Cytokine Profile of T Cells in the Joints of Rheumatoid Arthritis and Its Murine Models

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that results in the destruction of cartilage and bone in joints. The murine Collagen-Induced Arthritis (CIA) model has been used to investigate the pathogenesis of RA representatively, because it shares many features with RA (Courtenay, et al., 1980; Luross & Williams, 2001). Susceptibility to arthritis of both CIA and RA is associated with the specific major histocompatibility complex class II allele (Gregersen, et al., 1987; Wooley, et al., 1989). In addition, autoantibodies to type II collagen (CII) have been detected from the synovial fluid of RA patients and it has an aggravating effect in both CIA mice and RA (Clague & Moore, 1984; Cook, et al., 1996; Mullazehi, et al., 2007; Tarkowski, et al., 1989). Finally, pathogenic contributions of CD4+ helper T (Th) cells have been reported in both CIA mice and RA (Weyand & Goronzy, 1999; Weyand, et al., 1998). More recently, the SKG mouse which carries a point mutation of the gene encoding zeta-chain-associated protein kinase 70 (ZAP-70) has been reported as a new model of RA. However, there is little information available about the similarities and differences in the pathogenesis of arthritis among these murine models and RA. Interleukin-17 (IL-17) is a cytokine secreted by T cells, natural killer (NK) cells, and neutrophils (Ferretti, et al., 2003), and it induces IL-6, IL-8, chemokine, and metalloproteinase production by target cells (Weaver, et al., 2007). Central pathogenic roles of IL-17 in CIA have also been reported recently. For example, systemic or local IL-17 gene transfer aggravated CIA, whereas administration of an IL-17-blocking antibody ameliorated CIA even after the onset of arthritis (Lubberts, et al., 2001; Lubberts, et al., 2004) and IL-17 deficient mice also showed reduced severity of CIA (Nakae, et al., 2003). Furthermore, IL-23 deficient mice, which show impaired Th17 response, do not exhibit CIA because IL-23 is an essential factor for the maintenance of Th17 cells (Murphy, et al., 2003). Consequently, although the pathological contribution of IL-17 to CIA is evident, it remains unclear with RA. In the present study, we analyzed the phenotypes and cytokine profiles of T cells in the joints of CIA mice kinetically, for the first time, and then analyzed those of SKG mice and RA.