Selective inhibition of collagen gene expression in fibroblasts by an interferon-gamma transgene.
Because interferon-gamma (IFN-gamma) selectively inhibits collagen gene expression, we hypothesized that expression of IFN-gamma cDNA in fibroblasts might be a useful strategy to inhibit the development of fibrosis. A replication-deficient E1-, E3- adenovirus vector encoding murine IFN-gamma (AdCM VmIFN gamma) was constructed. Infection of murine fibroblasts with AdCM VmIFN gamma in vitro was well tolerated. The results showed that IN F-gamma mRNA was expressed in infected cells, and as much as 17.7 ng of mIFN-gamma/10(6) cells was secreted into culture supernatants. Steady-state levels of alpha 1 (I) procollagen mRNA were decreased by 90% in infected cells compared to uninfected cells. The inhibition of collagen mRNA expression was partially abrogated with a neutralizing anti-mIFN-gamma antibody. Secretion of total collagen by AdCM VmIFN gamma-infected fibroblasts was decreased by 60% compared to uninfected cells. Induction cells. Induction of cytokine responsive gene-2 expression in AdCM VmIFN gamma-infected cells demonstrated that suppression of collagen production was a selective response. The results suggest a novel strategy of cytokine gene transfer and expression for the treatment of fibrotic lung diseases.
Jaffe
H A
HA
Department of Medicine, University of Illinois at Chicago College of Medicine 60607-7173, USA.
Gao
Z
Z
Mori
Y
Y
Li
L
L
Varga
J
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics* / Q000378:metabolism; D003673:Defective Viruses; D005347:Fibroblasts / Q000378:metabolism* / Q000821:virology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013489:Suppression, Genetic; D019076:Transgenes / Q000502:physiology*
D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; D003094:Collagen; D007770:L-Lactate Dehydrogenase