Involvement of SHIP in TLR2-induced neutrophil activation and acute lung injury.
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.
Strassheim
Derek
D
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA. Derek.strassheim@uchsc.edu
Kim
Jae-Yeol
JY
Park
Jong-Sung
JS
Mitra
Sanchayita
S
Abraham
Edward
E
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D008168:Lung / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D010457:Peptidoglycan / Q000633:toxicity; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology*; D012720:Severity of Illness Index; D051195:Toll-Like Receptor 2; D051996:Transcription Factor RelA; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology
D016328:NF-kappa B; D010457:Peptidoglycan; D011518:Proto-Oncogene Proteins; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051996:Transcription Factor RelA; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases