Hexavalent Chromium Cr(VI) Up-Regulates COX-2 Expression through an NF kappa B/c-Jun/AP-1-Dependent Pathway
- 生命科学－已发表论文 
Background: Hexavalent chromium [Cr(VI)] is recognized as a human carcinogen via inhalation. However, the molecular mechanisms by which Cr(VI) causes cancers are not well understood. Objectives: We evaluated cyclooxygenase2 (COX 2) expression and the signaling pathway leading to this induction due to Cr(VI) exposure in cultured cells. Methods: We used the luciferase reporter assay and Western blotting to determine COX 2 induction by Cr(VI). We used dominant negative mutant, genetic knockout, gene knockdown, and chromatin immunoprecipitation approaches to elucidate the signaling pathway leading to COX 2 induction. Results: We found that Cr(VI) exposure induced COX 2 expression in both normal human bronchial epithelial cells and mouse embryonic fibroblasts in a concentration and timedependent manner. Deletion of IKK beta [inhibitor of transcription factor NF kappa B (I kappa B) kinase beta; an upstream kinase responsible for nuclear factor kappa B (NF kappa B) activation] or overexpression of TAM67 (a dominantnegative mutant of cJun) dramatically inhibited the COX 2 induction due to Cr(VI), suggesting that both NF kappa B and cJun/AP1 pathways were required for Cr(VI)induced COX 2 expression. Our results show that p65 and cJun are two major components involved in NF.B and AP1 activation, respectively. Moreover, our studies suggest crosstalk between NF.B and cJun/AP1 pathways in cellular response to Cr(VI) exposure for COX 2 induction. Conclusion: We demonstrate for the first time that Cr(VI) is able to induce COX 2 expression via an NF kappa B/cJun/AP1dependent pathway. Our results provide novel insight into the molecular mechanisms linking Cr(VI) exposure to lung inflammation and carcinogenesis.
出处ENVIRONMENTAL HEALTH PERSPECTIVES，2012,12(4):547-553