D. Alpert et al., Cell stress and MKK6b-mediated p38 MAP kinase activation inhibit tumor necrosis factor-induced I kappa B phosphorylation and NF-kappa B activation, J BIOL CHEM, 274(32), 1999, pp. 22176-22183
Tumor necrosis factor (TNF) exerts many actions through activation of the t
ranscription 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 phosphoryla
tion. Recently, we used the specific p38 mitogen-activated protein (MAP) ki
nase inhibitor SB203580 to demonstrate that inhibition of TNF-induced I kap
pa B alpha phosphorylation requires NaSal-induced p38 activation. We demons
trate that NaSal similarly inhibits TNF-induced I kappa beta beta degradati
on in a p38-dependent manner. To further examine the role of p38, we determ
ined 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, sor
bitol and H2O2 blocked TNF-induced but not interleukin-1-induced I kappa B
alpha phosphorylation, whereas arsenite inhibited I kappa B alpha phosphory
lation induced by TNF and interleukin-1. Transient expression of MAP kinase
kinase (MKK) 6b(E), a constitutive activator of p38, reduced both TNF-indu
ced phosphorylation of I kappa B alpha and NF-kappa B-dependent reporter ac
tivity. However, MKK7(D), a constitutive activator of c-Jun N-terminal kina
ses, failed to inhibit these TNF actions. Thus, sustained p38 activation by
various stimuli inhibits TNF-induced I kappa B phosphorylation and NF-kapp
a B activation.