Inhibition of Interleukin-1-Induced Effects in Synoviocytes Transduced with the Human IL-1 Receptor Antagonist cDNA Using an Adenoviral Vector

Abstract

In this report, we present data showing that a recombinant adenoviral vector (Ad.RSVIL-1ra) containing the cDNA for human interleukin-1 receptor antagonist protein (IL-1ra) can genetically modify synoviocytes both in vitro and in vivo. Human synoviocytes infected with Ad.RSVIL-1ra in vitro expressed and secreted high levels of human IL-1ra that were detected by ELISA of tissue culture supernatants. New Zealand White rabbits that received intra-articular injections of Ad.RSVIL-1ra expressed transgenic IL-1ra in synoviocytes, and secretion was detected for at least 4 weeks post-infection. Further, biological activity of the transgenic IL-1ra was demonstrated by its ability to inhibit IL-1-induced prostaglandin E₂ (PGE₂) synthesis in vitro and IL-1-induced glycosaminoglycan (GAG) degradation in vivo. These data demonstrate that recombinant adenoviral vectors can mediate the intra-articular expression of anti-inflammatory proteins and may be a reasonable method to deliver therapeutically relevant proteins for the regional treatment of synovial inflammation. Adenovirus-mediated gene transfer into the cells of the synovial membrane may provide a means to deliver therapeutically active proteins for the local modification of the immune response in inflammatory arthropathies. In this study, we infected type B human synoviocytes in vitro and rabbit synovial lining membrane in vivo with a recombinant human adenovirus containing the cDNA for the human interleukin-1 receptor antagonist protein (IL-1ra). Expression of human IL-1ra was observed both in the transduced synoviocytes in vitro and in the microenvironment of the transduced rabbit synovial membrane in vivo, and the functional activity of the transgenic IL-1ra was suggested by in vitro inhibition of interleukin-1 (IL-1)-induced prostaglandin E₂ (PGE₂) production and by in vivo inhibition of IL-1-induced glycosaminoglycan (GAG) degradation.