Redox/ROS regulation of lipopolysaccharide‐induced mitogen‐activated protein kinase (MAPK) activation and MAPK‐mediated TNF‐α biosynthesis
JJ Haddad, SC Land - British journal of pharmacology, 2002 - Wiley Online Library
JJ Haddad, SC Land
British journal of pharmacology, 2002•Wiley Online LibraryRedox and ROS regulation of MAPK‐mediated TNF‐α biosynthesis is not well
characterized. It was hypothesized that the involvement of the MAPK pathway in regulating
LPS‐mediated TNF‐α secretion is redox‐dependent, NF‐κB‐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 MAPKp38. This was associated with the
activation of MAPK‐activated protein kinase, which phosphorylated the small heat‐shock …
characterized. It was hypothesized that the involvement of the MAPK pathway in regulating
LPS‐mediated TNF‐α secretion is redox‐dependent, NF‐κB‐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 MAPKp38. This was associated with the
activation of MAPK‐activated protein kinase, which phosphorylated the small heat‐shock …
- Redox and ROS regulation of MAPK‐mediated TNF‐α biosynthesis is not well characterized. It was hypothesized that the involvement of the MAPK pathway in regulating LPS‐mediated TNF‐α secretion is redox‐dependent, NF‐κB‐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 MAPKp38. This was associated with the activation of MAPK‐activated protein kinase, which phosphorylated the small heat‐shock protein, Hsp27.
- MAPKp38 inhibition (SB‐203580) abrogated LPS‐induced TNF‐α production. MAPKERK blockade (PD‐98059) attenuated TNF‐α secretion, an effect synergistically amplified in the presence of SB‐203580.
- Regulation of NF‐κB by selective inhibitors revealed that this pathway is partially involved in regulating LPS‐mediated TNF‐α secretion. Whereas the proteasome inhibitor, MG‐132, had no effect on LPS‐mediated TNF‐α production, CAPE, sulfasalazine and SN‐50, a cell‐permeant NF‐κB inhibitor, attenuated but did not abrogate TNF‐α biosynthesis.
- LPS up‐regulated ROS, an effect abrogated by 4′‐hydroxy‐3′‐methoxy‐acetophenone and NAC, which reduced TNF‐α secretion, induced the accumulation of GSH, reduced the concentration of GSSG, and blockaded the phosphorylation/activation of MAPKp38 pathway.
- ROS induced MAPKp38 phosphorylation and selective antioxidants, including the permeant GSH precursor, γ‐GCE, reduced ROS‐dependent MAPKp38 phosphorylation.
- These results indicate that the MAPK pathway and MAPK‐mediated regulation of TNF‐α production is redox‐dependent, GSH‐mediated and requires, at least in part, a NF‐κB/ROS‐sensitive mechanism.
British Journal of Pharmacology (2002) 135, 520–536; doi:10.1038/sj.bjp.0704467
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