A two-component expression system that responds to inflammatory stimuli in vivo.
A therapeutic dilemma often complicates the management of inflammatory diseases; the benefits gained from reducing inflammation must be balanced against the potentially harmful consequences of chronic immunosuppression. Gene therapy might address this dilemma by producing anti-inflammatory proteins in response to a patient's endogenous signals, so that recombinant drug production is linked to the intensity and duration of the inflammatory condition. To test this, we have developed inflammation-inducible systems for regulating recombinant protein production in vivo. We describe a two-component expression construct in which (1) the murine complement factor 3 (C3) promoter regulates production of the human immunodeficiency virus (HIV) transactivator of transcription (Tat), and (2) the Tat protein then stimulates protein expression from genes inserted downstream of the the HIV promoter. When incorporated into a nonreplicating adenovirus (Ad.C3-tat/HIV-luc) and studied in a murine model, the construct produces large amounts of recombinant protein in vivo in response to two different inflammatory stimuli.
Varley
A W
AW
Molecular Host Defense Laboratory, UT Southwestern Medical Center, Dallas 75235-9113, USA.
Geiszler
S M
SM
Gaynor
R B
RB
Munford
R S
RS
D000818:Animals; D003176:Complement C3 / Q000235:genetics* / Q000276:immunology; D004790:Enzyme Induction / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000235:genetics; D015696:Gene Products, tat / Q000096:biosynthesis* / Q000235:genetics; D015316:Genetic Therapy / Q000639:trends*; D006801:Humans; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D007509:Irritants; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008813:Mice, Inbred ICR; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014425:Turpentine
D003176:Complement C3; D015696:Gene Products, tat; D007509:Irritants; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D008156:Luciferases; D014425:Turpentine