An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint

F. A J van de Loo, A. S K de Hooge, R. L. Smeets, A. C. Bakker, M. B. Bennink, O. J. Arntz, L. A B Joosten, H. M. van Beuningen, P. K. van der Kraan, A. W. Varley, W. B. van den Berg

Research output: Contribution to journalReview articlepeer-review

49 Scopus citations


To achieve a disease-regulated transgene expression for physiologically responsive gene therapy of arthritis, a hybrid promoter was constructed. The human IL-1β enhancer region (-3690 to -2720) upstream of the human IL-6 promoter region (-163 to +12) was essential in mounting a robust response in HIG-82 synovial fibroblasts and in RAW 264,7 macrophages. A replication-deficient adenovirus was engineered with luciferase (Luc) controlled by the IL-1/IL-6 promoter (Ad5.IL-1/IL-6-Luc). LPS caused a 23- and 4.6-fold induction of Luc. activity in RAW cells infected with Ad5.IL-1/ IL-6-Luc or the conventional Ad5.CMV-Luc construct, respectively. Next, adenoviruses (106 ffu) were injected into the knees of C57BI/6 mice. An intra-articular injection of zymosan, 3 days after Ad5.IL-1/IL-6-Luc, increased Luc. activity by 39-fold but had no effect in the Ad5.CMV-Luc joints. The constitutive CMV promoter was rapidly silenced and could not be reactivated in vivo. In contrast, the IL-1/IL-6 promoter could be reactivated by Streptococcal cell wall (SCW)-induced arthritis up to 21 days after infection. Next the IL-1/IL-6 promoter was compared to the C3-Tat/HIV-LTR two-component system in wild-type, IL-6-/- and IL-1-/- gene knockout mice. Both systems responded well to LPS-, zymosan- and SCW-induced arthritis. However, the basal activity of the IL-1/IL-6 promoter was lower and IL-6 independent. This study showed that the IL-1/IL-6 promoter is feasible to achieve disease-regulated transgene expression for treatment of arthritis.

Original languageEnglish (US)
Pages (from-to)581-590
Number of pages10
JournalGene Therapy
Issue number7
StatePublished - Apr 2004


  • Adenovirus
  • Arthritis
  • Gene knockout
  • Inducible promoter
  • Mice

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics


Dive into the research topics of 'An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint'. Together they form a unique fingerprint.

Cite this