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RI Up-Regulation Induced by Local Adenoviral-Mediated Interferon- Production Aggravates Chondrocyte Death during Immune Complex-Mediated Arthritis
From the Department of Experimental Rheumatology and Advanced Therapeutics,* University Medical Center, Nijmegen, The Netherlands; the Department of Human and Clinical Genetics, University Medical Center, Leiden, The Netherlands; and the Louisiana State University Health Science Center, New Orleans, Louisiana
Using various Fc
R-deficient mice, we have obtained suggestive evidence that FcRI on macrophages is responsible for severe cartilage destruction during arthritis mediated by immune complexes (ICs). This role of FcRI is pronounced in the presence of activated Th1 cells and a likely Th1 cell-derived cytokine mediating up-regulation of FcRI expression is interferon (IFN)-. We now investigated whether local overexpression of IFN- using an adenoviral vector is able to elevate cartilage destruction during experimental immune complex-mediated arthritis (ICA) and to what extent this process is FcRI-mediated. IFN- overexpression during ICA had no significant effect on the total cell mass infiltrating the knee joint. However, a higher percentage of macrophages expressing markers for a proinflammatory phenotype was found and these macrophages were situated in close proximity of the cartilage surface. Interestingly, cartilage destruction as studied by matrix metalloproteinase (MMP)-mediated proteoglycan damage (VDIPEN expression), chondrocyte death, and erosion was significantly increased. This effect of IFN- was only found in the presence of ICs, as IFN- overexpression during zymosan-induced arthritis, which is not IC-dependent, did not lead to severe cartilage destruction. These results imply a crucial role for ICs and the IgG-binding receptors in the aggravation of cartilage damage by IFN-. Local overexpression of IFN- induced increased FcRI mRNA levels in synovium. To study whether this up-regulation of FcRI mediates aggravation of cartilage destruction, ICA was raised in FcRI-/- and their wild-type controls. IFN- resulted in elevated VDIPEN expression, which was still present in FcRI-/-. Of great interest, chondrocyte death remained low in FcRI-/-. These results indicate that IFN- overexpression deteriorates cartilage destruction in the presence of ICs and that FcRI is crucial in the development of chondrocyte death.
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