文摘
Synovial fibroblast hyperplasia, T-cell hyperactivity, B-cell overactivation, and the self-perpetuating interactions among these cell types are major characteristics of rheumatoid arthritis (RA). The inflamed joints of RA patients are hypoxic, with upregulated expression of hypoxia-inducible factor-1 (HIF-1) in RA synovial fibroblasts (RASFs). It remains unknown whether HIF-1 regulates interactions between RASFs and T cells and B cells. We report here that HIF-1 promotes the expression of inflammatory cytokines IL-6, IL-8, TNF-, and IL-1β, and cell–cell contact mediators IL-15, vascular cell adhesion molecule (VCAM)-1, thrombospondin (TSP)-1, and stromal cell-derived factor (SDF)-1 in RASFs. Furthermore, HIF-1 perpetuates RASF-mediated inflammatory Th1- and Th17-cell expansion while differentially inhibiting regulatory B10 and innate-like B cells, leading to increased IFN-, IL-17, and IgG production and decreased protective natural IgM secretion. Our findings suggest that HIF-1 perpetuates the interactions between RASFs and T cells and B cells to induce inflammatory cytokine and autoantibody production, thus exacerbating the severity of RA. Targeting HIF-1 may provide new therapeutic strategies for overcoming this persistent disease.
