P38 beta MAP kinase protects rat mesangial cells from TNF-alpha-induced apoptosis

p38 MAP kinases (p38) and c-Jun N-terminal protein kinases (INK) have been associated with TNF-alpha -induced apoptosis. However, recent studies indic ate that an early but brief activation of INK and/or p38 may actually prote ct some cells from TNF-alpha -induced apoptosis. Whether the activation of INK 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 regul ation of TNF-alpha cytotoxicity in rat mesangial cells. Treatment of the ce lls with TNF-alpha alone had little effect on their viability, but they bec ame very sensitive to apoptosis when treated with TNF-alpha in the presence of the p38 inhibitor SB 203580. These results suggested that the p38 pathw ay is critical for mesangial cells to survive the toxic effect of TNF-alpha . Using adenovirus-mediated gene transfer technique, we further demonstrate d that p38 beta, but not p38 alpha, is essential to protect the cells from TNF-alpha toxicity. It has been speculated that there is a synergetic inter action between the p38 and the nuclear factor-kappaB (NF-kappaB) pathways i n protecting certain cells from apoptosis. However, expression of neither p 38 beta nor its dominant negative mutant in mesangial cells interfered with TNF-alpha -induced translocation of NF-kappaB, the initial step of NF-kapp aB activation. While it is unclear whether p38 beta regulates NF-kappaB tra nscription activity at other steps, it is apparent that p38 beta does not a ffect TNF-alpha -induced NF-kappaB activation at the stage of nuclear trans location. (C) 2001 Wiley-Liss, Inc.