|
|
 Previous Article | Table of Contents | Next Article 
Altered Interleukin-12 Responsiveness in Th1 and Th2 Cells Is
Associated With the Differential Activation of STAT5 and STAT1
Jared A. Gollob,
Erin A. Murphy,
Sudipta Mahajan,
Claudia P. Schnipper,
Jerome Ritz, and
David A. Frank
From the Department of Adult Oncology, Dana-Farber Cancer Institute,
Department of Medicine, Harvard Medical School, Boston, MA.
T-cell activation in response to interleukin-12 (IL-12) is mediated
through signaling events that include the tyrosine phosphorylation of
STAT4. IL-12 responsiveness and the ability of IL-12 to activate STAT4
is different in T cells induced to differentiate into a Th1 or Th2
phenotype. In this report, we show that STAT5, STAT1 , and STAT1 ,
in addition to STAT4, are tyrosine phosphorylated in response to IL-12
in phytohemagglutinin (PHA)-activated human T cells. To understand how
the activation of these STATs contributes to T-cell IL-12
responsiveness, we analyzed the IL-12-induced activation of STAT5 and
STAT1 in T cells stimulated to undergo Th1 or Th2 differentiation. The
IL-12-induced tyrosine phosphorylation of STAT5 and STAT1, but not
STAT4, is augmented in T cells activated into Th1 cells with PHA + interferon- (IFN-) compared with T cells activated with PHA
alone. STAT5 DNA binding induced by IL-12 is also augmented in T cells
activated with PHA + IFN- compared with T cells activated with PHA
alone, whereas STAT4 DNA binding is not increased. In contrast, the
IL-12-induced activation of these STATs is inhibited in T cells
activated into Th2 cells with PHA + IL-4. The enhancement of IL-12
signaling by IFN- is not a direct effect of IFN- on T cells, but
rather is mediated by IL-12 that is produced by antigen-presenting
cells in response to IFN-. This positive autoregulatory effect of
IL-12 on the activation of select STATs correlates with an increase in
T-cell IFN- production in response to IL-12. These findings suggest that the activation of STAT5 and STAT1 may augment select
STAT4-dependent functional responses to IL-12 in Th1 cells.
Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1341-1354
© 1998 by The American Society of Hematology.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
K. A. Casey and M. F. Mescher
IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype
J. Immunol.,
June 15, 2007;
178(12):
7640 - 7648.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Deng, X. Zeng, M. Newstead, T. A. Moore, W. C. Tsai, V. J. Thannickal, and T. J. Standiford
STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection
J. Immunol.,
September 15, 2004;
173(6):
4075 - 4083.
[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]
|
|
|
|
|
|
|
P. Anderson, A. Sundstedt, L. Li, E. J. O'Neill, S. Li, D. C. Wraith, and P. Wang
Differential activation of signal transducer and activator of transcription (STAT)3 and STAT5 and induction of suppressors of cytokine signalling in Th1 and Th2 cells
Int. Immunol.,
November 1, 2003;
15(11):
1309 - 1317.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Mitola, M. Strasly, M. Prato, P. Ghia, and F. Bussolino
IL-12 Regulates an Endothelial Cell-Lymphocyte Network: Effect on Metalloproteinase-9 Production
J. Immunol.,
October 1, 2003;
171(7):
3725 - 3733.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Valenzuela, C. Schmidt, and M. Mescher
The Roles of IL-12 in Providing a Third Signal for Clonal Expansion of Naive CD8 T Cells
J. Immunol.,
December 15, 2002;
169(12):
6842 - 6849.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Lin, L. Brown, D. W. Hedley, D. L. Barber, and S. Benchimol
The death-promoting activity of p53 can be inhibited by distinct signaling pathways
Blood,
December 1, 2002;
100(12):
3990 - 4000.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. B. Nguyen, T. P. Salazar-Mather, M. Y. Dalod, J. B. Van Deusen, X.-q. Wei, F. Y. Liew, M. A. Caligiuri, J. E. Durbin, and C. A. Biron
Coordinated and Distinct Roles for IFN-{alpha}{beta}, IL-12, and IL-15 Regulation of NK Cell Responses to Viral Infection
J. Immunol.,
October 15, 2002;
169(8):
4279 - 4287.
[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]
|
|
|
|
|
|
|
C. Parham, M. Chirica, J. Timans, E. Vaisberg, M. Travis, J. Cheung, S. Pflanz, R. Zhang, K. P. Singh, F. Vega, et al.
A Receptor for the Heterodimeric Cytokine IL-23 Is Composed of IL-12R{beta}1 and a Novel Cytokine Receptor Subunit, IL-23R
J. Immunol.,
June 1, 2002;
168(11):
5699 - 5708.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Takeba, H. Nagafuchi, M. Takeno, J.-i. Kashiwakura, and N. Suzuki
Txk, a Member of Nonreceptor Tyrosine Kinase of Tec Family, Acts as a Th1 Cell-Specific Transcription Factor and Regulates IFN-{gamma} Gene Transcription
J. Immunol.,
March 1, 2002;
168(5):
2365 - 2370.
