Tumor-Treating Fields Induce RAW264.7 Macrophage Activation Via NK-?B/MAPK Signaling Pathways

Park, Jeong-In; Song, Kyung-Hee; Jung, Seung-Youn; Ahn, Jiyeon; Hwang, Sang-Gu; Kim, Joon; Kim, Eun Ho; Song, Jie-Young

As essential pathways of inflammation, we therefore evaluated the effect of TTFs on NF-kB and MAPKs activation in RAW 264.7 cells. Nuclear factor-kB is a ubiquitous transcription factor that plays a crucial role in inflammatory processes via the induction of a wide variety of genes, including inflammatory cytokines, mediators, and chemokines. 37 The phosphorylation-induced degradation of IkBs activates and dissociates from NF-kB. As demonstrated in the present result, TTFs significantly increased the phosphorylation of IkB-a in RAW 264.7 cells, thereby inducing nuclear translocation and transcriptional activation of NF-kB in macrophages. Moreover, MAPKs regulate various inflammatory mediators, including TNF-a, IL-1b, IL-2, IL-6, cyclooxygenase 2, and iNOS, [38] [39] [40] suggesting that the inflammatory activity of TTFs is associated with its effect on the MAPK signaling pathway, a key upstream signaling pathway in the regulation of inflammatory mediators. 41 Mitogen-activated protein kinases, including ERK, p38, and JNK, participate in the activation of NF-kB to regulate the gene expression and protein synthesis of inflammatory mediators. 41 Interleukin 1b, a major proinflammatory cytokine, can easily activate MAPK pathways. 42, 43 Thus, we investigated whether the inflammatory effects of TTFs involved the MAPK regulation. Indeed, p38 MAPK signaling pathways were obviously activated in TTFs-treated macrophages. Therefore, our results indicate that TTFs may increase inflammatory responses by inducing p38 MAPK pathways in macrophages.