Cell Stress and MKK6b-mediated p38 MAP Kinase Activation Inhibit Tumor Necrosis Factor-induced IκB Phosphorylation and NF-κB Activation

摘要: Tumor necrosis factor (TNF) exerts many actions through activation of the transcription NF-κB. NF-κB is sequestered in cytosol by an inhibitory subunit IκB, which inducibly phosphorylated IκB kinase complex and subsequently degraded. Sodium salicylate (NaSal) can block inhibiting IκBα phosphorylation. Recently, we used specific p38 mitogen-activated protein (MAP) inhibitor SB203580 to demonstrate that inhibition TNF-induced phosphorylation requires NaSal-induced activation. We NaSal similarly inhibits IκBβ degradation a p38-dependent manner. To further examine role p38, determined whether other agents activate degradation. Sorbitol, H2O2, arsenite each blocked induced TNF, reversed effects sorbitol but not arsenite. In addition, H2O2 interleukin-1-induced phosphorylation, whereas inhibited TNF interleukin-1. Transient expression MAP (MKK) 6b(E), constitutive activator reduced both NF-κB-dependent reporter activity. However, MKK7(D), c-Jun N-terminal kinases, failed inhibit these actions. Thus, sustained various stimuli