The role of IFN regulatory factor-1 in synovitis and nitric oxide production.
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.
Shiraishi
A
A
Department of Medicine, University of California, San Diego, La Jolla 92093, USA.
Dudler
J
J
Lotz
M
M
D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D007270:Injections, Intra-Articular; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000502:physiology*; D007375:Interleukin-1 / Q000008:administration & dosage; D007719:Knee Joint; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000166:cytology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D013585:Synovitis / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D007375:Interleukin-1; C494258:Irf1 protein, mouse; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D014157:Transcription Factors; D009569:Nitric Oxide; D007371:Interferon-gamma