Abstract
The interleukin-1 receptor antagonist (IL-1Ra) is an endogenous protein that can prevent the binding of IL-1 to its cell-surface receptors. Among a number of techniques for gene transfer in vivo, the direct injection of naked DNA into muscle is simple, inexpensive and safe. In this study, we evaluated the potential of intramuscular gene therapy with plasmid DNA containing the cDNA for IL-1Ra in the prevention of murine collagen-induced arthritis (CIA). DBA/1 mice were immunized with bovine type II collagen. At 4 weeks after the initial immunization, expression plasmid for IL-1Ra was injected into four selected sites in the thigh and calf muscles of DBA/1 mice. Control mice received the same plasmid, but lacking the IL-1Ra coding sequence. Macroscopic analysis of paws for redness, swelling and deformities showed that the onset of moderate to severe CIA in the paws of mice injected with IL-1Ra DNA was significantly prevented (P<0.05). In addition, both the synovitis and the cartilage erosion in knee joints were dramatically reduced in mice treated with IL-1Ra DNA (P<0.05). The expression of IL-1β was significantly decreased in the ankle joints of mice treated with IL-1Ra (P<0.01). Interestingly, the levels of IL-1Ra in sera and joints after intramuscular injection of IL-1Ra DNA were significantly lower than when protein had been used in previous reports, suggesting that the therapeutic effect may be achieved by an alternative mechanism(s) rather than by systemic elevation of IL-1Ra. These observations provide the first evidence that direct intramuscular injection of expression plasmid for IL-1Ra may effectively suppress the inflammatory pathology in arthritis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kaklamanis PM . Experimental animal models resembling rheumatoid arthritis. Clin Rheumatol 1992; 11: 41–47.
Arend WP, Dayer JM . Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum 1995; 38: 151–160.
Arner EC, Pratta MA . Independent effects of interleukin-1 on proteoglycan breakdown, proteoglycan synthesis, and prostaglandin E2 release from cartilage in organ culture. Arthritis Rheum 1989; 32: 288–297.
Miyasaka N et al. Augmented interleukin-1 production and HLA-DR expression in the synovium of rheumatoid arthritis patients. Possible involvement in joint destruction. Arthritis Rheum 1988; 31: 480–486.
van de Loo FA, Arntz OJ, Otterness IG, van den Berg WB . Protection against cartilage proteoglycan synthesis inhibition by antiinterleukin 1 antibodies in experimental arthritis. J Rheumatol 1992; 19: 348–356.
Eisenberg SP et al. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature 1990; 343: 341–346.
Smith RJ, Chin JE, Sam LM, Justen JM . Biologic effects of an interleukin-1 receptor antagonist protein on interleukin-1-stimulated cartilage erosion and chondrocyte responsiveness. Arthritis Rheum 1991; 34: 78–83.
Hung GL et al. Suppression of intra-articular responses to interleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium. Gene Therapy 1994; 1: 64–69.
Otani K et al. Suppression of antigen-induced arthritis in rabbits by ex vivo gene therapy. J Immunol 1996; 156: 3558–3562.
Dayer JM . The saga of the discovery of IL-1 and TNF and their specific inhibitors in the pathogenesis and treatment of rheumatoid arthritis. Joint Bone Spine 2002; 69: 123–132.
Campion GV et al. Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study Group. Arthritis Rheum 1996; 39: 1092–1101.
Bresnihan B et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998; 41: 2196–2204.
Jiang Y et al. A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum 2000; 43: 1001–1009.
Wooley PH et al. The effect of an interleukin-1 receptor antagonist protein on type II collagen-induced arthritis and antigen-induced arthritis in mice. Arthritis Rheum 1993; 36: 1305–1314.
Joosten LA, Helsen MM, van de Loo FA, van den Berg WB . Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice. A comparative study using anti-TNF alpha, anti- IL-1 alpha/beta, and IL-1Ra. Arthritis Rheum 1996; 39: 797–809.
Granowitz EV et al. Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans. Cytokine 1992; 4: 353–360.
Bendele A et al. Efficacy of sustained blood levels of interleukin-1 receptor antagonist in animal models of arthritis: comparison of efficacy in animal models with human clinical data. Arthritis Rheum 1999; 42: 498–506.
Ghivizzani SC et al. Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc Natl Acad Sci USA 1998; 95: 4613–4618.
Bakker AC et al. Prevention of murine collagen-induced arthritis in the knee and ipsilateral paw by local expression of human interleukin-1 receptor antagonist protein in the knee. Arthritis Rheum 1997; 40: 893–900.
Pan RY et al. Therapy and prevention of arthritis by recombinant adeno-associated virus vector with delivery of interleukin-1 receptor antagonist. Arthritis Rheum 2000; 43: 289–297.
Nishikawa M, Huang L . Nonviral vectors in the new millennium: delivery barriers in gene transfer. Hum Gene Ther 2001; 12: 861–870.
Lee Y et al. Improved expression of vascular endothelial growth factor by naked DNA in mouse skeletal muscles: implication for gene therapy of ischemic diseases. Biochem Biophys Res Commun 2000; 272: 230–235.
