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.
Guo
Y L
YL
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA. yguo0002@astro.temple.edu
Kang
B
B
Han
J
J
Williamson
J R
JR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005822:Genetic Vectors; D005920:Glomerular Mesangium / Q000166:cytology* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D048290:Mitogen-Activated Protein Kinase 11; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048290:Mitogen-Activated Protein Kinase 11; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580