The IFN regulatory factor-1 (IRF-1) DNA binding protein regulates expression of genes that are involved with the induction of immune and inflammatory responses. The present study used mice with a targeted disruption of the IFN regulatory factor-1 gene (IRF-1-/-) to examine the role of this transcription factor in synovial inflammation and nitric oxide production. Intraarticular injection of IL-1 or LPS was associated with a significantly reduced intensity of synovial lining hyperplasia and leukocyte infiltration in the IRF-1-/- mice as compared with wild-type mice of the same parental lineage C57BL/6. Nitric oxide (NO) is involved with the pathogenesis of arthritis, and IRF-1 regulates expression of inducible NO synthase (iNOS) in mononuclear phagocytes. Articular chondrocytes from IRF-1-/- mice produced similar levels of NO in response to IL-1 or LPS. Furthermore, the synergistic induction of NO by IFN-gamma and IL-1 or LPS was almost identical in chondrocytes from wild-type and IRF-1-/- mice. This was in contrast to the expected decrease in NO production by peritoneal macrophages from IRF-1-/- mice, suggesting that IRF-1 is not required for iNOS expression in chondrocytes. These results indicate that IRF-1 has a tissue-specific role in the induction of iNOS. Inhibition of this transcription factor may represent a novel approach in controlling inflammatory diseases such as arthritis.