| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
-Inducing Signaling Pathways1
*
Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202 and Walther Cancer Institute, Indianapolis, IN 46208;
Akdeniz University Tip Fakultesi, Tibbi Biyologi, Arapsuyu, Antalya, Turkey;
Tularik, Inc., San Francisco, CA 94080; and
§
Department of Cancer Biology, Harvard School of Public Health, and Department of Medicine, Harvard Medical School, Boston, MA 02115
Stat4 is activated in response to IL-12. Most functions of IL-12,
including the induction of IFN-
, are compromised in the absence of
Stat4. Since the precise role of Stat4 in IFN- induction has not
been established, experiments were conducted to examine Stat4
activation of IFN- and other genes required for cytokine-induced
expression of IFN-. We first examined IL-12 signaling components.
Basal expression of IL-12Rß1 and IL-12Rß2 is decreased in
Stat4-deficient cells compared with that in control cells. However,
IL-12 was still capable of inducing equivalent phosphorylation of Jak2
and Tyk2 in wild-type and Stat4-deficient activated T cells. We have
further determined that other cytokine signaling pathways that induce
IFN- production are defective in the absence of Stat4. IL-18 induces
minimal IFN- production from Stat4-deficient activated T cells
compared with control cells. This is due to defective IL-18 signaling,
which results from the lack of IL-12-induced, and Stat4-dependent,
expression of the IL-18R. Following IL-12 pretreatment to induce
IL-18R, wild-type, but not Stat4-deficient, activated T cells
demonstrated IL-18-induced NF-
B DNA-binding activity. In addition,
IL-12-pretreated Stat4-deficient activated T cells have minimal IFN-
production followed by stimulation with IL-18 alone or in combination
with IL-12 compared with control cells. Thus, Stat4 activation by IL-12
is required for the function of multiple cytokine pathways that result
in induction of IFN-.
This article has been cited by other articles:
|
|
 |
|
  S. R. Good, V. T. Thieu, A. N. Mathur, Q. Yu, G. L. Stritesky, N. Yeh, J. T. O'Malley, N. B. Perumal, and M. H. Kaplan Temporal Induction Pattern of STAT4 Target Genes Defines Potential for Th1 Lineage-Specific Programming J. Immunol., September 15, 2009; 183(6): 3839 - 3847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Karpuzoglu, R. A. Phillips, R. Dai, C. Graniello, R. M. Gogal Jr., and S. A. Ahmed Signal Transducer and Activation of Transcription (STAT) 4{beta}, a Shorter Isoform of Interleukin-12-Induced STAT4, Is Preferentially Activated by Estrogen Endocrinology, March 1, 2009; 150(3): 1310 - 1320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Acosta-Iborra, A. Elorza, I. M. Olazabal, N. B. Martin-Cofreces, S. Martin-Puig, M. Miro, M. J. Calzada, J. Aragones, F. Sanchez-Madrid, and M. O. Landazuri Macrophage Oxygen Sensing Modulates Antigen Presentation and Phagocytic Functions Involving IFN-{gamma} Production through the HIF-1{alpha} Transcription Factor J. Immunol., March 1, 2009; 182(5): 3155 - 3164. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. O'Malley, R. D. Eri, G. L. Stritesky, A. N. Mathur, H.-C. Chang, H. HogenEsch, M. Srinivasan, and M. H. Kaplan STAT4 Isoforms Differentially Regulate Th1 Cytokine Production and the Severity of Inflammatory Bowel Disease J. Immunol., October 1, 2008; 181(7): 5062 - 5070. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yu, H.-C. Chang, A.-N. N. Ahyi, and M. H. Kaplan Transcription Factor-Dependent Chromatin Remodeling of Il18r1 during Th1 and Th2 Differentiation J. Immunol., September 1, 2008; 181(5): 3346 - 3352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Cao, P. D. Doodes, T. T. Glant, and A. Finnegan IL-27 Induces a Th1 Immune Response and Susceptibility to Experimental Arthritis J. Immunol., January 15, 2008; 180(2): 922 - 930. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Miyagi, M. P. Gil, X. Wang, J. Louten, W.-M. Chu, and C. A. Biron High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells J. Exp. Med., October 1, 2007; 204(10): 2383 - 2396. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Wickstrum, K.