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 Blood, 19 March 2009, Vol. 113, No. 12, pp. 2706-2714.
Prepublished online as a Blood First Edition Paper on December 5, 2008; DOI 10.1182/blood-2008-05-159285.

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IMMUNOBIOLOGY

Stem cell factor and interleukin-2/15 combine to enhance MAPK-mediated proliferation of human natural killer cells

Don M. Benson, Jr1, Jianhua Yu2,3, Brian Becknell4, Min Wei2, Aharon G. Freud4, Amy K. Ferketich5, Rossana Trotta2,3, Danilo Perrotti2,3, Roger Briesewitz3,6, and Michael A. Caligiuri1,3,4

1 Division of Hematology/Oncology, 2 Department of Molecular Virology, Immunology and Medical Genetics, 3 Comprehensive Cancer Center, 4 Medical Scientist Program, Integrated Biomedical Graduate Program, College of Medicine, 5 Division of Biostatistics, College of Public Health, and 6 Department of Pharmacology, The Ohio State University, Columbus

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.


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