%0 Journal Article
%T A Possible Mechanism of Cisplatin-Induced Tumor Necrosis Factor (TNF)-¦Á Production in Murine Macrophages
%A Seikou Kim
%A Kouichi Yamamoto
%A Yusuke Nakamura
%A Yuichi Otoyo
%A Atsushi Yamatodani
%J Pharmacology & Pharmacy
%P 146-151
%@ 2157-9431
%D 2013
%I Scientific Research Publishing
%R 10.4236/pp.2013.42021
%X Cisplatin has been used for the treatment of various solid cancers or sarcomas; however, it can induce severe adverse effects. Among these adverse effects, nephrotoxicity, which has the potential to be a dose-limiting factor of this agent, develops due to the secretion of tumor necrosis factor-¦Á (TNF-¦Á) from macrophages; however, the precise mechanisms are still unclear. To elucidate possible mechanisms, we investigated the involvement of mitogen-activated protein kinases (MAPK) and reactive oxygen species (ROS) in cisplatin-induced TNF-¦Á mRNA expression and protein production in the mouse macrophage-like cell line, RAW 264. Cisplatin (1 ¦ÌM) significantly increased TNF-¦Á mRNA expression and protein production. Extracellular-regulated kinase (ERK) and p38 MAPK, but not c-Jun N-terminal kinase (JNK), phosphorylation increased in response to cisplatin. Although an ERK inhibitor (PD98059) suppressed both cisplatin-induced TNF-¦Á mRNA expression and its protein production, a p38 MAPK inhibitor (SB203580) decreased TNF-¦Á protein production only. A JNK inhibitor (SP600125) had no effect on cisplatin-induced TNF-¦Á mRNA expression. Furthermore, a scavenger of ROS, N,N¡¯-dimethylthiourea, suppressed both ERK activation and TNF-¦Á mRNA expression. These results suggest that the phosphorylation of ERK by ROS is involved in cisplatin-induced TNF-¦Á mRNA expression and that the signaling pathway of p38 MAPK is related to TNF-¦Á protein production.
%K Cisplatin
%K Reactive Oxygen Species (ROS)
%K Macrophage
%K RAW264
%K MAPK
%K TNF-<
%K i>
%K ¦Á<
%K /i>
%U http://www.scirp.org/journal/PaperInformation.aspx?PaperID=29702