Granulocyte-colony-stimulatory factor: a strong inhibitor of natural killer cell function.
BACKGROUND
The human cytokine granulocyte-colony stimulatory factor (G-CSF) has found widespread application in the medical treatment of neutropenia and to mobilize hematopoietic stem cells used for transplantation. So far, the effect of G-CSF on natural killer (NK) cells has not been fully investigated.


METHODS
The effect of G-CSF on the phenotype, cytokine secretion profile, and cytotoxicity of NK cells was assessed. NK cells incubated in vitro in presence of G-CSF for 48 hours as well as NK cells isolated from peripheral blood of G-CSF-mobilized stem cell donors (in vivo) were used.


RESULTS
In vitro, G-CSF caused a strongly altered phenotype in NK cells with 49% down regulation of NKp44 frequency. Furthermore, the expression of the activating receptors NKp46 and NKG2D decreased 40 and 64%, respectively. The expression of KIR2DL1 and KIR2DL2 decreased by 46% each. In cytotoxicity assays, the lytic capacity of G-CSF-exposed NK cells is reduced by up to 68% in vitro and up to 83% in vivo. Accordingly, granzyme B levels of in vivo G-CSF-exposed NK cells were reduced by up to 87% in comparison to nonstimulated NK cells. Cytokine production of in vitro and in vivo incubated NK cells was strongly decreased for interferon-γ, tumor necrosis factor-α, and granulocyte macrophage colony-stimulating factor as well as interleukin (IL)-6 and IL-8. Furthermore, we observed a reduction in proliferation and a positive feedback loop that increased the expression of the G-CSF receptor.


CONCLUSIONS
G-CSF was demonstrated to be a strong inhibitor of NK cells activity and may prevent their graft-versus-leukemia effect after transplantation.
Schlahsa
Laura
L
Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
Jaimes
Yarúa
Y
Blasczyk
Rainer
R
Figueiredo
Constança
C
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003864:Depression, Chemical; D005786:Gene Expression Regulation / Q000187:drug effects; D020544:Graft vs Leukemia Effect / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects / Q000494:pharmacology*; D053804:Granzymes / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D000078224:Lenograstim; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis / Q000235:genetics; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000096:biosynthesis / Q000235:genetics; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000096:biosynthesis / Q000235:genetics; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology
D016207:Cytokines; C527085:KLRK1 protein, human; C112260:NCR1 protein, human; C112837:NCR2 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000078224:Lenograstim; C509213:GZMB protein, human; D053804:Granzymes