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-1beta 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.