| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
2 (IL-12R2)-Deficient Mice Are Defective in IL-12-Mediated Signaling Despite the Presence of High Affinity IL-12 Binding Sites
*
Department of Inflammation/Autoimmune Diseases, Hoffmann-LaRoche, Nutley, NJ 07110; and
Lymphocyte Cell Biology Section, Arthritis and Rheumatism Branch, National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD 20892
Two subunits of the IL-12 receptor (IL-12R), IL-12R
1 and
IL-12R2, have been identified and cloned. Previous studies
demonstrated that the IL-12R1 subunit was required for mouse T and
NK cells to respond to IL-12 in vivo. To investigate the role of
IL-12R2 in IL-12 signaling, we have generated IL-12R2-deficient
(IL-12R2-/-) mice by targeted mutation in embryonic
stem (ES) cells. Although Con A-activated splenocytes from
IL-12R2-/- mice still bind IL-12 with both high and
low affinity, no IL-12-induced biological functions can be detected.
Con A-activated splenocytes of IL-12R2-/- mice failed
to produce IFN-
or proliferate in response to IL-12 stimulation. NK
lytic activity of IL-12R2-/- splenocytes was not
induced when incubated with IL-12. IL-12R2-/-
splenocytes were deficient in IFN- secretion when stimulated with
either Con A or anti-CD3 mAb in vitro. Furthermore,
IL-12R2-/- mice were deficient in vivo in their
ability to produce IFN- following endotoxin administration and to
generate a type 1 cytokine response. IL-12-mediated signal transduction
was also defective as measured by phosphorylation of STAT4. These
results demonstrate that although mouse IL-12R1 is the subunit
primarily responsible for binding IL-12, IL-12R2 plays an essential
role in mediating the biological functions of IL-12 in
mice.
This article has been cited by other articles:
|
|
 |
|
  Z. Zhao, S. Yu, D. C. Fitzgerald, M. Elbehi, B. Ciric, A. M. Rostami, and G.-X. Zhang IL-12R{beta}2 Promotes the Development of CD4+CD25+ Regulatory T Cells J. Immunol., September 15, 2008; 181(6): 3870 - 3876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-J. Kim, J.-I. Youn, S.-H. Seo, H.-T. Jin, and Y.-C. Sung Differential Regulation of Antigen-Specific CD8+ T Cell Responses by IL-12p40 in a Dose-Dependent Manner J. Immunol., June 1, 2008; 180(11): 7167 - 7174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Guia, C. Cognet, L. de Beaucoudrey, M. S. Tessmer, E. Jouanguy, C. Berger, O. Filipe-Santos, J. Feinberg, Y. Camcioglu, J. Levy, et al. A role for interleukin-12/23 in the maturation of human natural killer and CD56+ T cells in vivo Blood, May 15, 2008; 111(10): 5008 - 5016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Wilson, S. Matthews, and G. S. Yap IL-12 Signaling Drives CD8+ T Cell IFN-{gamma} Production and Differentiation of KLRG1+ Effector Subpopulations during Toxoplasma gondii Infection J. Immunol., May 1, 2008; 180(9): 5935 - 5945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Salvatore, M. Fonseca-Aten, K. Katz-Gaynor, A. M. Gomez, and R. D. Hardy Intranasal Interleukin-12 Therapy Inhibits Mycoplasma pneumoniae Clearance and Sustains Airway Obstruction in Murine Pneumonia Infect. Immun., February 1, 2008; 76(2): 732 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Girart, M. B. Fuertes, C. I. Domaica, L. E. Rossi, and N. W. Zwirner Engagement of TLR3, TLR7, and NKG2D Regulate IFN-{gamma} Secretion but Not NKG2D-Mediated Cytotoxicity by Human NK Cells Stimulated with Suboptimal Doses of IL-12 J. Immunol., September 15, 2007; 179(6): 3472 - 3479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Airoldi, E. Di Carlo, C. Cocco, G. Taverniti, T. D'Antuono, E. Ognio, M. Watanabe, D. Ribatti, and V. Pistoia From the Cover: Endogenous IL-12 triggers an antiangiogenic program in melanoma cells PNAS, March 6, 2007; 104(10): 3996 - 4001. