- Meeting abstract
- Open Access
FcγRI up-regulation induced by local adenoviral-mediated IFN-γ production aggravates chondrocyte death during immune-complex-mediated arthritis
Arthritis Res Thervolume 5, Article number: 15 (2003)
Using various FcγR-deficient mice, we have obtained suggestive evidence that FcγRI on macrophages is responsible for severe cartilage destruction during arthritis mediated by immune complexes (ICs) and Th1 cells. In contrast, in arthritis mediated solely by ICs, FcγRIII seems more important. This suggests that T-cell-mediated FcγRI up-regulation promotes pronounced cartilage destruction. A likely Th1-cell-derived cytokine mediating FcγRI expression is interferon-γ (IFN-γ).
In the present study we investigated whether IFN-γ is able to up-regulate cartilage destruction during experimental immune complex-mediated arthritis (ICA) and, if so, whether this mechanism is indeed regulated by FcγRI. IFN-γ was locally overexpressed in the murine knee joint prior to ICA induction by the use of adenoviral vectors. This had no significant effect on joint inflammation as studied by histology. However, irreversible cartilage destruction as studied by the degree of chondrocyte death was markedly enhanced. IFN-γ overexpression resulted in a fivefold increase in chondrocyte death, in comparison with the control group, which had received a control adenoviral vector expressing GFP (AdGFP).
To study whether this effect of IFN-γ was related to the presence of ICs, IFN-γ was also overexpressed in a naive joint and during zymosan-induced arthritis, which is an IC-independent arthritis model. No severe cartilage destruction was found, implying a crucial role for ICs and their receptors (FcγRs) in the IFN-γ effect.
When IFN-γ was overexpressed in murine knee joints, FcγRI mRNA expression was up-regulated in synovial cells. To prove that the aggravation of chondrocyte death by IFN-γ is indeed FcγRI-mediated, ICA was raised in FcγRI-/-. IFN-γ overexpression did not result in significant elevation of joint inflammation either in FcγRI-/- or their wild-type controls. Interestingly, although IFN-γ was overexpressed, chondrocyte death remained absent in FcγRI-/-, whereas in wild-type controls chondrocyte death was highly increased after IFN-γ overexpression.
These results indicate that IFN-γ can aggravate cartilage destruction in an IC-dependent fashion, mediated by FcγRI.