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,
,
Department of Internal Medicine, Divisions of
*
Hematology/Oncology and
Human Cancer Genetics,
Department of Medical Microbiology and Immunology, and the Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210; and
§
PE Applied Biosystems, Foster City, CA 94404
NK cells constitutively express monocyte-derived cytokine
(monokine) receptors and secrete cytokines and chemokines following
monokine stimulation, and are therefore a critical component of the
innate immune response to infection. Here we compared the effects of
three monokines (IL-18, IL-15, and IL-12) on human NK cell cytokine and
chemokine production. IL-18, IL-15, or IL-12 alone did not stimulate
significant cytokine or chemokine production in resting NK cells. The
combination of IL-18 and IL-12 induced extremely high amounts of
IFN-
protein (225 ± 52 ng/ml) and a 1393 ± 643-fold
increase in IFN- gene expression over those in resting NK cells.
IL-15 and IL-12 induced less IFN- protein (24 ± 10 ng/ml;
p < 0.007) and only a 45 ± 19-fold increase
in IFN- gene expression over those in resting NK cells. The
CD56bright NK cell subset produced significantly more
IFN- following IL-18 and IL-12 compared with CD56dim NK
cells (p < 0.008). However, the combination of
IL-15 and IL-12 was significantly more potent than that of IL-18 and
IL-12 for NK cell production of IL-10, macrophage inflammatory
protein-1
, macrophage inflammatory protein-1ß, and TNF- at the
protein and transcript levels. Granulocyte-macrophage CSF was optimally
induced by IL-15 and IL-18. Resting CD56+ NK cells
expressed IL-18R transcript that was up-regulated by IL-12 or IL-15.
Our results show that distinct cytokine and chemokine patterns are
induced in NK cells in response to different costimulatory signals from
these three monokines. This suggests that NK cell cytokine production
may be governed in part by the monokine milieu induced during the early
proinflammatory response to infection and by the subset of NK cells
present at the site of inflammation.
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C. Pridgeon, G. P. Lennon, L. Pazmany, R. N. Thompson, S. E. Christmas, and R. J. Moots Natural killer cells in the synovial fluid of rheumatoid arthritis patients exhibit a CD56bright,CD94bright,CD158negative phenotype Rheumatology, July 1, 2003; 42(7): 870 - 878. [Abstract] [Full Text] [PDF]
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C. P. Kalberer, U. Siegler, and A. Wodnar-Filipowicz Human NK cell development in NOD/SCID mice receiving grafts of cord blood CD34+ cells Blood, July 1, 2003; 102(1): 127 - 135. [Abstract] [Full Text] [PDF]
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M. Strengell, S. Matikainen, J. Siren, A. Lehtonen, D. Foster, I. Julkunen, and T. Sareneva IL-21 in Synergy with IL-15 or IL-18 Enhances IFN-{gamma} Production in Human NK and T Cells J. Immunol., June 1, 2003; 170(11): 5464 - 5469. [Abstract] [Full Text] [PDF]
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M. Schroder, C. Meisel, K. Buhl, N. Profanter, N. Sievert, H.-D. Volk, and G. Grutz Different Modes of IL-10 and TGF-{beta} to Inhibit Cytokine-Dependent IFN-{gamma} Production: Consequences for Reversal of Lipopolysaccharide Desensitization J. Immunol., May 15, 2003; 170(10): 5260 - 5267. [Abstract] [Full Text] [PDF]
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E. G. Chiorean, S. J. Dylla, K. Olsen, T. Lenvik, Y. Soignier, and J. S. Miller BCR/ABL alters the function of NK cells and the acquisition of killer immunoglobulin-like receptors (KIRs) Blood, May 1, 2003; 101(9): 3527 - 3533. [Abstract] [Full Text] [PDF]
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T. A. Fehniger, M. A. Cooper, G. J. Nuovo, M. Cella, F. Facchetti, M. Colonna, and M. A. Caligiuri CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity Blood, April 15, 2003; 101(8): 3052 - 3057. [Abstract] [Full Text] [PDF]
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K. Artavanis-Tsakonas and E. M. Riley Innate Immune Response to Malaria: Rapid Induction of IFN-{gamma} from Human NK Cells by Live Plasmodium falciparum-Infected Erythrocytes J. Immunol., September 15, 2002; 169(6): 2956 - 2963. [Abstract] [Full Text] [PDF]
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S. S. Farag, S. L. George, E. J. Lee, M. Baer, R. K. Dodge, B. Becknell, T. Fehniger, L. R. Silverman, J. Crawford, C. D. Bloomfield, et al. Postremission Therapy with Low-dose Interleukin 2 with or without Intermediate Pulse Dose Interleukin 2 Therapy Is Well Tolerated in Elderly Patients with Acute Myeloid Leukemia: Cancer and Leukemia Group B Study 9420 Clin. Cancer Res., September 1, 2002; 8(9): 2812 - 2819. [Abstract] [Full Text] [PDF]