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Salvatore, M. Fonseca-Aten, K. Katz-Gaynor, A. M. Gomez, A. Mejias, C. Somers, S. Chavez-Bueno, G. H. McCracken, and R. D. Hardy Respiratory Tract Infection with Mycoplasma pneumoniae in Interleukin-12 Knockout Mice Results in Improved Bacterial Clearance and Reduced Pulmonary Inflammation Infect. Immun., January 1, 2007; 75(1): 236 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Usui, J. C. Preiss, Y. Kanno, Z. J. Yao, J. H. Bream, J. J. O'Shea, and W. Strober T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription J. Exp. Med., March 20, 2006; 203(3): 755 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Airoldi, E. Di Carlo, C. Cocco, C. Sorrentino, F. Fais, M. Cilli, T. D'Antuono, M. P. Colombo, and V. Pistoia Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy Blood, December 1, 2005; 106(12): 3846 - 3853. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Takahashi, M. Akahoshi, A. Matsuda, K. Ebe, N. Inomata, K. Obara, T. Hirota, K. Nakashima, M. Shimizu, M. Tamari, et al. Association of the IL12RB1 promoter polymorphisms with increased risk of atopic dermatitis and other allergic phenotypes Hum. Mol. Genet., November 1, 2005; 14(21): 3149 - 3159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Yun, A. Lundgren, J. Azem, A. Sjoling, J. Holmgren, A.-M. Svennerholm, and B. S. Lundin Natural Killer Cells and Helicobacter pylori Infection: Bacterial Antigens and Interleukin-12 Act Synergistically To Induce Gamma Interferon Production Infect. Immun., March 1, 2005; 73(3): 1482 - 1490. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-M. Yu, S. Wang, A. D. Keegan, M. S. Williams, and C.-K. Qu Abnormal Th1 Cell Differentiation and IFN-{gamma} Production in T Lymphocytes from Motheaten Viable Mice Mutant for Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase-1 J. Immunol., January 15, 2005; 174(2): 1013 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Persky, K. M. Murphy, and J. D. Farrar IL-12, but Not IFN-{alpha}, Promotes STAT4 Activation and Th1 Development in Murine CD4+ T Cells Expressing a Chimeric Murine/Human Stat2 Gene J. Immunol., January 1, 2005; 174(1): 294 - 301. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Newton, T. Lu, S. J. Nazian, I. Perkins, H. Friedman, and T. W. Klein The THC-induced suppression of Th1 polarization in response to Legionella pneumophila infection is not mediated by increases in corticosterone and PGE2 J. Leukoc. Biol., October 1, 2004; 76(4): 854 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Murphy, C. L. Langrish, Y. Chen, W. Blumenschein, T. McClanahan, R. A. Kastelein, J. D. Sedgwick, and D. J. Cua Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation J. Exp. Med., December 15, 2003; 198(12): 1951 - 1957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. D. Russell, Q. Yan, G. Fan, A. P. Khalifah, D. K. Bishop, S. L. Brody, and M. J. Walter IL-12 p40 Homodimer-Dependent Macrophage Chemotaxis and Respiratory Viral Inflammation Are Mediated through IL-12 Receptor {beta}1 J. Immunol., December 15, 2003; 171(12): 6866 - 6874. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-X. Zhang, S. Yu, B. Gran, J. Li, I. Siglienti, X. Chen, D. Calida, E. Ventura, M. Kamoun, and A. Rostami Role of IL-12 Receptor {beta}1 in Regulation of T Cell Response by APC in Experimental Autoimmune Encephalomyelitis J. Immunol., November 1, 2003; 171(9): 4485 - 4492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yoshimoto, M. Furuhata, S. Kamiya, M. Hisada, H. Miyaji, Y. Magami, K. Yamamoto, H. Fujiwara, and J. Mizuguchi Positive Modulation of IL-12 Signaling by Sphingosine Kinase 2 Associating with the IL-12 Receptor {beta}1 Cytoplasmic Region J. Immunol., August 1, 2003; 171(3): 1352 - 1359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. R. Brown, E. L. Lee, and D. L. Thiele TNF Enhances CD4+ T Cell Alloproliferation, IFN-{gamma} Responses, and Intestinal Graft-Versus-Host Disease by IL-12-Independent Mechanisms J. Immunol., May 15, 2003; 170(10): 5082 - 5088. