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To examine the potential role of high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of arthritis. Mice were injected intraarticularly with 1 μg or 5 μg of HMGB-1. Joints were dissected on days 4, 7, and 28 after injection and were evaluated histopathologically and immunohistochemically. To investigate the importance of different white blood cell populations for the development of arthritis, in vivo cell depletion procedures were performed. In addition, spleen cells were cultured in the presence of HMGB-1, and nuclear factor κB (NF-κB) activation was detected by electrophoretic mobility shift assay. Injection of recombinant HMGB-1 (rHMGB-1) into different mouse strains resulted in an overall frequency of arthritis in 80% of the animals. The inflammation was characterized by mild to moderate synovitis and lasted for at least 28 days. The majority of cells found in the inflamed synovium were Mac-1+ macrophages, whereas only a few CD4+ lymphocytes were detected. Pannus formation was observed in some cases 7 and 28 days after HMGB-1 injection. No significant differences were found with respect to incidence and severity of arthritis between mice depleted of monocytes, granulocytes, or lacking T/B lymphocytes. However, combined removal of monocytes and neutrophils resulted in a 43% lower incidence of arthritis. Mice rendered deficient in the interleukin-1 (IL-1) receptor did not develop inflammation upon challenge with HMGB-1. In vitro data corroborate this finding, showing that rHMGB-1 activated NF-κB, a major pathway leading to IL-1 production. Our results indicate that HMGB-1 is not a mere expression of inflammatory responses, but on its own, it triggers joint inflammation by activating macrophages and inducing production of IL-1 via NF-κB activation. [ABSTRACT FROM AUTHOR]