p38 mitogen-activated protein kinase mediates tumor necrosis factor-alpha-induced apoptosis in rat fetal brown adipocytes

Tumor necrosis factor-alpha (TNF alpha) induces apoptosis and cell growth i nhibition in primary rat fetal brown adipocytes. Here, we examine the role played by some members of the mitogen-activated protein kinase (MAPK) super family. TNFa activates extracellular regulated kinase-1/2 (ERK1/2) and p38M APK. Inhibition of p38MAPK by either SB203580 or SB202190 highly reduces ap optosis induced by TNF alpha, whereas ERK inhibition potentiates it. Moreov er, cotransfection of an active MKK3 mutant and p38MAPK induces apoptosis. p38MAPK inhibition also prevents TNF alpha -induced cell cycle arrest, wher eas MEK1 inhibition enhances this effect, which correlates with changes in proliferating cell nuclear antigen expression, but not in cyclin D1. c-Jun and activating transcription factor-1 are potential downstream effect ers of p38MAPK and ERKs upon TNF alpha treatment. Thus, TNF alpha -induced c-Jun messenger RNA expression requires ERKs activation, whereas p38MAPK in hibition enhances its expression. In addition, TNF alpha -induced activatin g transcription factor-1 phosphorylation is extensively decreased by SB2035 80. However, TNF alpha -induced NF-kappaB DNA-binding activity is independe nt of p38MAPK and ERK activation. On the other hand, C/EBP homology protein does not appear to mediate the actions of TNF alpha, because its expressio n is almost undetectable and even reduced by TNF alpha. Finally, although TNF alpha induces c-Jun N-terminal kinase (JNK) activatio n, transfection of a dominant negative of either JNK1 or JNK2 had no effect on TNF alpha -induced apoptosis. These results suggest that p38MAPK mediat es TNF alpha -induced apoptosis and cell cycle arrest, whereas ERKs do the opposite, and JNKs play no role in this process of apoptosis.