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-X. Zhang, B. Gran, S. Yu, J. Li, I. Siglienti, X. Chen, M. Kamoun, and A. Rostami Induction of Experimental Autoimmune Encephalomyelitis in IL-12 Receptor-{beta}2-Deficient Mice: IL-12 Responsiveness Is Not Required in the Pathogenesis of Inflammatory Demyelination in the Central Nervous System J. Immunol., February 15, 2003; 170(4): 2153 - 2160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Aggarwal, N. Ghilardi, M.-H. Xie, F. J. de Sauvage, and A. L. Gurney Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17 J. Biol. Chem., January 10, 2003; 278(3): 1910 - 1914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. R. Lankford and D. M. Frucht A unique role for IL-23 in promoting cellular immunity J. Leukoc. Biol., January 1, 2003; 73(1): 49 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nishikomori, T. Usui, C.-Y. Wu, A. Morinobu, J. J. O'Shea, and W. Strober Activated STAT4 Has an Essential Role in Th1 Differentiation and Proliferation That Is Independent of Its Role in the Maintenance of IL-12R{beta}2 Chain Expression and Signaling J. Immunol., October 15, 2002; 169(8): 4388 - 4398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Morinobu, M. Gadina, W. Strober, R. Visconti, A. Fornace, C. Montagna, G. M. Feldman, R. Nishikomori, and J. J. O'Shea STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation PNAS, September 17, 2002; 99(19): 12281 - 12286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-X. Zhang, H. Xu, M. Kishi, D. Calida, and A. Rostami The Role of IL-12 in the Induction of Intravenous Tolerance in Experimental Autoimmune Encephalomyelitis J. Immunol., March 1, 2002; 168(5): 2501 - 2507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mempel, C. Ronet, F. Suarez, M. Gilleron, G. Puzo, L. Van Kaer, A. Lehuen, P. Kourilsky, and G. Gachelin Natural Killer T Cells Restricted by the Monomorphic MHC Class 1b CD1d1 Molecules Behave Like Inflammatory Cells J. Immunol., January 1, 2002; 168(1): 365 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Matsumoto, A. Itakura, A. Tanaka, C. Fujisawa, and H. Matsuda Inability of IL-12 to Down-Regulate IgE Synthesis Due to Defective Production of IFN-{gamma} in Atopic NC/Nga Mice J. Immunol., November 15, 2001; 167(10): 5955 - 5962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lassmann, C. Kincaid, V. C. Asensio, and I. L. Campbell Induction of Type 1 Immune Pathology in the Brain Following Immunization Without Central Nervous System Autoantigen in Transgenic Mice With Astrocyte-Targeted Expression of IL-12 J. Immunol., November 1, 2001; 167(9): 5485 - 5493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Poltorak, T. Merlin, P. J. Nielsen, O. Sandra, I. Smirnova, I. Schupp, T. Boehm, C. Galanos, and M. A. Freudenberg A Point Mutation in the IL-12R{beta}2 Gene Underlies the IL-12 Unresponsiveness of Lps-Defective C57BL/10ScCr Mice J. Immunol., August 15, 2001; 167(4): 2106 - 2111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Wesa and A. Galy IL-1{beta} induces dendritic cells to produce IL-12 Int. Immunol., August 1, 2001; 13(8): 1053 - 1061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhang, R. Apilado, J. Coleman, S. Ben-Sasson, S. Tsang, J. Hu-Li, W. E. Paul, and H. Huang Interferon {gamma} Stabilizes the T Helper Cell Type 1 Phenotype J. Exp. Med., July 16, 2001; 194(2): 165 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nishikomori, S. Gurunathan, K. Nishikomori, and W. Strober BALB/c Mice Bearing a Transgenic IL-12 Receptor {{beta}}2 Gene Exhibit a Nonhealing Phenotype to Leishmania major Infection Despite Intact IL-12 Signaling J. Immunol., June 1, 2001; 166(11): 6776 - 6783. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Yap, R. Ortmann, E. Shevach, and A. Sher A Heritable Defect in IL-12 Signaling in B10.Q/J Mice. II. Effect on Acute Resistance to Toxoplasma gondii and Rescue by IL-18 Treatment J. Immunol., May 1, 2001; 166(9): 5720 - 5725. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
