Shao Wen-Hai, Del Prete Annalisa, Bock Cheryl B, Haribabu Bodduluri
James Graham Brown Cancer Center, and Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, KY 40202, USA.
J Immunol. 2006 May 15;176(10):6254-61. doi: 10.4049/jimmunol.176.10.6254.
Leukotriene B(4) mediates diverse inflammatory diseases through the G protein-coupled receptors BLT1 and BLT2. In this study, we developed mice deficient in BLT1 and BLT2 by simultaneous targeted disruption of these genes. The BLT1/BLT2 double-deficient mice developed normally and peritoneal exudate cells showed no detectable responses to leukotriene B(4) confirming the deletion of the BLT1/BLT2 locus. 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. 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. Despite these differences, all immunized BLT1(-/-) and BLT1/BLT2(-/-) animals had similar serum levels of anti-collagen Abs relative to BLT1/BLT2(+/+) animals. Thus, BLT1 may be a useful target for therapies directed at treating inflammation associated with arthritis.
白三烯B4通过G蛋白偶联受体BLT1和BLT2介导多种炎症性疾病。在本研究中，我们通过同时靶向破坏这些基因，培育出了BLT1和BLT2基因缺陷的小鼠。BLT1/BLT2双缺陷小鼠发育正常，腹膜渗出细胞对白三烯B4无明显反应，证实了BLT1/BLT2基因座的缺失。在C57BL/6背景的胶原诱导性关节炎模型中，BLT1/BLT2(-/-)小鼠以及先前描述的BLT1(-/-)小鼠对疾病发展具有完全的保护作用。疾病严重程度与组织病理学密切相关，包括BLT1/BLT2(+/+)小鼠关节结构破坏、炎症细胞浸润、纤维化、血管翳形成和骨侵蚀，而白三烯受体缺陷小鼠则完全没有疾病病理表现。尽管存在这些差异，但相对于BLT1/BLT2(+/+)小鼠，所有免疫的BLT1(-/-)和BLT1/BLT2(-/-)小鼠血清中抗胶原蛋白抗体水平相似。因此，BLT1可能是治疗与关节炎相关炎症的有用靶点。
