Inflammation-induced recombinant protein expression in vivo using promoters from acute-phase protein genes.
We report that promoters for two murine acute-phase protein (APP) genes, complement factor 3 (C3) and serum amyloid A3 (SAA3), can increase recombinant protein expression in response to inflammatory stimuli in vivo. To deliver APP promoter-luciferase reporter gene constructs to the liver, where most endogenous APP synthesis occurs, we introduced them into a nonreplicating adenovirus vector and injected the purified viruses intravenously into mice. When compared with the low levels of basal luciferase expression observed prior to inflammatory challenge, markedly increased expression from the C3 promoter was detected in liver in response to both lipopolysaccharide (LPS) and turpentine, and lower-level inducible expression was also found in lung. In contrast, expression from the SAA3 promoter was found only in liver and was much more responsive to LPS than to turpentine. After LPS challenge, hepatic luciferase expression increased rapidly and in proportion to the LPS dose. Use of cytokine-inducible promoters in gene transfer vectors may make it possible to produce antiinflammatory proteins in vivo in direct relationship to the intensity and duration of an individual's inflammatory response. By providing endogenously controlled production of recombinant antiinflammatory proteins, this approach might limit the severity of the inflammatory response without interfering with the beneficial components of host defense and immunity.
Varley
A W
AW
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Coulthard
M G
MG
Meidell
R S
RS
Gerard
R D
RD
Munford
R S
RS
D000209:Acute-Phase Proteins / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics*; D015850:Interleukin-6 / Q000097:blood; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; D017931:DNA Primers; D015850:Interleukin-6; D011994:Recombinant Proteins; D008156:Luciferases