-γ in BAL fluids and serum OVA-specific IgE were comparable. Transfection of BLT2-specific small interfering RNA enhanced IL-13 production in CD4(+) T cells in vitro. Expression of BLT2 mRNA in CD4(+) T cells was significantly reduced in patients with asthma compared to healthy control subjects. These findings indicate that BLT2 has a protective role in allergic airway inflammation and that diminished BLT2 expression in CD4(+) T cells may contribute to the pathophysiology of asthma.

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 ... -  《-》

A turn on and a turn off: BLT1 and BLT2 mechanisms in the lung.

Leukotriene B4 (LTB4), a potent lipid mediator of inflammation derived from arachidonic acid through the action of 5-lipoxygenase, has been implicated in the pathophysiology of several inflammatory diseases, including asthma and chronic obstructive pulmonary disease. A high-affinity LTB4 receptor BLT1 has been shown to exert proinflammatory roles. A cyclooxygenase metabolite, 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT), is an endogenous ligand for BLT2, a low-affinity LTB4 receptor. The recent study indicated that BLT2 has a protective role in allergic airway inflammation, suggesting different functions between BLT1 and BLT2 in the pathogenesis of asthma. Selective BLT1 antagonists may have a potential therapeutic application in patients with asthma, and BLT2 may represent a novel therapeutic target for lung diseases.

Watanabe M ，Machida K ，Inoue H 《-》

Nonredundant roles for leukotriene B4 receptors BLT1 and BLT2 in inflammatory arthritis.

Lipid mediators derived from arachidonic acid through the cyclooxygenase and lipoxygenase pathways are known to be important mediators of inflammation. Studies in mouse models demonstrated an important role for the high-affinity leukotriene B(4) receptor BLT1 in arthritis, atherosclerosis, and asthma. BLT2, a low-affinity leukotriene B(4) receptor, was also shown to be a high-affinity receptor for cyclooxygenase-1 derived 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid. However, its biochemical activities and physiological roles remain unknown. In this study, we developed mice deficient in BLT2 by targeted disruption. The BLT2(-/-) mice developed normally, and analysis of immune cells showed that disruption of BLT2 did not alter BLT1 expression or function. Mast cells from the C57BL/6 mice but not from the BLT2(-/-) mice showed intracellular calcium mobilization in response to 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid. In an autoantibody-induced inflammatory arthritis model, the BLT2(-/-) mice showed reduced incidence and severity of disease, including protection from bone and cartilage loss. Reciprocal bone marrow transplant experiments identified that loss of BLT2 expression on a bone marrow-derived cell lineage offers protection against severe disease. Thus, BLT2, a unique receptor for 5-lipoxygenase- and cyclooxygenase-1-derived lipid mediators, represents a novel target for therapies directed at treating inflammation associated with arthritis.

Mathis SP ，Jala VR ，Lee DM ，Haribabu B ... -  《-》

Inhibition of airway eosinophilia and pulmonary pathology in a mouse model of allergic asthma by the live vaccine strain of Francisella tularensis.

KuoLee R ，Zhou H ，Harris G ，Zhao X ，Qiu H ，Patel GB ，Chen W ... -  《-》

Anti-allergic activity of a Kampo (Japanese herbal) medicine "Sho-seiryu-to (Xiao-Qing-Long-Tang)" on airway inflammation in a mouse model.

Nagai T ，Arai Y ，Emori M ，Nunome SY ，Yabe T ，Takeda T ，Yamada H ... -  《INTERNATIONAL IMMUNOPHARMACOLOGY》