title: G-CSF induced reactive oxygen species involves Lyn-PI3-kinase-Akt and contributes to myeloid cell growth.
abstract: Granulocyte colony-stimulating factor (G-CSF) drives the production, survival, differentiation, and inflammatory functions of granulocytes. Reactive oxygen species (ROSs) provide a major thrust of the inflammatory response, though excessive ROSs may be deleterious. G-CSF stimulation showed a time- and dose-dependent increase in ROS production, correlating with activation of Lyn and Akt. Inhibition of Lyn, PI3-kinase, and Akt abrogated G-CSF-induced ROS production. This was also blocked by DPI, a specific inhibitor of NADPH oxidase. Following G-CSF stimulation, neutrophils from Lyn-/- mice produced less ROSs than wild-type littermates. G-CSF induced both serine phosphorylation and membrane translocation of p47phox, a subunit of NADPH oxidase. Because patients with a truncated G-CSF receptor have a high risk of developing acute myeloid leukemia (AML), we hypothesized that dysregulation of ROSs contributes to leukemogenesis. Cells expressing the truncated G-CSF receptor produced more ROSs than those with the full-length receptor. G-CSF-induced ROS production was enhanced in bone marrow-derived neutrophils expressing G-CSFRdelta715, a truncated receptor. The antioxidant N-acetyl-L-cysteine diminished G-CSF-induced ROS production and cell proliferation by inhibiting Akt activation. These data suggest that the G-CSF-induced Lyn-PI3K-Akt pathway drives ROS production. One beneficial effect of therapeutic targeting of Lyn-PI3K-kinase-Akt cascade is abrogating ROS production.
authors.affiliation: Division of Pediatrics, University of Texas--M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Quan-Sheng
authors.initials: QS
authors.lastname: Zhu
authors.forename: Ling
authors.initials: L
authors.lastname: Xia
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Touw
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Corey
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology; D002460:Cell Line; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D016179:Granulocyte Colony-Stimulating Factor / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000111:Acetylcysteine; D004791:Enzyme Inhibitors; D016179:Granulocyte Colony-Stimulating Factor; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D019061:src-Family Kinases; C060505:neutrophil cytosolic factor 1; C060902:lyn protein-tyrosine kinase