Liposome-mediated, nonviral gene transfer induces a systemic inflammatory response which can exacerbate pre-existing inflammation.
Cationic liposome and plasmid-mediated gene transfer has emerged as a novel technique for the targeted delivery of protein-based therapies in acute inflammatory diseases. However, concerns have arisen that cationic liposomes and plasmid DNA have inherent proinflammatory properties which could exacerbate pre-existing inflammatory processes. In healthy mice, intraperitoneal administration of cationic liposomes (200 nmol) complexed to plasmid DNA (100 microg) induced a proinflammatory response characterized by the induction of tumor necrosis factor alpha and interleukin-1beta mRNA expression. The plasma concentrations of the hepatic acute phase proteins interleukin-6, amyloid A, amyloid P, and seromucoid were also increased (P<0.05), and this response was seen in endotoxin-resistant (C3H/HeJ) mice. The inflammatory response associated with gene transfer increased the mortality and severity of experimentally induced sterile inflammation (pancreatitis). We conclude that systemic administration of cationic liposomes and plasmid DNA is associated with induction of the innate immune response which may exacerbate pre-existing inflammatory processes.
Norman
J
J
Department of Surgery, University of South Florida College of Medicine, Tampa 32610, USA.
Denham
W
W
Denham
D
D
Yang
J
J
Carter
G
G
Abouhamze
A
A
Tannahill
C L
CL
MacKay
S L
SL
Moldawer
L L
LL
D000682:Amyloid / Q000097:blood; D000818:Animals; D002412:Cations; D004247:DNA / Q000008:administration & dosage / Q000009:adverse effects*; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood; D008081:Liposomes / Q000008:administration & dosage / Q000009:adverse effects*; D051379:Mice; D008809:Mice, Inbred C3H; D009961:Orosomucoid / Q000032:analysis; D010195:Pancreatitis / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000682:Amyloid; D002412:Cations; D007375:Interleukin-1; D015850:Interleukin-6; D008081:Liposomes; D009961:Orosomucoid; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D004247:DNA