Different Amplifying Mechanisms of Interleukin-17 and Interferon-γ in Fcγ Receptor-Mediated Cartilage Destruction in Murine Immune Complex-Mediated Arthritis

Objective. Previously, we reported that interferon-gamma (IFN gamma) aggravates cartilage destruction in immune complex (IC)-mediated arthritis via up-regulation of activating Fc gamma receptors (Fc gamma R). Recently, we found that interleukin-17 (IL-17) also aggravates cartilage destruction in arthritis models in which ICs are involved, but the underlying mechanism remains unknown. This study was undertaken to determine the role of IL-17 in Fc gamma R-mediated cartilage destruction in IC-mediated arthritis and to compare its effect with that of IFN gamma. Methods. IC-mediated arthritis was passively induced in gamma-chain(-/-) mice, which lack functional activating Fc gamma R, and in wild-type controls. AdIL-17 or a control vector was injected into the knee joints 1 day prior to induction of IC-mediated arthritis. Knee joints were isolated for histologic analysis, and synovium samples were obtained for reverse transcriptase-polymerase chain reaction (RT-PCR). Macrophage (RAW 264.7) cell lines and polymorphonuclear cell (PMN; 32Dcl3) lines were stimulated with IFN gamma or IL-17 for analysis of Fc gamma R expression using RT-PCR and fluorescence-activated cell sorting. Results. IL-17 overexpression prior to induction of IC-mediated arthritis significantly aggravated cartilage destruction and inflammation, characterized by a massive influx of PMNs, which adhered to the cartilage surface. Although IL-17 overexpression increased Fc gamma R messenger RNA levels in the synovium, in vitro stimulation of macrophages and PMNs revealed that, in contrast to IFN gamma, IL-17 did not directly regulate Fc gamma R expression. Despite similar inflammation in AdIL-17-enhanced IC-mediated arthritis in gamma-chain(-/-) mice and wild-type controls, severe cartilage destruction and PMN adherence were completely absent in gamma-chain(-/-) mice. Conclusion. Our findings indicate that IL-17-mediated aggravation of cartilage destruction in IC-mediated arthritis is Fc gamma R dependent. However, in contrast to IFN gamma, which directly up-regulates Fc gamma R expression on macrophages and PMNs, IL-17 enhances cartilage destruction by increasing the local amount of Fc gamma R-bearing neutrophils.