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The role of the interferon regulatory factors, IRF-1 and IRF-2, in LPS-induced cyclooxygenase-2 (COX-2) expression in vivo and in vitro

Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA

Karen Thomas

Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA

Jorge C.G. Blanco

Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA

Cindy A. Salkowski

Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA

Stefanie N. Vogel

Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA, svogel{at}som.umaryland.edu, vogel{at}bob.usuhs.mil

Cyclooxygenase (COX) exists as two isoforms: COX-1, which is constitutively expressed in most cell types; and COX-2, which is inducible by lipopolysaccharide (LPS) and cytokines in a variety of cell types. Although previous studies have implicated two DNA binding proteins, interferon regulatory factor (IRF)-1 and IRF-2, in the regulation of LPS- and IFN--induced COX-2, their effects in vivo and in vitro are not well-defined. Using real-time PCR, COX-2 gene expression in the livers and lungs of mice challenged in vivo and in macrophages stimulated with LPS in vitro was investigated in wild-type and in IRF-1 and IRF-2 knockout mice. In response to 35 mg/kg LPS, IRF-1-, but not IRF-2-deficient mice, exhibited much poorer induction of COX-2 gene expression in both the livers and lungs. In vitro, COX-2 mRNA levels were also poorly induced in IRF-1-deficient macrophages, while IRF-2-deficient macrophages exhibited higher levels than in normal macrophages. IRF-1 and IRF-2 were confirmed to activate and repress expression of the COX-2 promoter, respectively, in a transient transfection system and the role of specific DNA binding sites confirmed by site-specific mutagenesis. Collectively, these data provide evidence for an important role for IRF-1 in vivo and in vitro and for IRF-2 in vitro in the regulation of COX-2 expression by LPS.

Journal of Endotoxin Research, Vol. 8, No. 5, 381-390 (2002)
DOI: 10.1177/09680519020080050101


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