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The Journal of Immunology, 1998, 160: 3642-3647.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: IL-12 and IL-18 Differentially Regulate the Transcriptional Activity of the Human IFN-{gamma} Promoter in Primary CD4+ T Lymphocytes1

Karina Barbulescu*, Christoph Becker*, Jörg F. Schlaak*, Edgar Schmitt{dagger}, Karl-Hermann Meyer zum Büschenfelde* and Markus F. Neurath2,*

* Laboratory of Immunology, I. Medical Clinic, and {dagger} Institute of Immunology, University of Mainz, Mainz, Germany

We analyzed the molecular mechanisms by which IL-12 and IL-18 induce transcriptional activity of the IFN-{gamma} promoter in primary human CD4+ T cells. In transfection experiments, we found that IL-18 directly induces IFN-{gamma} promoter activity, whereas significant activation with IL-12 required costimulation with {alpha}CD3/CD28. Furthermore, IL-12 caused in vivo protection of a STAT4 (-236) binding site, whereas stimulation with IL-18 or IL-12 plus {alpha}CD3/CD28 induced occupancy of a downstream AP-1 site. Mutation of this AP-1 site abrogated both IL-12- and IL-18-mediated promoter activation, whereas mutation of the STAT site inhibited IL-12-dependent activation. These data suggest that both AP-1 and STAT4 are required for IL-12-dependent IFN-{gamma} promoter activity, whereas IL-18 causes direct activation via AP-1. This differential activation of the IFN-{gamma} promoter gives further insights into molecular pathways governing Th1 T cell development and differentiation.




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Expression and Function of IL-12 and IL-18 Receptors on Human Tonsillar B Cells
J. Immunol., December 15, 2000; 165(12): 6880 - 6888.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
R. Debets, J. C. Timans, T. Churakowa, S. Zurawski, R. de Waal Malefyt, K. W. Moore, J. S. Abrams, A. O'Garra, J. F. Bazan, and R. A. Kastelein
IL-18 Receptors, Their Role in Ligand Binding and Function: Anti-IL-1RAcPL Antibody, a Potent Antagonist of IL-18
J. Immunol., November 1, 2000; 165(9): 4950 - 4956.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
A. R. Kitching, P. G. Tipping, M. Kurimoto, and S. R. Holdsworth
IL-18 Has IL-12-Independent Effects in Delayed-Type Hypersensitivity: Studies in Cell-Mediated Crescentic Glomerulonephritis
J. Immunol., October 15, 2000; 165(8): 4649 - 4657.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
C. M. Greene, G. Meachery, C. C. Taggart, C. P. Rooney, R. Coakley, S. J. O'Neill, and N. G. McElvaney
Role of IL-18 in CD4+ T Lymphocyte Activation in Sarcoidosis
J. Immunol., October 15, 2000; 165(8): 4718 - 4724.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
C. A. Salkowski, K. E. Thomas, M. J. Cody, and S. N. Vogel
Impaired IFN-{gamma} Production in IFN Regulatory Factor-1 Knockout Mice During Endotoxemia Is Secondary to a Loss of Both IL-12 and IL-12 Receptor Expression
J. Immunol., October 1, 2000; 165(7): 3970 - 3977.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
S. Zhang and M. H. Kaplan
The p38 Mitogen-Activated Protein Kinase Is Required for IL-12-Induced IFN-{gamma} Expression
J. Immunol., August 1, 2000; 165(3): 1374 - 1380.
[Abstract] [Full Text] [PDF]

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 Genes Dev.Home page
L. H. Glimcher and K. M. Murphy
Lineage commitment in the immune system: the T helper lymphocyte grows up
Genes & Dev., July 15, 2000; 14(14): 1693 - 1711.
[Full Text]

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 J. Immunol.Home page
T.-K. Yu, E. G. Caudell, C. Smid, and E. A. Grimm
IL-2 Activation of NK Cells: Involvement of MKK1/2/ERK But Not p38 Kinase Pathway
J. Immunol., June 15, 2000; 164(12): 6244 - 6251.
[Abstract] [Full Text] [PDF]

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 Int ImmunolHome page
T. Labuda, A. Sundstedt, and M. Dohlsten
Selective induction of p38 mitogen-activated protein kinase activity following A6H co-stimulation in primary human CD4+ T cells
Int. Immunol., March 1, 2000; 12(3): 253 - 261.
[Abstract] [Full Text] [PDF]

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 Int ImmunolHome page
K. Tominaga, T. Yoshimoto, K. Torigoe, M. Kurimoto, K. Matsui, T. Hada, H. Okamura, and K. Nakanishi
IL-12 synergizes with IL-18 or IL-1{beta} for IFN-{gamma} production from human T cells
Int. Immunol., February 1, 2000; 12(2): 151 - 160.
[Abstract] [Full Text] [PDF]

