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Potential gene therapy for glomerulonephritis: Transfection of NFKB decoy inhibited TNF-A induced cytokine and adhesion molecules expression in vivo

Publication ,  Journal Article
Tomita, N; Morishila, R; Gibbons, GH; Tomita, S; Horiuchi, M; Zhang, L; Kaneda, Y; Ogihara, T; Dzau, VJ
Published in: Journal of Investigative Medicine
January 1, 1996

Recent studies have demonstrated that numerous cytokines and adhesion molecules are expressed in lesions of experimental and human glomerulonephritis and have speculated their pathophysiological contributions. These genes are regulated by the transcription factor NFKB which in turn is activated by tumor necrosis factor alpha (TNF-a) and cytokines. In this study we employed a mouse model of nephritis induced by TNF-a to examine if NFKB regulated genes play a role in inflammatory responses in vivo. First, the transduction of NFKB decoy oligodeoxynucleotides (ODN) into cultured mouse mesangial cells abolished the TNF-a induced gene expression and the productions of interleukin(IL)-la, -l β,-6 and ICAM as assessed by RT-PCR and ELISA. Second, to deliver ODN in vivo into mouse kidneys, we infused initially HVJ-liposome containing FITC-labeled ODN into renal artery and demonstrated uptake by both glomeruli and tubules. To study the feasibility of decoy strategy in vivo, the reporter gene, chloramphenicol acetyltransferase (CAT) driven by three tandemly repeated binding sequence was transfected into mouse kidneys, TNF-a stimulated kidney CAT expression in vivo was completely abolished by the administration of NFKB decoy but not by scrambled decoy ODN. Finally we examined the effect of NFKB decoy iransfection on TNF-a induced cytokine and adhesion molecule gene expressions. NFKB decoy but not scrambled decoy, abolished TNF-a induced IL-1 a, IL-1 β, IL-6, ICAM and VCAM mRNA expressions and protein productions as assessed by RT-PCR and ELISA. These effects were specific since NFKB decoy had no effect on the expression of TGF-β and β-actin genes that do not contain the NFKB binding sequence. Our data using the transcription factor decoy strategy demonstrated the importance of NFKB in the regulations in vivo as well as in vitro. These results also suggest the potential usefulness of the NFKB decoy for gene therapy of inflammatory diseases such as glomerulonephritis.

Duke Scholars

Published In

Journal of Investigative Medicine

ISSN

1708-8267

Publication Date

January 1, 1996

Volume

44

Issue

3

Related Subject Headings

  • General Clinical Medicine
  • 3202 Clinical sciences
  • 1103 Clinical Sciences
 

Citation

APA
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MLA
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Tomita, N., Morishila, R., Gibbons, G. H., Tomita, S., Horiuchi, M., Zhang, L., … Dzau, V. J. (1996). Potential gene therapy for glomerulonephritis: Transfection of NFKB decoy inhibited TNF-A induced cytokine and adhesion molecules expression in vivo. Journal of Investigative Medicine, 44(3).
Tomita, N., R. Morishila, G. H. Gibbons, S. Tomita, M. Horiuchi, L. Zhang, Y. Kaneda, T. Ogihara, and V. J. Dzau. “Potential gene therapy for glomerulonephritis: Transfection of NFKB decoy inhibited TNF-A induced cytokine and adhesion molecules expression in vivo.” Journal of Investigative Medicine 44, no. 3 (January 1, 1996).
Tomita N, Morishila R, Gibbons GH, Tomita S, Horiuchi M, Zhang L, et al. Potential gene therapy for glomerulonephritis: Transfection of NFKB decoy inhibited TNF-A induced cytokine and adhesion molecules expression in vivo. Journal of Investigative Medicine. 1996 Jan 1;44(3).
Tomita N, Morishila R, Gibbons GH, Tomita S, Horiuchi M, Zhang L, Kaneda Y, Ogihara T, Dzau VJ. Potential gene therapy for glomerulonephritis: Transfection of NFKB decoy inhibited TNF-A induced cytokine and adhesion molecules expression in vivo. Journal of Investigative Medicine. 1996 Jan 1;44(3).

Published In

Journal of Investigative Medicine

ISSN

1708-8267

Publication Date

January 1, 1996

Volume

44

Issue

3

Related Subject Headings

  • General Clinical Medicine
  • 3202 Clinical sciences
  • 1103 Clinical Sciences