Induction of TNF alpha in macrophages by vanadate is dependent on activation of transcription factor NF-kappa B and free radical reactions

Citation
Jp. Ye et al., Induction of TNF alpha in macrophages by vanadate is dependent on activation of transcription factor NF-kappa B and free radical reactions, MOL C BIOCH, 198(1-2), 1999, pp. 193-200
Citations number
43
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell & Developmental Biology
Journal title
MOLECULAR AND CELLULAR BIOCHEMISTRY
ISSN journal
0300-8177 → ACNP
Volume
198
Issue
1-2
Year of publication
1999
Pages
193 - 200
Database
ISI
SICI code
0300-8177(199908)198:1-2<193:IOTAIM>2.0.ZU;2-2
Abstract
Vanadium-induced TNF alpha production is believed to play an important role in respiratory disease associated with air pollution and occupational expo sure. While vanadium is able to induce TNF alpha in macrophages or airway e pithelial cells, the underlying mechanism is not well defined. In the prese nt study, mechanisms of vanadate-induced TNF alpha production were analyzed in the murine Raw264.7 cells. Vanadate induces a significant amount of TNF alpha at both the protein and mRNA levels, and the induction is vanadate d ose-dependent. The mechanism analysis was focused on transcriptional regula tion of TNF alpha gene by vanadate. Transient transfection studies show tha t the TNF alpha gene promoter was activated by vanadate and this activation was associated with an increase in DNA binding activity of the nuclear fac tor-kappa B (NF-kappa B). Mutation of the NF-kappa B binding site in the ge ne promoter led to a loss of the promoter responsiveness to vanadate, indic ating requirement of NF-kappa B. This is supported by evidence that inhibit ion of NF-kappa B activation by SN50, a specific NF-kappa B inhibitor, resu lted in a decrease in the TNF alpha production. A role of reactive oxygen s pecies (ROS) was explored in vanadate activity. The result shows that vanad ate-induced TNF alpha production is elevated by NADPH, which enhances vanad ate-mediated generation of ROS, but is inhibited by an antioxidant, N-acety l-L-cysteine (NAC). Modification of TNF alpha production is associated with an enhancement or a repression of NF-kappa B activity by NADPH or NAC, res pectively. Taken together, these results indicate that: (a) activation of t he TNF alpha gene promoter contributes to the vanadate-induced TNF alpha pr oduction; (b) NF-kappa B is required for the vanadate-induced promoter acti vity of TNF alpha gene; (c) free radical reactions are involved in the vana date-induced TNF alpha production and NF-kappa B activation.