A redox microenvironment is essential for MAPK-dependent secretion of pro-inflammatory cytokines: modulation by glutathione (GSH/GSSG) biosynthesis and equilibrium in the alveolar epithelium.
Cell Immunol
; 270(1): 53-61, 2011.
Article
em En
| MEDLINE
| ID: mdl-21550026
ABSTRACT
The characterization of oxidant (glutathione)-dependent regulation of MAPK(p38/RK)-mediated TNF-α secretion was undertaken in vitro, and the ramifications of the influence of a redox microenvironment were unraveled. Intermittent exposure of alveolar epithelial cells (FATEII) to LPS (endotoxin) transiently and temporally induced the expression of MAPK(p38/RK). This upregulation was associated with the activation of MAPKAP-K(2), manifested by the specific phosphorylation of the downstream heat-shock protein (Hsp)-27. Selective blockading of the MAPK(p38/RK) pathway using the pyridinyl imidazole SB-203580 abrogated the LPS-dependent release of TNF-α. N-acetyl-l-cysteine (NAC), a precursor of glutathione, reduced TNF-α secretion and increased [GSH]. Conversely, l-buthionine-(S,R)-sulfoximine (BSO), an irreversible inhibitor of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting enzyme in the pathway mediating GSH biosynthesis, augmented the secretion of TNF-α and [GSSG] accumulation. Whereas NAC abrogated the phosphorylation of MAPK(p38/RK), BSO reversibly amplified this effect. Furthermore, intermittent exposure of FATEII cells to the exogenous oxidants X/XO and H(2)O(2) upregulated the secretion of pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α; this upregulation was correlated with increasing activity of key glutathione-related enzymes, closely involved with maintaining the cyclic GSH/GSSG equilibrium. These results indicate that a redox microenvironment plays a major role in regulating MAPK-dependent production of cytokines in the alveolar epithelium.
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Base de dados:
MEDLINE
Assunto principal:
Alvéolos Pulmonares
/
Dissulfeto de Glutationa
/
Células Epiteliais Alveolares
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article