p38beta MAP kinase protects rat mesangial cells from TNF-alpha-induced apoptosis

p38 MAP kinases (p38) and c-Jun N-terminal protein kinases (JNK) have been associated with TNF-alpha-induced apoptosis. However, recent studies indicate that an early but brief activation of JNK and/or p38 may actually protect some cells from TNF-alpha-induced apoptosis. Whether the activation of JNK and p38 provides a pro- or anti-apoptotic signal for TNF-alpha has been controversial. In this study, we investigated the role of p38 in the regulation of TNF-alpha cytotoxicity in rat mesangial cells. Treatment of the cells with TNF-alpha alone had little effect on their viability, but they became very sensitive to apoptosis when treated with TNF-alpha in the presence of the p38 inhibitor SB 203580. These results suggested that the p38 pathway is critical for mesangial cells to survive the toxic effect of TNF-alpha. Using adenovirus-mediated gene transfer technique, we further demonstrated that p38beta, but not p38alpha, is essential to protect the cells from TNF-alpha toxicity. It has been speculated that there is a synergetic interaction between the p38 and the nuclear factor-kappaB (NF-kappaB) pathways in protecting certain cells from apoptosis. However, expression of neither p38beta nor its dominant negative mutant in mesangial cells interfered with TNF-alpha-induced translocation of NF-kappaB, the initial step of NF-kappaB activation. While it is unclear whether p38beta regulates NF-kappaB transcription activity at other steps, it is apparent that p38beta does not affect TNF-alpha-induced NF-kappaB activation at the stage of nuclear translocation.