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Original Article

Interferon Regulatory Factor (Irf)-1 and Irf-2 Regulate Interferon –Dependent Cyclooxygenase 2 Expression

^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
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, Maryland 20814.301-295-1545301-295-3446

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)- alone or in synergy with lipopolysaccharide (LPS) or interleukin 1 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-–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- 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

Abbreviations used in this paper: Cox, cyclooxygenase(s); EMSA, electrophoretic mobility shift assay; GBP, guanylate binding protein; HPRT, hypoxanthine guanine phosphoribosyl transferase; ICSBP, IFN consensus sequence binding protein; iNOS, inducible nitric oxide synthase; IRF, IFN regulatory factor; ISG15, IFN-–stimulated protein 15; ISRE, IFN-stimulated responsive element; JAK, Janus kinase; NF, nuclear factor; NO, nitric oxide; PGHS, PG endoperoxidase H synthase; RT, reverse transcription.

© 2000 The Rockefeller University Press

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