[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]
|
|
|
|
|
|
|
K. S. Wang, E. Zorn, and J. Ritz
Specific down-regulation of interleukin-12 signaling through induction of phospho-STAT4 protein degradation
Blood,
June 15, 2001;
97(12):
3860 - 3866.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Gollob, K. G. Veenstra, H. Jyonouchi, A. M. Kelly, P. Ferrieri, D. J. Panka, F. Altare, C. Fieschi, J.-L. Casanova, D. A. Frank, et al.
Impairment of STAT Activation by IL-12 in a Patient with Atypical Mycobacterial and Staphylococcal Infections
J. Immunol.,
October 1, 2000;
165(7):
4120 - 4126.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
C. E. Verhagen, T. de Boer, H. H. Smits, F. A.W. Verreck, E. A. Wierenga, M. Kurimoto, D. A. Lammas, D. S. Kumararatne, O. Sanal, F. P. Kroon, et al.
Residual Type 1 Immunity in Patients Genetically Deficient for Interleukin 12 Receptor {beta}1 (IL-12R{beta}1): Evidence for an IL-12R{beta}1-independent Pathway of IL-12 Responsiveness in Human T Cells
J. Exp. Med.,
August 14, 2000;
192(4):
517 - 528.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Nagayama, K. Sato, H. Kawasaki, M. Enomoto, C. Morimoto, K. Tadokoro, T. Juji, S. Asano, and T. A. Takahashi
IL-12 Responsiveness and Expression of IL-12 Receptor in Human Peripheral Blood Monocyte-Derived Dendritic Cells
J. Immunol.,
July 1, 2000;
165(1):
59 - 66.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-i. Kashiwakura, N. Suzuki, H. Nagafuchi, M. Takeno, Y. Takeba, Y. Shimoyama, and T. Sakane
Txk, a Nonreceptor Tyrosine Kinase of the Tec Family, Is Expressed in T Helper Type 1 Cells and Regulates Interferon {gamma} Production in Human T Lymphocytes
J. Exp. Med.,
October 18, 1999;
190(8):
1147 - 1154.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. C. Showe, F. E. Fox, D. Williams, K. Au, Z. Niu, and A. H. Rook
Depressed IL-12-Mediated Signal Transduction in T Cells from Patients with Sezary Syndrome Is Associated with the Absence of IL-12 Receptor {beta}2 mRNA and Highly Reduced Levels of STAT4
J. Immunol.,
October 1, 1999;
163(7):
4073 - 4079.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Marshall, J. Chehimi, G. Gri, J. R. Kostman, L. J. Montaner, and G. Trinchieri
The Interleukin-12-Mediated Pathway of Immune Events Is Dysfunctional in Human Immunodeficiency Virus-Infected Individuals
Blood,
August 1, 1999;
94(3):
1003 - 1011.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Galon, C. Sudarshan, S. Ito, D. Finbloom, and J. J. O'Shea
IL-12 Induces IFN Regulating Factor-1 (IRF-1) Gene Expression in Human NK and T Cells
J. Immunol.,
June 15, 1999;
162(12):
7256 - 7262.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M.-Y. Ho, B. K. Beattie, J. A. Squire, D. A. Frank, and D. L. Barber
Fusion of the ets Transcription Factor TEL to Jak2 Results in Constitutive Jak-Stat Signaling
Blood,
June 15, 1999;
93(12):
4354 - 4364.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Gollob, C. P. Schnipper, E. A. Murphy, J. Ritz, and D. A. Frank
The Functional Synergy Between IL-12 and IL-2 Involves p38 Mitogen-Activated Protein Kinase and Is Associated with the Augmentation of STAT Serine Phosphorylation
J. Immunol.,
April 15, 1999;
162(8):
4472 - 4481.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. K. Naeger, J. McKinney, A. Salvekar, and T. Hoey
Identification of a STAT4 Binding Site in the Interleukin-12 Receptor Required for Signaling
J. Biol. Chem.,
January 22, 1999;
274(4):
1875 - 1878.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. S. Wang, J. Ritz, and D. A. Frank
IL-2 Induces STAT4 Activation in Primary NK Cells and NK Cell Lines, But Not in T Cells
J. Immunol.,
January 1, 1999;
162(1):
299 - 304.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