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 JEMHome page
T. Kaisho, H. Tsutsui, T. Tanaka, T. Tsujimura, K. Takeda, T. Kawai, N. Yoshida, K. Nakanishi, and S. Akira
Impairment of Natural Killer Cytotoxic Activity and Interferon {gamma} Production in Ccaat/Enhancer Binding Protein {gamma}-Deficient Mice
J. Exp. Med., December 6, 1999; 190(11): 1573 - 1582.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
F. Zhang, T. Nakamura, and T. M. Aune
TCR and IL-12 Receptor Signals Cooperate to Activate an Individual Response Element in the IFN-{gamma} Promoter in Effector Th Cells
J. Immunol., July 15, 1999; 163(2): 728 - 735.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
W. Walker, M. Aste-Amezaga, R. A. Kastelein, G. Trinchieri, and C. A. Hunter
IL-18 and CD28 Use Distinct Molecular Mechanisms to Enhance NK Cell Production of IL-12-Induced IFN-{gamma}
J. Immunol., May 15, 1999; 162(10): 5894 - 5901.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
V. E. Garcia, K. Uyemura, P. A. Sieling, M. T. Ochoa, C. T. Morita, H. Okamura, M. Kurimoto, T. H. Rea, and R. L. Modlin
IL-18 Promotes Type 1 Cytokine Production from NK Cells and T Cells in Human Intracellular Infection
J. Immunol., May 15, 1999; 162(10): 6114 - 6121.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
H. Kojima, Y. Aizawa, Y. Yanai, K. Nagaoka, M. Takeuchi, T. Ohta, H. Ikegami, M. Ikeda, and M. Kurimoto
An Essential Role for NF-{kappa}B in IL-18-Induced IFN-{gamma} Expression in KG-1 Cells
J. Immunol., May 1, 1999; 162(9): 5063 - 5069.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
T. A. Fehniger, M. H. Shah, M. J. Turner, J. B. VanDeusen, S. P. Whitman, M. A. Cooper, K. Suzuki, M. Wechser, F. Goodsaid, and M. A. Caligiuri
Differential Cytokine and Chemokine Gene Expression by Human NK Cells Following Activation with IL-18 or IL-15 in Combination with IL-12: Implications for the Innate Immune Response
J. Immunol., April 15, 1999; 162(8): 4511 - 4520.
[Abstract] [Full Text] [PDF]

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 JEMHome page
P. Kanakaraj, K. Ngo, Y. Wu, A. Angulo, P. Ghazal, C. A. Harris, J. J. Siekierka, P. A. Peterson, and W.-P. Fung-Leung
Defective Interleukin (IL)-18-mediated Natural Killer and T Helper Cell Type 1 Responses in IL-1 Receptor-associated Kinase (IRAK)-deficient Mice
J. Exp. Med., April 5, 1999; 189(7): 1129 - 1138.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
W. Ouyang, N. G. Jacobson, D. Bhattacharya, J. D. Gorham, D. Fenoglio, W. C. Sha, T. L. Murphy, and K. M. Murphy
The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway
PNAS, March 30, 1999; 96(7): 3888 - 3893.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
M. H. Claesson, S. Bregenholt, K. Bonhagen, S. Thoma, P. Moller, M. J. Grusby, F. Leithauser, M. H. Nissen, and J. Reimann
Colitis-Inducing Potency of CD4+ T Cells in Immunodeficient, Adoptive Hosts Depends on Their State of Activation, IL-12 Responsiveness, and CD45RB Surface Phenotype
J. Immunol., March 15, 1999; 162(6): 3702 - 3710.
[Abstract] [Full Text] [PDF]

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 BloodHome page
C. Pardoux, X. Ma, S. Gobert, S. Pellegrini, P. Mayeux, F. Gay, G. Trinchieri, and S. Chouaib
Downregulation of Interleukin-12 (IL-12) Responsiveness in Human T Cells by Transforming Growth Factor-beta : Relationship With IL-12 Signaling
Blood, March 1, 1999; 93(5): 1448 - 1455.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
S. Wirtz, S. Finotto, S. Kanzler, A. W. Lohse, M. Blessing, H. A. Lehr, P. R. Galle, and M. F. Neurath
Cutting Edge: Chronic Intestinal Inflammation in STAT-4 Transgenic Mice: Characterization of Disease and Adoptive Transfer by TNF- Plus IFN-{gamma}-Producing CD4+ T Cells That Respond to Bacterial Antigens
J. Immunol., February 15, 1999; 162(4): 1884 - 1888.
[Abstract] [Full Text] [PDF]

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 Toxicol PatholHome page
B. D. Car, V. M. Eng, J. M. Lipman, and T. D. Anderson
The Toxicology of Interleukin-12: A Review
Toxicol Pathol, January 1, 1999; 27(1): 58 - 63.
[Abstract] [PDF]

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 J. Biol. Chem.Home page
M. T. Sweetser, T. Hoey, Y.-L. Sun, W. M. Weaver, G. A. Price, and C. B. Wilson
The Roles of Nuclear Factor of Activated T Cells and Ying-Yang 1 in Activation-induced Expression of the Interferon-gamma Promoter in T Cells
J. Biol. Chem., December 25, 1998; 273(52): 34775 - 34783.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
G. B. Ehret, P. Reichenbach, U. Schindler, C. M. Horvath, S. Fritz, M. Nabholz, and P. Bucher
DNA Binding Specificity of Different STAT Proteins. COMPARISON OF IN VITRO SPECIFICITY WITH NATURAL TARGET SITES
J. Biol. Chem., February 23, 2001; 276(9): 6675 - 6688.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
S. C. Whitman, P. Ravisankar, and A. Daugherty
Interleukin-18 Enhances Atherosclerosis in Apolipoprotein E-/- Mice Through Release of Interferon-{gamma}
Circ. Res., February 8, 2002; 90 (2): e34 - e38.
[Abstract] [Full Text] [PDF]


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