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Rheumatology Research Lab, Department of Rheumatology, University Hospital Nijmegen, Nijmegen, The Netherlands; and
Department of Pathology, McMaster University, Hamilton, Ontario, Canada
Rheumatoid arthritis is a chronic inflammatory joint
disease, leading to cartilage and bone destruction. In this study, we
investigated the effects of local IL-4 application, introduced by a
recombinant human type 5 adenovirus vector, in the knee joint of mice
with collagen-induced arthritis. One intraarticular injection with an
IL-4-expressing virus caused overexpression of IL-4 in the mouse knee
joint. Enhanced onset and aggravation of the synovial inflammation were
found in the IL-4 group. However, despite ongoing inflammation,
histologic analysis showed impressive prevention of chondrocyte death
and cartilage erosion. In line with this, chondrocyte proteoglycan
synthesis was enhanced in the articular cartilage. This was quantified
with ex vivo 35S-sulfate incorporation in patellar
cartilage and confirmed by autoradiography on whole knee joint
sections. Reduction of cartilage erosion was further substantiated by
lack of expression of the stromelysin-dependent cartilage proteoglycan
breakdown neoepitope VDIPEN in the Ad5E1 mIL-4-treated knee joint.
Reduced metalloproteinase activity was also supported by markedly
diminished mRNA expression of stromelysin-3 in the synovial tissue.
Histologic analysis revealed marked reduction of polymorphonuclear
cells in the synovial joint space in the IL-4-treated joints. This was
confirmed by immunolocalization studies on knee joint sections using
NIMP-R14 staining and diminished mRNA expression of
macrophage-inflammatory protein-2 in the synovium tissue. mRNA levels
of TNF-
and IL-1ß were suppressed as well, and IL-1ß and nitric
oxide production by arthritic synovial tissue were strongly reduced.
Our data show an impressive cartilage-protective effect of local IL-4
and underline the feasibility of local gene therapy with this cytokine
in arthritis.
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