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 D. Haller, P. Serrant, D. Granato, E. J. Schiffrin, and S. Blum Activation of Human NK Cells by Staphylococci and Lactobacilli Requires Cell Contact-Dependent Costimulation by Autologous Monocytes Clin. Vaccine Immunol., May 1, 2002; 9(3): 649 - 657. [Abstract] [Full Text] [PDF]
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 B. G. Dorner, A. Scheffold, M. S. Rolph, M. B. Huser, S. H. E. Kaufmann, A. Radbruch, I. E. A. Flesch, and R. A. Kroczek MIP-1alpha , MIP-1beta , RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines PNAS, April 30, 2002; 99(9): 6181 - 6186. [Abstract] [Full Text] [PDF]
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 R. Hoontrakoon, H. W. Chu, S. J. Gardai, S. E. Wenzel, P. McDonald, V. A. Fadok, P. M. Henson, and D. L. Bratton Interleukin-15 Inhibits Spontaneous Apoptosis in Human Eosinophils via Autocrine Production of Granulocyte Macrophage-Colony Stimulating Factor and Nuclear Factor-kappa B Activation Am. J. Respir. Cell Mol. Biol., April 1, 2002; 26(4): 404 - 412. [Abstract] [Full Text] [PDF]
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R. Vankayalapati, B. Wizel, S. E. Weis, H. Safi, D. L. Lakey, O. Mandelboim, B. Samten, A. Porgador, and P. F. Barnes The NKp46 Receptor Contributes to NK Cell Lysis of Mononuclear Phagocytes Infected with an Intracellular Bacterium J. Immunol., April 1, 2002; 168(7): 3451 - 3457. [Abstract] [Full Text] [PDF]
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M. J. Robertson Role of chemokines in the biology of natural killer cells J. Leukoc. Biol., February 1, 2002; 71(2): 173 - 183. [Abstract] [Full Text] [PDF]
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I. R. Blanca, E. W. Bere, H. A. Young, and J. R. Ortaldo Human B Cell Activation by Autologous NK Cells Is Regulated by CD40-CD40 Ligand Interaction: Role of Memory B Cells and CD5+ B Cells J. Immunol., December 1, 2001; 167(11): 6132 - 6139. [Abstract] [Full Text] [PDF]
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R. Faggioni, R. C. Cattley, J. Guo, S. Flores, H. Brown, M. Qi, S. Yin, D. Hill, S. Scully, C. Chen, et al. IL-18-Binding Protein Protects Against Lipopolysaccharide- Induced Lethality and Prevents the Development of Fas/Fas Ligand-Mediated Models of Liver Disease in Mice J. Immunol., November 15, 2001; 167(10): 5913 - 5920. [Abstract] [Full Text] [PDF]
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P. A. Reche, V. Soumelis, D. M. Gorman, T. Clifford, M.-r. Liu, M. Travis, S. M. Zurawski, J. Johnston, Y.-J. Liu, H. Spits, et al. Human Thymic Stromal Lymphopoietin Preferentially Stimulates Myeloid Cells J. Immunol., July 1, 2001; 167(1): 336 - 343. [Abstract] [Full Text] [PDF]
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H. H. Tong, Y. Chen, M. James, J. Van Deusen, D. B. Welling, and T. F. DeMaria Expression of Cytokine and Chemokine Genes by Human Middle Ear Epithelial Cells Induced by Formalin-Killed Haemophilus influenzae or Its Lipooligosaccharide htrB and rfaD Mutants Infect. Immun., June 1, 2001; 69(6): 3678 - 3684. [Abstract] [Full Text] [PDF]
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R. Vankayalapati, B. Wizel, D. L. Lakey, Y. Zhang, K. A. Coffee, D. E. Griffith, and P. F. Barnes T Cells Enhance Production of IL-18 by Monocytes in Response to an Intracellular Pathogen J. Immunol., June 1, 2001; 166(11): 6749 - 6753. [Abstract] [Full Text] [PDF]
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M. A. Cooper, T. A. Fehniger, S. C. Turner, K. S. Chen, B. A. Ghaheri, T. Ghayur, W. E. Carson, and M. A. Caligiuri Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset Blood, May 15, 2001; 97(10): 3146 - 3151. [Abstract] [Full Text] [PDF]
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N. J. Horwood, J. Elliott, T. J. Martin, and M. T. Gillespie IL-12 Alone and in Synergy with IL-18 Inhibits Osteoclast Formation In Vitro J. Immunol., April 15, 2001; 166(8): 4915 - 4921. [Abstract] [Full Text] [PDF]
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K. Suzuki, H. Nakazato, H. Matsui, M. Hasumi, Y. Shibata, K. Ito, Y. Fukabori, K. Kurokawa, and H. Yamanaka NK cell-mediated anti-tumor immune response to human prostate cancer cell, PC-3: immunogene therapy using a highly secretable form of interleukin-15 gene transfer J. Leukoc. Biol., April 1, 2001; 69(4): 531 - 537. [Abstract] [Full Text]