Lim BK et al. Local expression of interleukin-1 receptor antagonist by plasmid DNA improves mortality and decreases myocardial inflammation in experimental coxsackieviral myocarditis. Circulation 2002; 105: 1278–1281.
Stuart JM, Townes AS, Kang AH . Collagen autoimmune arthritis. Annu Rev Immunol 1984; 2: 199–218.
Holmdahl R et al. Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol Rev 1990; 118: 193–232.
Piguet PF et al. Evolution of collagen arthritis in mice is arrested by treatment with anti-tumour necrosis factor (TNF) antibody or a recombinant soluble TNF receptor. Immunology 1992; 77: 510–514.
Geiger T et al. Neutralization of interleukin-1 beta activity in vivo with a monoclonal antibody alleviates collagen-induced arthritis in DBA/1 mice and prevents the associated acute-phase response. Clin Exp Rheumatol 1993; 11: 515–522.
Dinarello CA . Interleukin-1 and interleukin-1 antagonism. Blood 1991; 77: 1627–1652.
Hom JT, Bendele AM, Carlson DG . In vivo administration with IL-1 accelerates the development of collagen-induced arthritis in mice. J Immunol 1988; 141: 834–841.
Nouri AM, Panayi GS, Goodman SM . Cytokines and the chronic inflammation of rheumatic disease. I. The presence of interleukin-1 in synovial fluids. Clin Exp Immunol 1984; 55: 295–302.
MacNaul KL et al. Analysis of IL-1 and TNF-alpha gene expression in human rheumatoid synoviocytes and normal monocytes by in situ hybridization. J Immunol 1990; 145: 4154–4166.
Marucha PT, Zeff RA, Kreutzer DL . Cytokine-induced IL-1 beta gene expression in the human polymorphonuclear leukocyte: transcriptional and post-transcriptional regulation by tumor necrosis factor and IL-1. J Immunol 1991; 147: 2603–2608.
Bethea JR et al. Interleukin-1 beta induction of tumor necrosis factor-alpha gene expression in human astroglioma cells. J Neuroimmunol 1992; 36: 179–191.
Song XY et al. Plasmid DNA encoding transforming growth factor-beta1 suppresses chronic disease in a streptococcal cell wall-induced arthritis model. J Clin Invest 1998; 101: 2615–2621.
Dreja H, Annenkov A, Chernajovsky Y . Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis. Arthritis Rheum 2000; 43: 1698–1709.
Ghivizzani SC et al. Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc Natl Acad Sci USA 1998; 4613–4618.
Kim SH et al. Ex vivo gene delivery of IL-1Ra and soluble TNF receptor confers a distal synergistic therapeutic effect in antigen-induced arthritis. Mol Ther 2002; 6: 591–600.
Casares S et al. Antigen presentation by dendritic cells after immunization with DNA encoding a major histocompatibility complex class II-restricted viral epitope. J Exp Med 1997; 186: 1481–1486.
Parker SE et al. Plasmid DNA malaria vaccine: tissue distribution and safety studies in mice and rabbits. Hum Gene Ther 1999; 10: 741–758.
Lew D et al. Cancer gene therapy using plasmid DNA: pharmacokinetic study of DNA following injection in mice. Hum Gene Ther 1995; 6: 553–564.
Kim JM et al. Angiostatin gene transfer as an effective treatment strategy in murine collagen-induced arthritis. Arthritis Rheum 2002; 46: 793–801.
Kim SH et al. Effective treatment of established murine collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express IL-4. J Immunol 2001; 166: 3499–3505.
Bessis N et al. Syngeneic fibroblasts transfected with a plasmid encoding interleukin-4 as non-viral vectors for anti-inflammatory gene therapy in collagen-induced arthritis. J Gene Med 2002; 4: 300–307.
Lubberts E et al. Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction. J Immunol 1999; 163: 4546–4556.
Acknowledgements
J-M Kim and J-G Jeong contributed equally to this work. This work was supported by grant from the Korean Ministry of Health and Welfare (Grant No. 02-PJ1-PG11-VN01-SV01-0031).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kim, JM., Jeong, JG., Ho, SH. et al. Protection against collagen-induced arthritis by intramuscular gene therapy with an expression plasmid for the interleukin-1 receptor antagonist. Gene Ther 10, 1543–1550 (2003). https://doi.org/10.1038/sj.gt.3302042
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3302042
Keywords
This article is cited by
-
Artesunate interfere in modulation of Foxp3 expression in synovial cells in collagen-induced arthritis rats
Chinese Journal of Integrative Medicine (2016)
-
TNFα and IL-1β influence the differentiation and migration of murine MSCs independently of the NF-κB pathway
Stem Cell Research & Therapy (2014)
-
Interleukin-12 as a genetic adjuvant enhances hepatitis C virus NS3 DNA vaccine immunogenicity
Virologica Sinica (2013)
-
Genetic mismatch affects the immunosuppressive properties of mesenchymal stem cells in vitro and their ability to influence the course of collagen-induced arthritis
Arthritis Research & Therapy (2012)
-
Naked DNA expressing two isoforms of hepatocyte growth factor induces collateral artery augmentation in a rabbit model of limb ischemia
Gene Therapy (2010)