Basic Studies of Novel Gene Therapy by Regulation of Transcription of the Inflammation-Related Gene.

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To investigate novel anti-inflammatory therapies, we studied a novel carrier for antisense DNA, targeted to pro-inflammatory cytokines. We developed poly-L-lysine/L-serine-polyethylene glycol (PLSP) as a carrier for antisense DNA. Our previous study (Antisense Nucl Acid Drug Dev 6:55-61, 1996) showed that antisense phosphorothioate oligonucleotide targeted to the initiation codon of human interliukin-1β(Il-1β) suppressed production of IL-1β of U937 cells. Then, we used the antisense DNA of IL-1β to examine the effects of several kinds of PLSP. 10kDa and 15kDa molecules of the PSLP were the most potent among them. However, a considerable toxicity and instability were observed when the PSLP was used. We further examined the effects of antisense phosphorothioate oligonucleotide targeted to some sequences of human tumor necrosis factor (TNF)-α gene. In this case, no positive effect was observed. We then studied the anti-inflammatory effects of Tripterygium wilfordii Hook F extract (GTW). GTW inhibited prostaglandin EィイD22ィエD2 production in the human synovial cells due to suppression of cyclooxgenase-2 protein and mRNA, which is similar to those of glucocorticoid. However, the mechanism of action of the GTW was different from that of glucocorticoid. It inhibited nuclear factor-ィイD2KィエD2B activity without acting on glucocorticoid receptor. We also examined effects of changes in signal transduction by introduction of Ki-ras gene into human synovial cells from patients with rheumatoid arthritis. Stimulation by cytokines including TNF-α reduced proliferation rate of ras-introduced synovial cells, whereas they enhanced proliferation on nontreated synovial cells. The mechanism remains to be studied.