p85α subunit of class IA PI-3 kinase is crucial for macrophage growth and migration
p85α subunit of class IA PI-3 kinase is crucial for macrophage growth and migration
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DOI：
10.1182/blood-2004-10-4041
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发表时间：
2005-07-01
期刊：
影响因子：
20.3
通讯作者：
Kapur, R
中科院分区：
文献类型：
--
作者：
Munugalavadla, V;Borneo, J;Kapur, R
巨噬细胞通过迁移到感染部位、清除凋亡细胞和分泌炎症细胞因子，在防御入侵病原体方面发挥着重要作用。巨噬细胞调节这些过程的分子机制尚不清楚。使用骨髓来源的巨噬细胞； (BMM) 缺乏 IA 类磷脂酰肌醇 3 (PI-3) 激酶 p85 α 亚基的表达，我们证明与野生型对照相比，巨噬细胞集落刺激因子 (M-CSF) 以及粒细胞巨噬细胞集落刺激因子 (GM-CSF) 的增殖减少了 50%。此外，与野生型对照相比，p85 α(-/-) BMM 在伤口愈合测定中显示迁移显着减少。 BMM 中 p85 α 缺陷导致的迁移减少与纤连蛋白和血管细胞粘附分子 1 上的粘附和定向迁移减少有关。此外，BMM中p85α的缺乏也会导致绵羊红细胞的吞噬功能缺陷。从生化角度来看，BMMS 中 p85 α 的缺失会导致 Akt 和 Rac 的激活减少，但不会导致 Erk（细胞外信号相关激酶）丝裂原激活蛋白 (MAP) 激酶的激活减少。总而言之，我们的结果为 p85 α 在调节巨噬细胞中基于肌动蛋白和生长的功能的重要性提供了遗传证据，并为治疗涉及巨噬细胞的疾病（包括炎症）提供了潜在的治疗靶点。
Macrophages play an essential role in defending against invading pathogens by migrating to the sites of infection, removing apoptotic cells, and secreting inflammatory cytokines. The molecular mechanisms whereby macrophages regulate these processes are poorly understood. Using bone marrow-derived macrophages; (BMMs) deficient in the expression of p85 alpha-subunit of class IA phosphatidylinositol 3 (PI-3) kinase, we demonstrate 50% reduction in proliferation in response to macrophage-colony-stimulating factor (M-CSF) as well as granulocyte macrophage-colony-stimulatIng factor (GM-CSF) compared with wildtype controls. Furthermore, p85 alpha(-/-) BMMs demonstrate a significant reduction in migration in a wound-healing assay compared with wild-type controls. The reduction in migration due to p85 alpha deficiency in BMMs is associated with reduced adhesion and directed migration on fibronectin and vascular cell adhesion molecule-1. In addition, deficiency of p85 alpha in BMMs also results in defective phagocytosis of sheep red blood cells. Biochemically, loss of p85 alpha in BMMS results in reduced activation of Akt and Rac, but not Erk (extracellular signal-related kinase) mitogen-activated protein (MAP) kinase. Taken together, our results provide genetic evidence for the importance of p85 alpha in regulating both actin- and growth-based functions in macrophages, and provide a potential therapeutic target for the treatment of diseases involving macrophages, including inflammation.