-J. Hong, S. Bokhari, N. Reed, N. McWilliams, R. T. Horvat, and M. J. Parmely Coactivating Signals for the Hepatic Lymphocyte Gamma Interferon Response to Francisella tularensis Infect. Immun., March 1, 2007; 75(3): 1335 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Berenson, M. Gavrieli, J. D. Farrar, T. L. Murphy, and K. M. Murphy Distinct Characteristics of Murine STAT4 Activation in Response to IL-12 and IFN-{alpha} J. Immunol., October 15, 2006; 177(8): 5195 - 5203. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Tortorella, I. Stella, G. Piazzolla, V. Cappiello, O. Simone, A. Pisconti, and S. Antonaci Impaired Interleukin-12-Dependent T-Cell Functions During Aging: Role of Signal Transducer and Activator of Transcription 4 (STAT4) and Suppressor of Cytokine Signaling 3 (SOCS3). J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2006; 61(2): 125 - 135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Wozniak, A. A. Ryan, J. A. Triccas, and W. J. Britton Plasmid Interleukin-23 (IL-23), but Not Plasmid IL-27, Enhances the Protective Efficacy of a DNA Vaccine against Mycobacterium tuberculosis Infection Infect. Immun., January 1, 2006; 74(1): 557 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Boyton, S. Davies, C. Marden, C. Fantino, C. Reynolds, K. Portugal, H. Dewchand, and D. M. Altmann Stat4-null non-obese diabetic mice: protection from diabetes and experimental allergic encephalomyelitis, but with concomitant epitope spread Int. Immunol., September 1, 2005; 17(9): 1157 - 1165. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Robertson, H.-C. Chang, D. Pelloso, and M. H. Kaplan Impaired interferon-{gamma} production as a consequence of STAT4 deficiency after autologous hematopoietic stem cell transplantation for lymphoma Blood, August 1, 2005; 106(3): 963 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Lund, Z. Chen, J. Scheinin, and R. Lahesmaa Early Target Genes of IL-12 and STAT4 Signaling in Th Cells J. Immunol., June 1, 2004; 172(11): 6775 - 6782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Papadakis, J. L. Prehn, C. Landers, Q. Han, X. Luo, S. C. Cha, P. Wei, and S. R. Targan TL1A Synergizes with IL-12 and IL-18 to Enhance IFN-{gamma} Production in Human T Cells and NK Cells J. Immunol., June 1, 2004; 172(11): 7002 - 7007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Toyoda, M. Ido, T. Hayashi, E. C. Gabazza, K. Suzuki, J. Bu, S. Tanaka, T. Nakano, H. Kamiya, J. Chipeta, et al. Impairment of IL-12-Dependent STAT4 Nuclear Translocation in a Patient with Recurrent Mycobacterium avium Infection J. Immunol., March 15, 2004; 172(6): 3905 - 3912. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. O'Sullivan, H.-C. Chang, Q. Yu, and M. H. Kaplan STAT4 Is Required for Interleukin-12-induced Chromatin Remodeling of the CD25 Locus J. Biol. Chem., February 20, 2004; 279(8): 7339 - 7345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-H. Chiang, L. Wang, C. A. Bonham, X. Liang, J. J. Fung, L. Lu, and S. Qian Mechanistic Insights into Impaired Dendritic Cell Function by Rapamycin: Inhibition of Jak2/Stat4 Signaling Pathway J. Immunol., February 1, 2004; 172(3): 1355 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Wang, N. S. Ostlie, B. M. Conti-Fine, and M. Milani The Susceptibility to Experimental Myasthenia Gravis of STAT6-/- and STAT4-/- BALB/c Mice Suggests a Pathogenic Role of Th1 Cells J. Immunol., January 1, 2004; 172(1): 97 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Monick, L. Samavati, N. S. Butler, M. Mohning, L. S. Powers, T. Yarovinsky, D. R. Spitz, and G. W. Hunninghake Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production J. Immunol., November 15, 2003; 171(10): 5107 - 5115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Lafont, S. Loisel, J. Liautard, S. Dudal, M. Sable-teychene, J.-P. Liautard, and J. Favero Specific Signaling Pathways Triggered by IL-2 in Human V{gamma}9V{delta}2 T Cells: An Amalgamation of NK and {alpha}{beta} T Cell Signaling J. Immunol., November 15, 2003; 171(10): 5225 - 5232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Freudenberg, C. Kalis, Y. Chvatchko, T. Merlin, M. Gumenscheimer, and C. Galanos Role of interferons in LPS hypersensitivity Innate Immunity, October 1, 2003; 9(5): 308 - 312. [Abstract] [PDF]
|
|
|
|
|
|
