|
|
 Previous Article | Table of Contents | Next Article 
Blood, 15 June 2001, Vol. 97, No. 12, pp. 3860-3866
IMMUNOBIOLOGY
Specific down-regulation of interleukin-12 signaling
through induction of phospho-STAT4 protein
degradation
Kathy S. Wang,
Emmanuel Zorn, and
Jerome Ritz
From the Center for Hematologic Oncology, Department of
Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine,
Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Interleukin-12 (IL-12) plays a critical role in modulating the
function of T lymphocytes and natural killer cells. IL-12 has potent
antitumor effects in animal models, mediated primarily by its ability
to enhance cytolytic activity and secretion of interferon-
(IFN-). Unfortunately, the antitumor effect of IL-12 has not been
demonstrated in clinical trials. Repeated administration of IL-12 in
humans results in decreasing levels of IFN- secretion. To understand
the mechanism underlying this loss of responsiveness, the effect of
IL-12 on its own signaling in activated human T cells was
examined. These experiments demonstrate that the level of the
signal transducer and activator of transcription 4 (STAT4) protein, a
critical IL-12 signaling component, is dramatically decreased 24 hours
after IL-12 stimulation, whereas levels of STAT4 messenger RNA are not
affected. The decrease of STAT4 protein appears to be due to specific
degradation of phospho-STAT4, possibly through the proteasome
degradation pathway. Decreased levels of STAT4 protein lead to
decreased STAT4 DNA-binding activity and reduced proliferation and
secretion of IFN-. This down-regulation of STAT4 is specific for
IL-12 signaling, presumably owing to the prolonged activation of STAT4
induced by IL-12. IFN- stimulation, which leads to transient
phosphorylation of STAT4, does not reduce the level of STAT4 protein.
These findings provide new insights into the regulation of IL-12
signaling in human T cells, where IL-12 promotes TH1
responses, but persistent IL-12 stimulation may also limit this
response. The cellular depletion of STAT4 following prolonged IL-12
stimulation may also explain the loss of responsiveness following the
repeated administration of IL-12 in clinical trials.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
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]
|
|
|
|
|
|
|
Y. Ren, L. Lu, T. B. Guo, J. Qiu, Y. Yang, A. Liu, and J. Z. Zhang
Novel Immunomodulatory Properties of Berbamine through Selective Down-Regulation of STAT4 and Action of IFN-{gamma} in Experimental Autoimmune Encephalomyelitis
J. Immunol.,
July 15, 2008;
181(2):
1491 - 1498.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Becknell, T. L. Hughes, A. G. Freud, B. W. Blaser, J. Yu, R. Trotta, H. C. Mao, M. L. Caligiuri de Jesus, M. Alghothani, D. M. Benson Jr, et al.
Hlx homeobox transcription factor negatively regulates interferon-{gamma} production in monokine-activated natural killer cells
Blood,
March 15, 2007;
109(6):
2481 - 2487.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
V. Sanchez-Guajardo, J. A. M. Borghans, M.-E. Marquez, S. Garcia, and A. A. Freitas
Different Competitive Capacities of Stat4- and Stat6-Deficient CD4+ T Cells during Lymphophenia-Driven Proliferation
J. Immunol.,
February 1, 2005;
174(3):
1178 - 1187.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Athie-Morales, H. H. Smits, D. A. Cantrell, and C. M. U. Hilkens
Sustained IL-12 Signaling Is Required for Th1 Development
J. Immunol.,
January 1, 2004;
172(1):
61 - 69.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. A. Portielje, C. H. J. Lamers, W. H. J. Kruit, A. Sparreboom, R. L. H. Bolhuis, G. Stoter, C. Huber, and J. W. Gratama
Repeated Administrations of Interleukin (IL)-12 Are Associated with Persistently Elevated Plasma Levels of IL-10 and Declining IFN-{gamma}, Tumor Necrosis Factor-{alpha}, IL-6, and IL-8 Responses
Clin. Cancer Res.,
January 1, 2003;
9(1):
76 - 83.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. L. Wurster, V. L. Rodgers, A. R. Satoskar, M. J. Whitters, D. A. Young, M. Collins, and M. J. Grusby
Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon {gamma}-producing Th1 Cells
J. Exp. Med.,
October 7, 2002;
196(7):
969 - 977.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A. Ansari, A. E. Mayne, J. B. Sundstrom, P. Bostik, B. Grimm, J. D. Altman, and F. Villinger
Administration of Recombinant Rhesus Interleukin-12 during Acute Simian Immunodeficiency Virus (SIV) Infection Leads to Decreased Viral Loads Associated with Prolonged Survival in SIVmac251-Infected Rhesus Macaques
J. Virol.,
February 15, 2002;
76(4):
1731 - 1743.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
