The major role of macrophages and their product tumor necrosis factor alpha in the induction of arthritis triggered by bacterial DNA containing CpG motifs

Objective, To understand the mechanisms of arthritis triggered by CpG-conta ining oligonucleotides (ODN), Methods. Following the induction of CpG ODN-triggered arthritis in mice, we analyzed the impact of depletion of immune cells, including neutrophils, n atural killer (NK) cells, and monocyte/macrophages, on the arthritis, as we ll as the impact in SCID mice lacking T and B cells. In addition, tumor nec rosis factor alpha (TNF alpha) knockout mice were studied, and intraarticul ar administration of p65 antisense to nuclear factor kappa B (NF-kappa B) w as used to examine effects in CpG ODN-triggered arthritis. Cytokine messeng er RNA expression in synovial tissue was evaluated by in situ hybridization , Results. The presence of macrophages was mandatory for the mediation of art hritis triggered by CpG ODN, whereas the absence of neutrophils, NK cells, T cells, and B cells was of minor importance in this regard, The proinflamm atory cytokines TNF alpha, interleukin-1 beta, and interleukin-12, which or iginate from macrophages, were frequently found in the inflamed joints, and TNF alpha was confirmed to be an important mediator in the development of arthritis, since the incidence and severity of joint inflammation were mark edly reduced in TNF alpha knockout mice. NF-kappa B exerted an important re gulatory role in the development of CpG ODN-mediated arthritis, since local administration of antisense to the p65 subunit of NF-kappa B diminished th e incidence of inflammation by 50%, Conclusion. Macrophages and their products play an important role in the de velopment of arthritis triggered by bacterial DNA containing CpG motifs.