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T. A. Fehniger, K. Suzuki, A. Ponnappan, J. B. VanDeusen, M. A. Cooper, S. M. Florea, A. G. Freud, M. L. Robinson, J. Durbin, and M. A. Caligiuri Fatal Leukemia in Interleukin 15 Transgenic Mice Follows Early Expansions in Natural Killer and Memory Phenotype CD8+ T Cells J. Exp. Med., January 16, 2001; 193(2): 219 - 232. [Abstract] [Full Text] [PDF]
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G. Lertmemongkolchai, G. Cai, C. A. Hunter, and G. J. Bancroft Bystander Activation of CD8+ T Cells Contributes to the Rapid Production of IFN-{{gamma}} in Response to Bacterial Pathogens J. Immunol., January 15, 2001; 166(2): 1097 - 1105. [Abstract] [Full Text] [PDF]
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S. Hyun Kim, L. L. Reznikov, R. J. L. Stuyt, C. H. Selzman, G. Fantuzzi, T. Hoshino, H. A. Young, and C. A. Dinarello Functional Reconstitution and Regulation of IL-18 Activity by the IL-18R{beta} Chain J. Immunol., January 1, 2001; 166(1): 148 - 154. [Abstract] [Full Text] [PDF]
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T. A. Fehniger and M. A. Caligiuri Interleukin 15: biology and relevance to human disease Blood, January 1, 2001; 97(1): 14 - 32. [Full Text] [PDF]
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 G. S. Deepe Jr. and R. Gibbons Recombinant Murine Granulocyte-Macrophage Colony-Stimulating Factor Modulates the Course of Pulmonary Histoplasmosis in Immunocompetent and Immunodeficient Mice Antimicrob. Agents Chemother., December 1, 2000; 44(12): 3328 - 3336. [Abstract] [Full Text]
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G. Cai, R. Kastelein, and C. A. Hunter Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii Infect. Immun., December 1, 2000; 68(12): 6932 - 6938. [Abstract] [Full Text] [PDF]
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C K Wong, C. Y Ho, E. Li, and C. Lam Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus Lupus, October 1, 2000; 9(8): 589 - 593. [Abstract] [PDF]
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S. Goodbourn, L. Didcock, and R. E. Randall Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures J. Gen. Virol., October 1, 2000; 81(10): 2341 - 2364. [Full Text]
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C. K. Wong, E. K. Li, C. Y. Ho, and C. W. K. Lam Elevation of plasma interleukin-18 concentration is correlated with disease activity in systemic lupus erythematosus Rheumatology, October 1, 2000; 39(10): 1078 - 1081. [Abstract] [Full Text] [PDF]
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E. Di Carlo, A. Comes, S. Basso, A. De Ambrosis, R. Meazza, P. Musiani, K. Moelling, A. Albini, and S. Ferrini The Combined Action of IL-15 and IL-12 Gene Transfer Can Induce Tumor Cell Rejection Without T and NK Cell Involvement J. Immunol., September 15, 2000; 165(6): 3111 - 3118. [Abstract] [Full Text] [PDF]
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B. R. Lauwerys, N. Garot, J.-C. Renauld, and F. A. Houssiau Cytokine Production and Killer Activity of NK/T-NK Cells Derived with IL-2, IL-15, or the Combination of IL-12 and IL-18 J. Immunol., August 15, 2000; 165(4): 1847 - 1853. [Abstract] [Full Text] [PDF]
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W. E. Carson, J. E. Dierksheide, S. Jabbour, M. Anghelina, P. Bouchard, G. Ku, H. Yu, H. Baumann, M. H. Shah, M. A. Cooper, et al. Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice: critical role of natural killer cell interferon-gamma production and STAT-mediated signal transduction Blood, August 15, 2000; 96(4): 1465 - 1473. [Abstract] [Full Text] [PDF]
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M. Lohoff, G. S. Duncan, D. Ferrick, H.-W. Mittrucker, S. Bischof, S. Prechtl, M. Rollinghoff, E. Schmitt, A. Pahl, and T. W. Mak Deficiency in the Transcription Factor Interferon Regulatory Factor (IRF)-2 Leads to Severely Compromised Development of Natural Killer and T Helper Type 1 Cells J. Exp. Med., July 31, 2000; 192(3): 325 - 336. [Abstract] [Full Text] [PDF]
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P. Hochholzer, G. B. Lipford, H. Wagner, K. Pfeffer, and K. Heeg Role of Interleukin-18 (IL-18) during Lethal Shock: Decreased Lipopolysaccharide Sensitivity but Normal Superantigen Reaction in IL-18-Deficient Mice Infect. Immun., June 1, 2000; 68(6): 3502 - 3508. [Abstract] [Full Text] [PDF]
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T. A. Fehniger, H. Yu, M. A. Cooper, K. Suzuki, M. H. Shah, and M. A. Caligiuri Cutting Edge: IL-15 Costimulates the Generalized Shwartzman Reaction and Innate Immune IFN-{gamma} Production In Vivo J. Immunol., February 15, 2000; 164(4): 1643 - 1647. [Abstract] [Full Text] [PDF]
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