Local interleukin-12 gene transfer promotes conversion of an acute arthritis to a chronic destructive arthritis
Corresponding Author
Leo A. B. Joosten
University Medical Center Nijmegen, Nijmegen, The Netherlands
Rheumatology Research Laboratory, University Medical Center Nijmegen, PO Box 9101, Nijmegen 6500 HB, The NetherlandsSearch for more papers by this authorMarleen Heuvelmans-Jacobs
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorErik Lubberts
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorFons A. J. Van De Loo
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorAndrew C. Bakker
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorMonique M. A. Helsen
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorCarl D. Richards
McMaster University, Hamilton, Ontario, Canada
Search for more papers by this authorWim B. Van Den Berg
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorCorresponding Author
Leo A. B. Joosten
University Medical Center Nijmegen, Nijmegen, The Netherlands
Rheumatology Research Laboratory, University Medical Center Nijmegen, PO Box 9101, Nijmegen 6500 HB, The NetherlandsSearch for more papers by this authorMarleen Heuvelmans-Jacobs
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorErik Lubberts
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorFons A. J. Van De Loo
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorAndrew C. Bakker
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorMonique M. A. Helsen
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorCarl D. Richards
McMaster University, Hamilton, Ontario, Canada
Search for more papers by this authorWim B. Van Den Berg
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorAbstract
Objective
To 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.
Methods
C57BL/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.
Results
In 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.
Conclusion
These 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.
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