N‐acetylcysteine attenuates TNF‐α‐induced p38 MAP kinase activation and p38 MAP kinase‐mediated IL‐8 production by human pulmonary vascular endothelial cells
- 29 January 2001
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 132 (1), 270-276
- https://doi.org/10.1038/sj.bjp.0703787
Abstract
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.Keywords
This publication has 36 references indexed in Scilit:
- Thioredoxin Negatively Regulates p38 MAP Kinase Activation and IL-6 Production by Tumor Necrosis Factor-αBiochemical and Biophysical Research Communications, 1999
- Proinflammatory cytokine–induced and chemical mediator–induced IL-8 expression in human bronchial epithelial cells through p38 mitogen-activated protein kinase–dependent pathwayJournal of Allergy and Clinical Immunology, 1998
- Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK/JNK and p38 Signaling PathwaysScience, 1997
- Purification and Identification of a Major Activator for p38 from Osmotically Shocked CellsPublished by Elsevier BV ,1996
- MAPKs: new JNK expands the groupTrends in Biochemical Sciences, 1994
- A MAP Kinase Targeted by Endotoxin and Hyperosmolarity in Mammalian CellsScience, 1994
- HIV-induced cysteine deficiency and T-cell dysfunction — a rationale for treatment with N-acetylcysteineImmunology Today, 1992
- Regulation of Rransendothelial Neutrophil Migration by Endogenous Interleukin-8Science, 1991
- Southwestern Internal Medicine Conference: Adult Respiratory Distress SyndromeThe American Journal of the Medical Sciences, 1989
- Cytokines as communication signals between leukocytes and endothelial cellsImmunology Today, 1989