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Src Homology 2–Containing Inositol 5'-Phosphatase 1 Negatively Regulates IFN- Production by Natural Killer Cells Stimulated with Antibody-Coated Tumor Cells and Interleukin-12

Departments of ¹ Molecular Virology, Immunology, and Medical Genetics and ² Internal Medicine; ³ Integrated Biomedical Graduate Program; Departments of ⁴ Biostatistics and ⁵ Surgery, Arthur G. James Comprehensive Cancer Center and Solove Research Institute, Ohio State University, Columbus, Ohio

Requests for reprints: William E. Carson III, Ohio State University College of Medicine, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-6306; Fax: 614-688-4366; E-mail: carson-1{at}medctr.osu.edu.

We have previously shown that natural killer (NK) cells secrete a distinct profile of immunomodulatory cytokines in response to dual stimulation with antibody-coated tumor cells and interleukin-12 (IL-12). This NK cell cytokine response is dependent on synergistic signals mediated by the activating receptor for the Fc portion of IgG (FcRIIIa) and the IL-12 receptor (IL-12R), both constitutively expressed on NK cells. The phosphatase Src homology 2–containing inositol 5'-phosphatase 1 (SHIP1) is known to exert inhibitory effects on Fc receptor (FcR) signaling via its enzymatic activity on phosphatidylinositol 3-kinase (PI3-K) products within many cells of the immune system, most notably mast cells, B cells, and monocytes. However, its activity in the context of FcR activation on NK cells has not been fully explored. The current study focused on the regulation of FcRIIIa-induced NK cell cytokine production by SHIP1. Inhibitor studies showed that NK cell IFN- production following FcR stimulation in the presence of IL-12 depended, in part, on the downstream products of PI3-K. Overexpression of wild-type (WT) SHIP1, but not a catalytic-deficient mutant, via retroviral transfection of primary human NK cells, resulted in a >70% reduction of NK cell IFN- production in response to costimulation. In addition, NK cells from SHIP1^–/– mice produced 10-fold greater amounts of IFN- following culture with antibody-coated tumor cells plus IL-12 compared with NK cells from WT mice. Further, activation of the mitogen-activated protein kinase (MAPK) family member extracellular signal-regulated kinase (Erk; a downstream target of PI3-K) was significantly enhanced within SHIP1^–/– NK cells compared with WT NK cells following costimulation. Pharmacologic inhibition of Erk activity, but not Jnk MAPK activity, led to significantly decreased IFN- production from both SHIP1^–/– and WT NK cells under these conditions. These results are the first to show a physiologic role for SHIP1 in the regulation of NK cell cytokine production and implicate PI3-K in the induction of MAPK signal transduction following costimulation of NK cells via the FcR and the IL-12R.

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