Tumor necrosis factor alpha small interfering RNA decreases herpes simplex virus-induced inflammation in a mouse model

Background: Anti-TNF alpha antibodies have been used for treating inflammation in patients. But, more effective and safer drugs need to be developed for improved future therapeutic use. Objectives: To inhibit the expression of TNF alpha we used small interfering RNAs (siRNAs) to reduce over expression of TNF alpha in vitro in cell cultures and in an in vivo Behcet's disease-like (BD) mouse model for amelioration of chronic inflammation. Methods: TNF alpha siRNA was injected intraperitoneally twice with a 1-week interval. To compare the efficacy of TNF alpha siRNA versus an anti-TNF alpha, antibody, Infliximab and Etanercept were administered to symptomatic mice with inflamed tissue. Results: Intraperitoneal delivery of TNF alpha siRNA effectively decreased BD symptoms in 18 of 32 cases (56.3%). Scrambled siRNA treatment decreased BD symptoms in 2 of 19 cases (10.5%). Infliximab was effective in 11 of 27cases (40.7%) and Etanercept was also effective in 9 of 25 cases (36.0%) at the end of the second week after treatment. TNF alpha siRNA reduced serum levels of TNF alpha (1.57 +/- 0.43 pg/ml), compared to levels in mice not injected (84.02 +/- 24.59 pg/ml) (p < 0.01) or scramble injected (118.89 +/- 20.08 pg/ml) (p < 0.01). After single injection of TNF alpha siRNA, improvement of BD symptoms showed at 9 +/- 7th day on an average, contrary, in Infliximab injected group, improvement was apparent at 15 +/- 4th day after injection (P < 0.05). Conclusion: We show that siRNAs can be employed to inhibit cytokine gene expression in an in vivo disease mouse model. This inhibition may, therefore, be attributed to the improvement of inflammatory symptoms. (C) 2008 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.