Interleukin (IL)-12 is a heterodimeric cytokine consisting of the p40 and p35 chains encoded on separate chromosomes. Coordinated expression of the two constituent genes is crucial for appropriate immune responses in timing, location, and magnitude. Interferon (IFN)-γ priming of IL-12 production by macrophages represents an important physiological process in vivo for escalated cellular response to microbial infections. We provide evidence that IFN regulatory factor (IRF)-1–deficient macrophages have a selective impairment in mRNA synthesis of IL-12 p35 but not the p40 gene, and a strong deficiency in the production of IL-12 p70 but not p40. We demonstrate that the levels of IL-12 p35 protein stimulated by IFN-γ and lipopolysaccharide (LPS) correspond to those of its mRNA, and that the nuclear factor κB signaling pathway is essential for the induction of IL-12 p35 transcription by LPS. IRF-1 plays a major role in the transcriptional activation of the IL-12 p35 gene, but not of the p40 gene, by physically interacting with an inverted IRF element within the IL-12 p35 promoter upon IFN-γ activation. Moreover, IRF-1–mediated transcriptional activation of the p35 promoter requires the cooperation of two adjacent Sp1 elements. Thus, IRF-1 acts as a critical component of IFN-γ signaling in the selective activation of IL-12 p35 transcription in synergy with LPS-mediated events.
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20 October 2003
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October 20 2003
Differential Regulation of Interleukin (IL)-12 p35 and p40 Gene Expression and Interferon (IFN)-γ–primed IL-12 Production by IFN Regulatory Factor 1
Jianguo Liu,
Jianguo Liu
1Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021
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Shanjin Cao,
Shanjin Cao
1Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021
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Lisa M. Herman,
Lisa M. Herman
2Center for Genomics and Human Genetics, North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030
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Xiaojing Ma
Xiaojing Ma
1Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021
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Jianguo Liu
1Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021
Shanjin Cao
1Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021
Lisa M. Herman
2Center for Genomics and Human Genetics, North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030
Xiaojing Ma
1Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021
Address correspondence to Xiaojing Ma, Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021. Phone: (212) 746-4404; Fax: (212) 746-4427; email: [email protected]
Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; IRF, IFN regulatory factor; MOI, multiplicity of infection; NF, nuclear factor; RPA, RNase protection assay.
Received:
January 08 2003
Revision Received:
August 28 2003
Accepted:
September 16 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 198 (8): 1265–1276.
Article history
Received:
January 08 2003
Revision Received:
August 28 2003
Accepted:
September 16 2003
Citation
Jianguo Liu, Shanjin Cao, Lisa M. Herman, Xiaojing Ma; Differential Regulation of Interleukin (IL)-12 p35 and p40 Gene Expression and Interferon (IFN)-γ–primed IL-12 Production by IFN Regulatory Factor 1 . J Exp Med 20 October 2003; 198 (8): 1265–1276. doi: https://doi.org/10.1084/jem.20030026
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