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Involvement of SHIP in TLR2-Induced Neutrophil Activation and Acute Lung Injury¹

Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262

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-, IL-1, 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-B between PGN-stimulated SHIP^–/– and SHIP^+/+ neutrophils. However, phosphorylation of the p65 subunit of NF-B, an event essential for optimal transcriptional activity of NF-B, 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.