Nabbe Karin C, van Lent Peter L, Holthuysen Astrid E, Kolls Jay K, Verbeek Sjef, van den Berg Wim B
Department of Experimental Rheumatology and Advanced Therapeutics, University Medical Center, Nijmegen, The Netherlands.
Am J Pathol. 2003 Aug;163(2):743-52. doi: 10.1016/s0002-9440(10)63701-7.
Using various FcgammaR-deficient mice, we have obtained suggestive evidence that FcgammaRI on macrophages is responsible for severe cartilage destruction during arthritis mediated by immune complexes (ICs). This role of FcgammaRI is pronounced in the presence of activated Th1 cells and a likely Th1 cell-derived cytokine mediating up-regulation of FcgammaRI expression is interferon (IFN)-gamma. We now investigated whether local overexpression of IFN-gamma using an adenoviral vector is able to elevate cartilage destruction during experimental immune complex-mediated arthritis (ICA) and to what extent this process is FcgammaRI-mediated. IFN-gamma 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-gamma was only found in the presence of ICs, as IFN-gamma 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-gamma. Local overexpression of IFN-gamma induced increased FcgammaRI mRNA levels in synovium. To study whether this up-regulation of FcgammaRI mediates aggravation of cartilage destruction, ICA was raised in FcgammaRI(-/-) and their wild-type controls. IFN-gamma resulted in elevated VDIPEN expression, which was still present in FcgammaRI(-/-). Of great interest, chondrocyte death remained low in FcgammaRI(-/-). These results indicate that IFN-gamma overexpression deteriorates cartilage destruction in the presence of ICs and that FcgammaRI is crucial in the development of chondrocyte death.
利用各种FcγR缺陷小鼠，我们获得了提示性证据，表明巨噬细胞上的FcγRI在免疫复合物（IC）介导的关节炎期间导致严重的软骨破坏。在活化的Th1细胞存在的情况下，FcγRI的这一作用尤为明显，一种可能由Th1细胞衍生的介导FcγRI表达上调的细胞因子是干扰素（IFN）-γ。我们现在研究了使用腺病毒载体局部过表达IFN-γ是否能够在实验性免疫复合物介导的关节炎（ICA）期间加剧软骨破坏，以及这一过程在多大程度上由FcγRI介导。ICA期间IFN-γ的过表达对浸润膝关节的总细胞量没有显著影响。然而，发现表达促炎表型标志物的巨噬细胞百分比更高，并且这些巨噬细胞位于软骨表面附近。有趣的是，通过基质金属蛋白酶（MMP）介导的蛋白聚糖损伤（VDIPEN表达）、软骨细胞死亡和侵蚀所研究的软骨破坏显著增加。IFN-γ的这种作用仅在IC存在的情况下才被发现，因为在不依赖IC的酵母聚糖诱导的关节炎期间IFN-γ过表达并未导致严重的软骨破坏。这些结果暗示IC和IgG结合受体在IFN-γ加重软骨损伤中起关键作用。IFN-γ的局部过表达导致滑膜中FcγRI mRNA水平升高。为了研究FcγRI的这种上调是否介导软骨破坏的加重，在FcγRI（-/-）及其野生型对照中引发了ICA。IFN-γ导致VDIPEN表达升高，这在FcγRI（-/-）中仍然存在。非常有趣的是，FcγRI（-/-）中的软骨细胞死亡仍然很低。这些结果表明，在IC存在的情况下，IFN-γ过表达会使软骨破坏恶化，并且FcγRI在软骨细胞死亡的发生中至关重要。
