title: G-CSF downregulates natural killer cell-mediated cytotoxicity in donors for hematopoietic SCT.
abstract: In G-CSF-mobilized hematopoietic SCT (HSCT), natural killer (NK) cells have a critical role in GVHD and GVL effects. However, regulation of NK cell response to G-CSF remains unclear. This study assayed G-CSF effects in both HSCT donors and NK-92MI cells. The donors who received G-CSF had significantly decreased NK cell cytotoxicity. Levels of phosphatidylinositol 3-kinase (PI3K) and phosphorylated (p)-Akt, but not mammalian target of rapamycin (mTOR), were downregulated in NK cells from G-CSF-injected donors. G-CSF also decreased cytotoxicity without affecting viability and NF-κB of NK-92MI cells. PI3K and p-ERK expression were also decreased in G-CSF-treated NK-92MI cells, and their inhibitors, wortmannin and PD98059, respectively, both enhanced the downregulation of cytotoxicity. These effects were accompanied by decreased expression of a cytotoxicity-related gene, triosephosphate isomerase (TPI). Wortmannin, but not PD98059, enhanced the downregulation of TPI in G-CSF-treated NK-92MI cells, indicating a correlation between PI3K and TPI. We conclude that G-CSF-impaired NK cell cytotoxicity may accompany PI3K/Akt signaling. The effect is transient and NK cells may recover after G-CSF clearance, suggesting that G-CSF-mobilized HSCT may benefit both acute GVHD prevention and late-phase GVL promotion in HSCT recipients.
authors.affiliation: Department of Medicine, College of Medicine, Tzu Chi University, Hualien, Taiwan, ROC.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Su
authors.forename: S-C
authors.initials: SC
authors.lastname: Li
authors.forename: C-K
authors.initials: CK
authors.lastname: Hsu
authors.forename: C-C
authors.initials: CC
authors.lastname: Yu
authors.forename: T-J
authors.initials: TJ
authors.lastname: Lin
authors.forename: C-Y
authors.initials: CY
authors.lastname: Lee
authors.forename: H-F
authors.initials: HF
authors.lastname: Liao
mesh_terms: D000328:Adult; D000730:Androstadienes / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects* / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D020544:Graft vs Leukemia Effect / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008297:Male; D036102:Peripheral Blood Stem Cell Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D014019:Tissue Donors; D014305:Triose-Phosphate Isomerase / Q000096:biosynthesis / Q000276:immunology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D016179:Granulocyte Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014305:Triose-Phosphate Isomerase; D000077191:Wortmannin; C546842:MTOR protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one