The Journal of Experimental Medicine
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Published online 19 June 2000.
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© The Rockefeller University Press, 0022-1007/2000/6/2131/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 12, June 19, 2000 2131-2144

Original Article

Interferon Regulatory Factor (IRF)-1 and IRF-2 Regulate Interferon {gamma}–dependent Cyclooxygenase 2 Expression

Jorge C. G. Blancoa, Cristina Contursib, Cindy A. Salkowskia, David L. DeWittc, Keiko Ozatob, and Stefanie N. Vogela
a Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
b Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892
c Department of Biochemistry, Michigan State University, East Lansing, Michigan 48824

Correspondence to: Stefanie N. Vogel, Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, Maryland 20814. Tel:301-295-3446 Fax:301-295-1545 E-mail:vogel{at}bob.usuhs.mil.

Cyclooxygenases (Cox) are rate-limiting enzymes that initiate the conversion of arachidonic acid to prostanoids. Cox-2 is the inducible isoform that is upregulated by proinflammatory agents, initiating many prostanoid-mediated pathological aspects of inflammation. In this study, we demonstrate that interferon (IFN)-{gamma} alone or in synergy with lipopolysaccharide (LPS) or interleukin 1{alpha} induces Cox-2 expression in mouse peritoneal macrophages, which is paralleled by changes in Cox-2 protein levels and prostaglandin E2 (PGE2) release. Induction of Cox-2 was abrogated in macrophages that lack IFN regulatory factor (IRF)-1, consistent with an attenuated hepatic mRNA response in IRF-1-/- mice injected with LPS. Conversely, the absence of IRF-2 in macrophages resulted in a significant increase in both basal and inducible Cox-2 gene and protein expression as well as IFN-{gamma}–stimulated PGE2 release, identifying IRF-2 as negative regulator of this promoter. Two IFN stimulation response elements were identified in the mouse Cox-2 promoter that were highly conserved in the human Cox-2 gene. Both bind endogenous IRF-1 and IRF-2 and regulate transcription in an IRF-1/2–dependent manner. Our data demonstrate conclusively the importance of IFN-{gamma} as a direct activator and coactivator of the Cox-2 gene, and the central role of IRF-1/2 family members in this process.

Key Words: inflammation, prostaglandin, macrophage, cytokine, septic shock


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