Co-expression of IL-18 binding protein and IL-4 regulates Th1/Th2 cytokine response in murine collagen-induced arthritis.
We constructed a recombinant adenoviral 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-18BP and 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 microl 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-alpha (TNF-alpha), gamma-interferon (IFN-gamma), IL-4, IL-10, and IL-18 in mice with CIA were assessed by ELISA. IFN-gamma-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 intra-articular 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-gamma, TNF-alpha, 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-gamma-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.
Leng
Jianhang
J
Center of Clinical Experimental Medicine, The First People's Hospital of Hangzhou, Hangzhou 310006, China. lengjh5@hotmail.com
Yao
Hangping
H
Shen
Junya
J
Wang
Keyi
K
Zhuo
Guangchao
G
Wang
Ziwei
Z
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D013583:Synovial Membrane / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; C118370:interleukin-18 binding protein; D015847:Interleukin-4; D007371:Interferon-gamma