Shiraishi A, Dudler J, Lotz M
Department of Medicine, University of California, San Diego, La Jolla 92093, USA.
J Immunol. 1997 Oct 1;159(7):3549-54.
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.
干扰素调节因子-1（IRF-1）DNA结合蛋白可调节参与免疫和炎症反应诱导的基因的表达。本研究使用干扰素调节因子-1基因靶向敲除的小鼠（IRF-1-/-）来研究这种转录因子在滑膜炎症和一氧化氮产生中的作用。与同一亲本品系C57BL/6的野生型小鼠相比，向IRF-1-/-小鼠关节腔内注射白细胞介素-1（IL-1）或脂多糖（LPS）后，滑膜衬里增生和白细胞浸润的强度显著降低。一氧化氮（NO）参与关节炎的发病机制，IRF-1调节单核吞噬细胞中诱导型一氧化氮合酶（iNOS）的表达。来自IRF-1-/-小鼠的关节软骨细胞对IL-1或LPS产生的NO水平相似。此外，在野生型和IRF-1-/-小鼠的软骨细胞中，干扰素-γ与IL-1或LPS协同诱导NO的情况几乎相同。这与预期的IRF-1-/-小鼠腹膜巨噬细胞中NO产生的减少形成对比，表明软骨细胞中iNOS的表达不需要IRF-1。这些结果表明，IRF-1在诱导iNOS方面具有组织特异性作用。抑制这种转录因子可能代表一种控制关节炎等炎症性疾病的新方法。
