Wang Yanxia, Zhang Lei, Wei Ping, Zhang Huailiang, Liu Cuijie
Department of Nephrology, General Hospital of Jinan Military Command, Jinan, 250031, China.
Inflammation. 2014 Jun;37(3):978-83. doi: 10.1007/s10753-014-9818-0.
Systemic lupus erythematosus (SLE) is an autoimmune disease accompanying excessive inflammatory responses. Phosphoinositide 3-kinase p110δ (PI3Kδ) is reported to associate with autoimmune conditions. We here aimed to determine whether selective inhibition of PI3Kδ is effective in a lupus model of BXSB mice, using the selective PI3Kδ inhibitor IC87114, which was intraperitoneally administrated to BXSB mice aged from 14 to 22 weeks. We showed that IC87114 improved renal function by decreasing the levels of proteinuria and serum creatinine, ameliorating the pathologic changes of kidneys and IgG and C3 deposition. Serum anti-autoantibody to nuclear antigen, anti-dsDNA, IL-1β, and IL-17 were markedly reduced by IC87114 therapy. Hepatic damage was also inhibited by administration of IC87114. Expression of phosphorylated AKT (p-AKT) and monocyte chemoattractant protein-1 was inhibited and mouse survival improved. In sum, PI3Kδ activation may be a critical factor for escalating autoimmune renal and hepatic damage, and its inhibition may alleviate the autoimmune damage. Our study reveals that the selective blockade of PI3Kδ is effective for mouse SLE.
系统性红斑狼疮（SLE）是一种伴有过度炎症反应的自身免疫性疾病。据报道，磷酸肌醇3激酶p110δ（PI3Kδ）与自身免疫性疾病有关。我们在此旨在确定使用选择性PI3Kδ抑制剂IC87114对BXSB小鼠狼疮模型进行选择性抑制PI3Kδ是否有效，该抑制剂经腹腔注射给14至22周龄的BXSB小鼠。我们发现，IC87114通过降低蛋白尿和血清肌酐水平、改善肾脏病理变化以及IgG和C3沉积来改善肾功能。IC87114治疗可显著降低血清抗核抗原自身抗体、抗双链DNA抗体、IL-1β和IL-17水平。给予IC87114还可抑制肝脏损伤。磷酸化AKT（p-AKT）和单核细胞趋化蛋白-1的表达受到抑制，小鼠存活率提高。总之，PI3Kδ激活可能是自身免疫性肾和肝损伤加剧的关键因素，抑制其活性可能减轻自身免疫性损伤。我们的研究表明，选择性阻断PI3Kδ对小鼠SLE有效。
