Co-expression of IL-18 binding protein and IL-4 regulates Th1/Th2 cytokine response in murine collagen-induced arthritis

摘要

We constructed a recombinant adeno viral vector containing a murine interleukin (IL)-18 binding protein (mIL-18BP) and murine IL-4 (mIL-4) fusion gene (AdmIL-18BP/mIL-4) and used a gene therapy approach to investigate the role of IL-18BPand IL-4 in modulating the T-helper1 and T-helper2 (Th1/Th2) balance in mice with collagen-induced arthritis (CIA). Mice with CIA were intra-articularly injected with 107 pfu/6 μl of either AdmIL- 18BP/mIL-4, or a control adenovirus, or with the control vehicle (phosphate-buffered saline). After intra-articular gene therapy with AdmIL-18BP/mIL-4, the serum levels of tumor necrosis factor-α (TNF-α), γ-inter-feron (IFN-γ), IL-4, IL-10, and IL-18 in mice with CIA were assessed by ELISA. IFN-γ-expressing and IL-4-expressing CD4~+ T cells from mice splenocytes were monitored by flow cytometry. Mice with CIA at weeks 1,2, and 4 after intraarticular injection of AdmIL-18BP/mIL-4 showed significantly increased serum concentrations of IL-4 and IL-10 (P＜0.01 at all time points) but greatly decreased serum concentrations of IFN-γ, TNF-α, and IL-18 (P＜0.01 at all time points) compared to both the control adenovirus and phosphate-buffered saline control groups. The percentage of IFN-γ-producing CD4~+ T cells was significantly decreased in response to local AdmIL-18BP/mIL-4 treatment. The percentage of IL-4-producing CD4~+ T cells increased significantly at 1 week after local injection of AdmIL-18BP/ mIL-4 then returned to normal by week 4. These data indicated the significant modifying effects on the Th1/Th2 imbalance in murine CIA produced by local overexpression of IL-18BP and IL-4. Combination treatment with IL-18BP and IL-4 is a promising potential therapy for rheumatoid arthritis.