Stem cell factor and interleukin-2/15 combine to enhance MAPK-mediated proliferation of human natural killer cells.
Stem cell factor (SCF) promotes synergistic cellular proliferation in combination with several growth factors, and appears important for normal natural killer (NK)-cell development. CD34(+) hematopoietic precursor cells (HPCs) require interleukin-15 (IL-15) for differentiation into human NK cells, and this effect can be mimicked by IL-2. Culture of CD34(+) HPCs or some primary human NK cells in IL-2/15 and SCF results in enhanced growth compared with either cytokine alone. The molecular mechanisms responsible for this are unknown and were investigated in the present work. Activation of NK cells by IL-2/15 increases expression of c-kit whose kinase activity is required for synergy with IL-2/15 signaling. Mitogen-activated protein kinase (MAPK) signaling intermediaries that are activated both by SCF and IL-2/15 are enhanced in combination to facilitate earlier cell-cycle entry. The effect results at least in part via enhanced MAPK-mediated modulation of p27 and CDK4. Collectively the data reveal a novel mechanism by which SCF enhances cellular proliferation in combination with IL-2/15 in primary human NK cells.
Benson
Don M
DM
Division of Hematology/Oncology, The Ohio State University, Columbus, OH 43210-1240, USA.
Yu
Jianhua
J
Becknell
Brian
B
Wei
Min
M
Freud
Aharon G
AG
Ferketich
Amy K
AK
Trotta
Rossana
R
Perrotti
Danilo
D
Briesewitz
Roger
R
Caligiuri
Michael A
MA
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D016895:Culture Media, Serum-Free; D051358:Cyclin-Dependent Kinase 4 / Q000502:physiology; D004357:Drug Synergism; D006801:Humans; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D016895:Culture Media, Serum-Free; D019409:Interleukin-15; D007376:Interleukin-2; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D020032:Tyrphostins; C106250:6,7-dimethoxy-3-phenylquinoxaline; D019009:Proto-Oncogene Proteins c-kit; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C500026:palbociclib