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

Abstract

Tumor necrosis factor (TNF) exerts many actions through activation of the transcription factor NF-κB. NF-κB is sequestered in the cytosol by an inhibitory subunit IκB, which is inducibly phosphorylated by an IκB kinase complex and subsequently degraded. Sodium salicylate (NaSal) can block NF- κB activation by inhibiting IκBα phosphorylation. Recently, we used the specific p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 to demonstrate that inhibition of TNF-induced IκBα phosphorylation requires NaSal-induced p38 activation. We demonstrate that NaSal similarly inhibits TNF-induced IκBβ 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 IκB phosphorylation and degradation. Sorbitol, H2O2, and arsenite each blocked IκBα 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 IκBα phosphorylation, whereas arsenite inhibited IκBα 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 IκBα and NF-κB-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 IκB phosphorylation and NF-κB activation.