H.-C. Chang, S. Zhang, I. Oldham, L. Naeger, T. Hoey, and M. H. Kaplan STAT4 Requires the N-terminal Domain for Efficient Phosphorylation J. Biol. Chem., August 22, 2003; 278(34): 32471 - 32477. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Lugo-Villarino, R. Maldonado-Lopez, R. Possemato, C. Penaranda, and L. H. Glimcher T-bet is required for optimal production of IFN-{gamma} and antigen-specific T cell activation by dendritic cells PNAS, June 24, 2003; 100(13): 7749 - 7754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
N. Suzuki, N.-J. Chen, D. G. Millar, S. Suzuki, T. Horacek, H. Hara, D. Bouchard, K. Nakanishi, J. M. Penninger, P. S. Ohashi, et al. IL-1 Receptor-Associated Kinase 4 Is Essential for IL-18-Mediated NK and Th1 Cell Responses J. Immunol., April 15, 2003; 170(8): 4031 - 4035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Monteleone, J. Holloway, V. M. Salvati, S. L.-F. Pender, P. D. Fairclough, N. Croft, and T. T. MacDonald Activated STAT4 and a Functional Role for IL-12 in Human Peyer's Patches J. Immunol., January 1, 2003; 170(1): 300 - 307. [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]
|
|
|
|
|
|
A. Finnegan, M. J. Grusby, C. D. Kaplan, S. K. O'Neill, H. Eibel, T. Koreny, M. Czipri, K. Mikecz, and J. Zhang IL-4 and IL-12 Regulate Proteoglycan-Induced Arthritis Through Stat-Dependent Mechanisms J. Immunol., September 15, 2002; 169(6): 3345 - 3352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Freudenberg, T. Merlin, C. Kalis, Y. Chvatchko, H. Stubig, and C. Galanos Cutting Edge: A Murine, IL-12-Independent Pathway of IFN-{gamma} Induction by Gram-Negative Bacteria Based on STAT4 Activation by Type I IFN and IL-18 Signaling J. Immunol., August 15, 2002; 169(4): 1665 - 1668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Shen and M. H. Kaplan The Homeostasis But Not the Differentiation of T Cells Is Regulated by p27Kip1 J. Immunol., July 15, 2002; 169(2): 714 - 721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shimoda, H. Tsutsui, K. Aoki, K. Kato, T. Matsuda, A. Numata, K. Takase, T. Yamamoto, H. Nukina, T. Hoshino, et al. Partial impairment of interleukin-12 (IL-12) and IL-18 signaling in Tyk2-deficient mice Blood, March 15, 2002; 99(6): 2094 - 2099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nakahira, H.-J. Ahn, W.-R. Park, P. Gao, M. Tomura, C.-S. Park, T. Hamaoka, T. Ohta, M. Kurimoto, and H. Fujiwara Synergy of IL-12 and IL-18 for IFN-{gamma} Gene Expression: IL-12-Induced STAT4 Contributes to IFN-{gamma} Promoter Activation by Up-Regulating the Binding Activity of IL-18-Induced Activator Protein 1 J. Immunol., February 1, 2002; 168(3): 1146 - 1153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Afanasyeva, Y. Wang, Z. Kaya, E. A. Stafford, K. M. Dohmen, A. A. Sadighi Akha, and N. R. Rose Interleukin-12 Receptor/STAT4 Signaling Is Required for the Development of Autoimmune Myocarditis in Mice by an Interferon-{gamma}-Independent Pathway Circulation, December 18, 2001; 104(25): 3145 - 3151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Iwasaki, T. Mukai, C. Nakajima, Y.-F. Yang, P. Gao, N. Yamaguchi, M. Tomura, H. Fujiwara, and T. Hamaoka A Mandatory Role for STAT4 in IL-12 Induction of Mouse T Cell CCR5 J. Immunol., December 15, 2001; 167(12): 6877 - 6883. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Godshall, A. B. Lentsch, J. C. Peyton, M. J. Scott, and W. G. Cheadle STAT4 Is Required for Antibacterial Defense but Enhances Mortality during Polymicrobial Sepsis Clin. Vaccine Immunol., November 1, 2001; 8(6): 1044 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Ethuin, C. Delarche, S. Benslama, M.-A. Gougerot-Pocidalo, L. Jacob, and S. Chollet-Martin Interleukin-12 increases interleukin 8 production and release by human polymorphonuclear neutrophils J. Leukoc. Biol., September 1, 2001; 70(3): 439 - 446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nakahira, M. Tomura, M. Iwasaki, H.-J. Ahn, Y. Bian, T. Hamaoka, T. Ohta, M. Kurimoto, and H. Fujiwara An Absolute Requirement for STAT4 and a Role for IFN-{gamma} as an Amplifying Factor in IL-12 Induction of the Functional IL-18 Receptor Complex J. Immunol., August 1, 2001; 167(3): 1306 - 1312. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
