The Journal of Experimental Medicine
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Published 20 October 2003. doi:10.1084/jem.20030026
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© Rockefeller University Press, 0022-1007/2003/10/1265 $5.00
The Journal of Experimental Medicine, Volume 198, Number 8, 1265-1276

Differential Regulation of Interleukin (IL)-12 p35 and p40 Gene Expression and Interferon (IFN)-{gamma}–primed IL-12 Production by IFN Regulatory Factor 1

Jianguo Liu1, Shanjin Cao1, Lisa M. Herman2 and Xiaojing Ma1

1 Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021
2 Center for Genomics and Human Genetics, North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030

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: xim2002{at}med.cornell.edu

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)-{gamma} 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-{gamma} and lipopolysaccharide (LPS) correspond to those of its mRNA, and that the nuclear factor {kappa}B 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-{gamma} 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-{gamma} signaling in the selective activation of IL-12 p35 transcription in synergy with LPS-mediated events.

Key Words: IL-12 • IFN-{gamma} • IRF-1 • macrophage • transcription


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