Inhibition of the expression of mitogen-activated protein phosphatase-1 potentiates apoptosis induced by tumor necrosis factor-α in rat mesangial cells

Previously we showed that rat mesangial cells are normally resistant to tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis, They are made susceptible to the apoptotic effect of TNF-alpha when pretreated with actinomycin D, cycloheximide or vanadate, A sustained c-Jun N-terminal protein kinase (JNK) activation was closely correlated with the initiation of apoptosis under these conditions. We proposed that a TNF-alpha-inducible phosphatase was responsible for preventing a sustained activation of JNK and consequent apoptosis in these cells (Guo, Y,-L,, Baysal, K., Kang, B., Yang, L,-J., and Williamson, J. R. (1998) J. Biol. Chem. 273, 4027-4034), In the present study we provide further evidence to support this hypothesis. Ro318220, although originally identified as a specific inhibitor of protein kinase C, was subsequently found to be a strong inhibitor of MKP-1 expression, In rat mesangial cells, pretreatment of the cells with Ro318220 blocked expression of MKP-1 induced by TNF-alpha. This treatment also prolonged JNK activation and caused apoptosis, Taken together, our results support the currently controversial hypothesis that the JNK pathway is involved in TNF-alpha-induced apoptosis, In addition, we provide a mechanistic explanation for how mesangial cells in primary culture achieve resistance to TNF-alpha cytotoxicity. Specifically, induction of MKP-1 by TNF-alpha appears to be responsible for protection of the cells from apoptosis by preventing a prolonged activation of JNK.