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Essential Role of C-Rel in Nitric-Oxide Synthase-2 Transcriptional Activation: Time-Dependent Control by Salicylate

Vascular Biology Research Center at the Brown Foundation Institute of Molecular Medicine and Division of Hematology, Department of Internal Medicine at the Medical School, University of Texas Health Science Center at Houston, Houston, Texas

To determine the role of C-Rel in nitric-oxide synthase-2 (NOS-2) transcriptional activation, we evaluated the effect of lipopolysaccharide and interferon- (LPS/IFN) on C-Rel DNA binding in RAW 264.7. LPS/IFN-stimulated C-Rel binding peaked at 4 to 8 h and declined at 24 h. Transfection of cells with a C-Rel small interfering RNA abrogated C-Rel binding at all time points. LPS/IFN produced superoxide at 4 h, which subsided at 8 h. C-Rel binding and NOS-2 expression were abrogated by superoxide dismutase or apocynin at 4 h, suggesting a key role that superoxide plays in mediating C-Rel binding and NOS-2 transactivation only at 4 h. We have reported previously that salicylate at 10^-5 M inhibited LPS/IFN-induced CCAAT/enhancer binding protein (C/EBP) binding at 4 h but not at 8 or 24 h. A single dose of salicylate did not inhibit C-Rel binding at any time point. The addition of a second dose of salicylate 4 h before an indicated endpoint suppressed C-Rel but not C/EBP or interferon--regulated factor-1 binding at 8 and 24 h. A single dose of salicylate added with LPS/IFN inhibited NOS-2 expression only at 4 h. However, salicylate supplement inhibited NOS-2 promoter activities and mRNA and protein levels throughout 24 h. Signal profiling with a panel of inhibitors revealed time-dependent switch of signaling pathways. These results demonstrate temporal regulation of transactivator binding by LPS/IFN via evolving signaling pathways. We propose that salicylate inhibits C/EBP binding at 4 h and C-Rel binding at 8 and 24 h by targeting related kinases.

Address correspondence to: Dr. Kenneth K. Wu, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 5.016, Houston, Texas 77030. E-mail: kenneth.k.wu{at}uth.tmc.edu

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