A Critical Role for Allograft Inflammatory Factor-1 in the Pathogenesis of Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is characterized by massive synovial proliferation, angiogenesis, subintimal infiltration of inflammatory cells and the production of cytokines such as TNF-α and IL-6. Allograft inflammatory factor-1 (AIF-1) has been identified in chronic rejection of rat cardiac allografts as well as tissue inflammation in various autoimmune diseases. AIF-1 is thought to play an important role in chronic immune inflammatory processes, especially those involving macrophages. In the current work, we examined the expression of AIF-1 in synovial tissues and measured AIF-1 in synovial fluid (SF) derived from patients with either RA or osteoarthritis (OA). We also examined the proliferation of synovial cells and induction of IL-6 following AIF-1 stimulation. Immunohistochemical staining showed that AIF-1 was strongly expressed in infiltrating mononuclear cells and synovial fibroblasts in RA compared with OA. Western blot analysis and semiquantitative RT-PCR analysis demonstrated that synovial expression of AIF-1 in RA was significantly greater than the expression in OA. AIF-1 induced the proliferation of cultured synovial cells in a dose-dependent manner and increased the IL-6 production of synovial fibroblasts and PBMC. The levels of AIF-1 protein were higher in synovial fluid from patients with RA compared with patients with OA (p < 0.05). Furthermore, the concentration of AIF-1 significantly correlated with the IL-6 concentration (r = 0.618, p < 0.01). These findings suggest that AIF-1 is closely associated with the pathogenesis of RA and is a novel member of the cytokine network involved in the immunological processes underlying RA.

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

“…42 Also, a number of studies have implicated this protein in other AIDs, 41 including a recent report showing that AIF1 may be crucial in the pathogenesis of rheumatoid arthritis. 43 In addition to rs2259571, we observed an independent association of rs3132451 in the promoter of the same gene, but this result was most likely an artifact, both judging from the heterogeneity within each of the two individual DRB1-DQA1-DQB1 haplotypes the associations mapped to and the negative result in the T1DGC families. The replication attempt in the T1DGC data set was also negative for rs2259571 for the regression analyses, raising the possibility of a type I error.…”

AIF1 Gene RS2269475:C>T Polymorphism is Associated With Rheumatoid Arthritis Development but not With Disease Activity

“…Kimura et al 6 examined the expression of AIF-1 in synovial tissues and measured AIF-1 in synovial fluid derived from patients with either RA or osteoarthritis as well as assessed the proliferation of synovial cells and induction of interleukin 6 (IL-6) following AIF-1 stimulation. The authors have shown that AIF-1 was strongly expressed in infiltrating mononuclear cells and synovial fibroblasts in RA compared with osteoarthritis.…”

“…The authors suggest that AIF-1 is closely associated with the pathogenesis of RA and is a novel member of the cytokine network involved in the immunological processes underlying RA. 6 AIF-1 is a cytokine playing the significant role in chronic inflammatory processes, Expression of AIF-1 can affect macrophage functional state. In vitro experiments showed that interferon gamma could up-regulate the expression of AIF-1 in macrophages.…”

“…4 In the pathogenesis of RA, numerous proinflammatory cytokines and other mediators enhancing inflammatory response are involved. 5 Kimura et al 6 suggest that AIF-1 is the cytokine playing the significant role in RA pathogenesis.…”

Daintain/AIF-1 accelerates the activation of insulin-like growth factor-1 receptor signaling pathway in HepG2 cells

“…Daintain/AIF-1 can be constitutively expressed in monocytes and macrophages, and is involved in macrophage activation (11,12). It plays a crucial role in many autoimmune diseases (9,(13)(14)(15). In previous studies, daintain/AIF-1 was confirmed to promote the proliferation and migration of breast cancer cells (16,17).…”