Local interleukin‐12 gene transfer promotes conversion of an acute arthritis to a chronic destructive arthritis
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AbstractObjectiveTo determine whether local overexpression of interleukin‐12 (IL‐12), a pleiotropic cytokine that promotes the development of naive T cells into Th1 cells, could aggravate murine streptococcal cell wall (SCW)‐induced arthritis, a model of acute arthritis.MethodsC57BL/6 mice were injected intraarticularly with saline or with 107 plaque‐forming units of control vector (Ad5del70‐3) or IL‐12 vector (AdmIL‐12.1) into the right knee joint 1 day before intraarticular injection of 25 μg of SCW fragments. The development of joint swelling, changes in chondrocyte proteoglycan (PG) synthesis, and joint destruction were examined thereafter.ResultsIn normal joints, high levels of IL‐12 (20 ng/ml on day 1) could be detected after application of the AdmIL‐12.1 vector. After 14 days, expression of IL‐12 was still found locally, but IL‐12 alone did not induce protracted inflammation. Local expression of IL‐12, in combination with SCW, markedly aggravated SCW‐induced arthritis, as determined by enhanced joint swelling and prolonged inhibition of chondrocyte PG synthesis. Histologic examination on day 21 showed a chronic inflammatory process, with persistent cartilage PG depletion, cartilage erosion, and VDIPEN neoepitope expression (indicative of metalloproteinase activation). The mixture of IL‐12 with SCW fragments did not lead to a chronic destructive process in mice deficient for recombination‐activating gene 2, indicating the involvement of lymphocytes. In addition, systemic flare of smoldering SCW arthritis, produced by intravenous injection of SCW fragments, was only seen in the AdmIL‐12/SCW group.ConclusionThese results indicate that local overexpression of IL‐12 promotes conversion of an acute arthritis to a chronic destructive immune‐mediated process, which is more susceptible to flares.
