OBJECTIVE: Previously, we reported that interferon-gamma (IFNgamma) aggravates cartilage destruction in immune complex (IC)-mediated arthritis via up-regulation of activating Fcgamma receptors (FcgammaR). 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 FcgammaR-mediated cartilage destruction in IC-mediated arthritis and to compare its effect with that of IFNgamma. METHODS: IC-mediated arthritis was passively induced in gamma-chain(-/-) mice, which lack functional activating FcgammaR, 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 IFNgamma or IL-17 for analysis of FcgammaR 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 FcgammaR messenger RNA levels in the synovium, in vitro stimulation of macrophages and PMNs revealed that, in contrast to IFNgamma, IL-17 did not directly regulate FcgammaR 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 FcgammaR dependent. However, in contrast to IFNgamma, which directly up-regulates FcgammaR expression on macrophages and PMNs, IL-17 enhances cartilage destruction by increasing the local amount of FcgammaR-bearing neutrophils.