Strassheim Derek, Kim Jae-Yeol, Park Jong-Sung, Mitra Sanchayita, Abraham Edward
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
J Immunol. 2005 Jun 15;174(12):8064-71. doi: 10.4049/jimmunol.174.12.8064.
The SHIP converts phosphatidylinositol 3,4,5 triphosphate to phosphatidyl 3,4 biphosphate. SHIP has negative regulatory functions on PI3K-dependent signaling pathways, which occupy important roles in modulating neutrophil functions. We used neutrophils from transgenic SHIP(-/-) and SHIP(+/+) mice that were stimulated with peptidoglycan (PGN) to examine the role of SHIP in TLR2-induced neutrophil activation. SHIP(-/-) neutrophils demonstrated significantly increased activation of the PI3K-dependent kinase Akt after exposure to PGN. Release of cytokines and chemokines, including TNF-alpha, IL-1beta, IL-6, IL-10, and MIP-2, was also increased in SHIP(-/-) compared with SHIP(+/+) neutrophils. There was no difference in the nuclear translocation of the transcriptional factor NF-kappaB between PGN-stimulated SHIP(-/-) and SHIP(+/+) neutrophils. However, phosphorylation of the p65 subunit of NF-kappaB, an event essential for optimal transcriptional activity of NF-kappaB, was increased in TLR2-activated SHIP(-/-) neutrophils. SHIP(-/-) neutrophils demonstrated greater activation of ERK1/2 and p38 MAPKs than did SHIP(+/+) neutrophils after exposure to PGN. The severity of acute lung injury induced by PGN was greater in SHIP(-/-) as compared with SHIP(+/+) mice. These results demonstrate that SHIP has a negative regulatory role in TLR2-induced neutrophil activation and in the development of related in vivo neutrophil-dependent inflammatory processes, such as acute lung injury.
SHIP将磷脂酰肌醇3,4,5 -三磷酸转化为磷脂酰3,4 -二磷酸。SHIP对PI3K依赖性信号通路具有负调控作用，而该信号通路在调节中性粒细胞功能中起重要作用。我们使用来自转基因SHIP(-/-)和SHIP(+/+)小鼠的中性粒细胞，用肽聚糖（PGN）刺激以研究SHIP在TLR2诱导的中性粒细胞活化中的作用。SHIP(-/-)中性粒细胞在暴露于PGN后，PI3K依赖性激酶Akt的活化显著增加。与SHIP(+/+)中性粒细胞相比，SHIP(-/-)中细胞因子和趋化因子的释放，包括TNF-α、IL-1β、IL-6、IL-10和MIP-2也增加。PGN刺激的SHIP(-/-)和SHIP(+/+)中性粒细胞之间转录因子NF-κB的核转位没有差异。然而，NF-κB最佳转录活性所必需的事件——NF-κB的p65亚基的磷酸化，在TLR2激活的SHIP(-/-)中性粒细胞中增加。暴露于PGN后，SHIP(-/-)中性粒细胞比SHIP(+/+)中性粒细胞表现出更强的ERK1/2和p38 MAPK活化。与SHIP(+/+)小鼠相比，PGN诱导的SHIP(-/-)小鼠急性肺损伤的严重程度更大。这些结果表明，SHIP在TLR2诱导的中性粒细胞活化以及相关的体内中性粒细胞依赖性炎症过程（如急性肺损伤）的发展中具有负调控作用。
