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Departments of
*
Microbiology and Immunology and
Medicine (Rheumatology), Vanderbilt University, Nashville, TN 37232;
Tularik, South San Francisco, CA 94080; and Departments of
§
Cell Biology and
¶
Medicine (Rheumatology), Baylor College of Medicine, Houston, TX 77030
The cytokines IL-4 and IFN-
exert biologically antagonistic
effects that in part reflect opposing influences on gene transcription.
While the molecular mechanisms for IL-4-mediated transcription
activation have been extensively studied, little is known about
molecular mechanisms required for IL-4 inhibition of IFN- signaling.
We have investigated IL-4 inhibition of the IFN--inducible promoter
for IFN regulatory factor-1 (IRF-1). In a cell line with low endogenous
Stat6, increasing levels of activated Stat6 at constant doses of
IFN- and IL-4 leads to inhibition of the IRF-1 promoter. The
Stat1-dependent IFN- activation sequence element of the IRF-1
promoter is a target for Stat6-mediated inhibition despite apparently
normal Stat1 DNA binding. However, our data are inconsistent with
competition between Stat1 and Stat6 for access to the IRF-1 IFN-
activation sequence or for an essential coactivator as a mechanism for
this Stat6-mediated inhibition. Instead, the data demonstrate that a
threshold of Stat6 transcription activation domains is required for
IL-4-dependent inhibition. The findings provide evidence of a novel
mechanism in which the Stat6 transcription activation domains play a
critical role in the IL-4-mediated inhibition of an IFN--inducible
promoter.
This article has been cited by other articles:
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  S. Goenka, S. H. Cho, and M. Boothby Collaborator of Stat6 (CoaSt6)-associated Poly(ADP-ribose) Polymerase Activity Modulates Stat6-dependent Gene Transcription J. Biol. Chem., June 29, 2007; 282(26): 18732 - 18739. [Abstract] [Full Text] [PDF]
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 S. Goenka and M. Boothby Selective potentiation of Stat-dependent gene expression by collaborator of Stat6 (CoaSt6), a transcriptional cofactor. PNAS, March 14, 2006; 103(11): 4210 - 4215. [Abstract] [Full Text] [PDF]
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 L. Stephenson, M. H. Johns, E. Woodward, A. L. Mora, and M. Boothby An IL-4R{alpha} Allelic Variant, I50, Acts as a Gain-of-Function Variant Relative to V50 for Stat6, But Not Th2 Differentiation J. Immunol., October 1, 2004; 173(7): 4523 - 4528. [Abstract] [Full Text] [PDF]
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C. K. Hwang, C. S. Kim, H. S. Choi, S. R. McKercher, and H. H. Loh Transcriptional Regulation of Mouse {micro} Opioid Receptor Gene by PU.1 J. Biol. Chem., May 7, 2004; 279(19): 19764 - 19774. [Abstract] [Full Text] [PDF]
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S. Goenka, C. Marlar, U. Schindler, and M. Boothby Differential Roles of C-terminal Activation Motifs in the Establishment of Stat6 Transcriptional Specificity J. Biol. Chem., December 12, 2003; 278(50): 50362 - 50370. [Abstract] [Full Text] [PDF]
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Z. Chen, R. Lund, T. Aittokallio, M. Kosonen, O. Nevalainen, and R. Lahesmaa Identification of Novel IL-4/Stat6-Regulated Genes in T Lymphocytes J. Immunol., October 1, 2003; 171(7): 3627 - 3635. [Abstract] [Full Text] [PDF]
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R. A. Corn, M. A. Aronica, F. Zhang, Y. Tong, S. A. Stanley, S. R. A. Kim, L. Stephenson, B. Enerson, S. McCarthy, A. Mora, et al. T Cell-Intrinsic Requirement for NF-{kappa}B Induction in Postdifferentiation IFN-{gamma} Production and Clonal Expansion in a Th1 Response J. Immunol., August 15, 2003; 171(4): 1816 - 1824. [Abstract] [Full Text] [PDF]
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C. M. Litterst and E. Pfitzner An LXXLL Motif in the Transactivation Domain of STAT6 Mediates Recruitment of NCoA-1/SRC-1 J. Biol. Chem., September 20, 2002; 277(39): 36052 - 36060. [Abstract] [Full Text] [PDF]
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J. Major, J. E. Fletcher, and T. A. Hamilton IL-4 Pretreatment Selectively Enhances Cytokine and Chemokine Production in Lipopolysaccharide-Stimulated Mouse Peritoneal Macrophages J. Immunol., March 1, 2002; 168(5): 2456 - 2463. [Abstract] [Full Text] [PDF]
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C. M. Litterst and E. Pfitzner Transcriptional Activation by STAT6 Requires the Direct Interaction with NCoA-1 J. Biol. Chem., November 30, 2001; 276(49): 45713 - 45721. [Abstract] [Full Text] [PDF]
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V. T. Nguyen and E. N. Benveniste IL-4-Activated STAT-6 Inhibits IFN-{gamma}-Induced CD40 Gene Expression in Macrophages/Microglia J. Immunol., December 1, 2000; 165(11): 6235 - 6243. [Abstract] [Full Text] [PDF]
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Y. Ohmori and T. A. Hamilton Interleukin-4/STAT6 Represses STAT1 and NF-kappa B-dependent Transcription through Distinct Mechanisms J. Biol. Chem., November 22, 2000; 275(48): 38095 - 38103. [Abstract] [Full Text] [PDF]
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