Cell stress and MKK6b-mediated p38 MAP kinase activation inhibit tumor necrosis factor-induced IκB phosphorylation and NF-κB activation

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