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.