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Redox/ROS regulation of lipopolysaccharide-induced mitogen-activated protein kinase (MAPK) activation and MAPK-mediated TNF-alpha biosynthesis.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2002 Jan; Vol. 135 (2), pp. 520-36. - Publication Year :
- 2002
-
Abstract
- Redox and ROS regulation of MAPK-mediated TNF-alpha biosynthesis is not well characterized. It was hypothesized that the involvement of the MAPK pathway in regulating LPS-mediated TNF-alpha secretion is redox-dependent, NF-kappaB-sensitive and attenuated by N-acetyl-L-cysteine (NAC) and other antioxidants. In alveolar epithelial cells, LPS induced a time- and dose-dependent phosphorylation of MAPK(p38). This was associated with the activation of MAPK-activated protein kinase, which phosphorylated the small heat-shock protein, Hsp27. MAPK(p38) inhibition (SB-203580) abrogated LPS-induced TNF-alpha production. MAPK(ERK) blockade (PD-98059) attenuated TNF-alpha secretion, an effect synergistically amplified in the presence of SB-203580. Regulation of NF-kappaB by selective inhibitors revealed that this pathway is partially involved in regulating LPS-mediated TNF-alpha secretion. Whereas the proteasome inhibitor, MG-132, had no effect on LPS-mediated TNF-alpha production, CAPE, sulfasalazine and SN-50, a cell-permeant NF-kappaB inhibitor, attenuated but did not abrogate TNF-alpha biosynthesis. LPS up-regulated ROS, an effect abrogated by 4'-hydroxy-3'-methoxy-acetophenone and NAC, which reduced TNF-alpha secretion, induced the accumulation of GSH, reduced the concentration of GSSG, and blockaded the phosphorylation/activation of MAPK(p38) pathway. ROS induced MAPK(p38) phosphorylation and selective antioxidants, including the permeant GSH precursor, gamma-GCE, reduced ROS-dependent MAPK(p38) phosphorylation. These results indicate that the MAPK pathway and MAPK-mediated regulation of TNF-alpha production is redox-dependent, GSH-mediated and requires, at least in part, a NF-kappaB/ROS-sensitive mechanism.
- Subjects :
- Acetylcysteine pharmacology
Animals
Culture Techniques
Dose-Response Relationship, Drug
Enzyme Activation
Female
Glutathione metabolism
Intracellular Signaling Peptides and Proteins
Mitogen-Activated Protein Kinases antagonists & inhibitors
Mitogen-Activated Protein Kinases physiology
Oxidation-Reduction
Phosphorylation drug effects
Pregnancy
Protein Serine-Threonine Kinases metabolism
Pulmonary Alveoli cytology
Pulmonary Alveoli drug effects
Pulmonary Alveoli enzymology
Rats
Rats, Sprague-Dawley
Signal Transduction drug effects
p38 Mitogen-Activated Protein Kinases
Lipopolysaccharides pharmacology
Mitogen-Activated Protein Kinases metabolism
Reactive Oxygen Species metabolism
Tumor Necrosis Factor-alpha biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1188
- Volume :
- 135
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 11815388
- Full Text :
- https://doi.org/10.1038/sj.bjp.0704467