| RRC ID |
2037
|
| 著者 |
Iwaki T, Sugimura M, Nishihira J, Matsuura T, Kobayashi T, Kanayama N.
|
| タイトル |
Recombinant adenovirus vector bearing antisense macrophage migration inhibitory factor cDNA prevents acute lipopolysaccharide-induced liver failure in mice.
|
| ジャーナル |
Lab Invest
|
| Abstract |
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine involved in delayed hypersensitivity and cellular immunity. MIF also acts as a proinflammatory cytokine and counterregulates the anti-inflammatory effects of glucocorticoids. Exogenous gene transfer mediated by adenovirus is useful to study a particular molecular function as well as to develop gene therapy strategies. A recombinant adenovirus containing sense and antisense murine MIF (mMIF) cDNA inserts was constructed using a cosmid-terminal protein complex method. The sense mMIF adenovirus (AxCA-mMIFS) efficiently induced mMIF in COS-7 cells that endogenously lack mMIF in a dose-dependent manner. In contrast, the antisense mMIF adenovirus (AxCA-mMIFAS) inhibited the expression of mMIF in NIH3T3 cells in a dose-dependent manner. To assess the pathophysiologic role of MIF in acute liver failure, we induced acute onset of liver damage in mice (male Jcl:ICR) by a combined treatment of Bacille Calmette-Guerin (BCG) and lipopolysaccharide (LPS). mMIF level in the liver of mice infected with AxCA-mMIFAS showed a significant reduction in MIF production in response to BCG-LPS compared with mice treated without viral infection and with AxCA-mMIFS. In addition, the immunohistochemical staining demonstrated that F4/80 antigen on macrophage was enhanced in liver infected with AxCA-mMIFS but reduced in liver infected with AxCA-mMIFAS. The staining intensity is correlated with the mMIF antigen level in liver tissue. The survival rate of mice infected with AxCA-mMIFAS was significantly higher than that of mice treated with PBS and infected with AxCA-LacZ in BCG-LPS. These results suggest that inhibition of MIF production, using recombinant adenovirus bearing the antisense MIF gene, reduced the mortality rate in BCG-LPS-induced liver failure in mice. This finding might aid in the further development of gene therapy targeting MIF.
|
| 巻・号 |
83(4)
|
| ページ |
561-70
|
| 公開日 |
2003-4-1
|
| DOI |
10.1097/01.lab.0000062857.26210.ef
|
| PMID |
12695559
|
| MeSH |
3T3 Cells
Adenoviridae / genetics*
Animals
BCG Vaccine / administration & dosage
COS Cells
DNA, Complementary / genetics*
Disease Models, Animal
Escherichia coli / immunology
Gene Transfer Techniques
Genetic Vectors*
Lipopolysaccharides / toxicity
Liver / drug effects
Liver / metabolism
Liver / pathology
Liver Failure / chemically induced
Liver Failure / mortality
Liver Failure / pathology
Liver Failure / prevention & control*
Macrophage Migration-Inhibitory Factors / genetics*
Macrophage Migration-Inhibitory Factors / metabolism
Male
Mice
Mice, Inbred ICR
Oligonucleotides, Antisense / therapeutic use*
Recombinant Fusion Proteins
Specific Pathogen-Free Organisms
Survival Rate
Transfection
|
| IF |
4.197
|
| 引用数 |
15
|
|
WOS 分野
|
MEDICINE, RESEARCH & EXPERIMENTAL
PATHOLOGY
|
| リソース情報 |
| 遺伝子材料 |
AxCALacZ (RDB1745) |
