N-acetylcysteine attenuates TNF-α-induced p38 MAP kinase activation and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells
Autor: | Hashimoto, Shu, Gon, Yasuhiro, Matsumoto, Ken, Takeshita, Ikuko, Horie, Takashi |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2001 |
Předmět: |
Mitogen-Activated Protein Kinase Kinases
Tumor Necrosis Factor-alpha MAP Kinase Kinase 3 Blotting Western Interleukin-8 Hydrogen Peroxide MAP Kinase Kinase 6 Protein-Tyrosine Kinases Pulmonary Artery Glutathione p38 Mitogen-Activated Protein Kinases Muscle Smooth Vascular Acetylcysteine Enzyme Activation Papers Calcium-Calmodulin-Dependent Protein Kinases Humans Endothelium Vascular Mitogen-Activated Protein Kinases Phosphorylation Cells Cultured |
Popis: | 1. We have previously shown that tumour necrosis factor-alpha (TNF-alpha) activates p38 mitogen-activated protein (MAP) kinase to produce interleukin-8 (IL-8) by human pulmonary vascular endothelial cells. Reactive oxygen species (ROS) including H(2)O(2) generated by TNF-alpha can act as signalling intermediates for cytokine induction; therefore, scavenging ROS by anti-oxidants is important for the regulation of cytokine production. However, the effect of N-acetylcysteine (NAC), which acts as a precursor of glutathione (GSH) synthesis, on TNF-alpha-induced activation of p38 MAP kinase pathway and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells has not been determined. To clarify these issues, we examined the effect of NAC on TNF-alpha-induced activation of p38 MAP kinase, MAP kinase kinase (MKK) 3 and MKK6 which are upstream regulators of p38 MAP kinase, and p38 MAP kinase-mediated IL-8 production. 2. Human pulmonary vascular endothelial cells that had been preincubated with NAC were stimulated with TNF-alpha and then the activation of p38 MAP kinase and MKK3/MKK6 in the cells and IL-8 concentrations in the culture supernatants were determined. 3. Intracellular GSH levels increased in NAC-treated cells. 4. NAC attenuated TNF-alpha-induced activation of p38 MAP kinase and MKK3/MKK6. 5. NAC attenuated p38 MAP kinase-mediated IL-8 production by TNF-alpha-stimulated cells. 6. These results indicate that the cellular reduction and oxidation (redox) regulated by intracellular GSH is critical for TNF-alpha-induced activation of p38 MAP kinase pathway and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells, and we emphasize that anti-oxidant therapy is an important strategy for the treatment of acute lung injury. |
Databáze: | OpenAIRE |
Externí odkaz: |