Program

PO3-4-22

Mild electrical stimulation exerts immunosuppressive effect via hydrogen peroxide production

[Speaker] Mariam Piruzyan:1,2
[Co-author] Ihori Shitanda:1, Yuichiro Shimauchi:1, Marry Ann Suico:1, Tsuyoshi Shuto:1, Hirofumi Kai:1,2
1:Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan, 2:HIGO Program, Kumamoto University, Japan

 Background The inflammatory response is a part of the innate immune response, and employs cellular and plasma-derived agents, such as interferons and cytokines. Excessive cytokine production, however, leads to acute or chronic inflammation. Thus, suppressing excessive production of inflammatory cytokines such as IL-2 and TNF-α can be effective in the treatment of various inflammatory-related diseases. In clinical practice, IL-2 immunosuppressive drugs are being used, but because of their side effects, a need to develop safer methods of inhibiting cytokine production is required. Our previous studies have suggested that mild electrical stimulation (MES) had a dampening effect on inflammatory cytokines. Here, we further investigated the effect of MES on general inflammation in vitro and in vivo.
 Methods For in vitro studies, Jurkat T cells were treated with MES at pulse rate 5500 pps, 1 V/cm for 10 min, and then stimulated with phorbol myristate acetate (PMA)/Ionomycin to cause inflammatory responses. For in vivo studies, we used BALB/c mice stimulated with concanavalin A (ConA) and treated for 20 min with MES (0.1 ms duration, 8 volts and 5500 pps) before (pre-) and after (post-) ConA administration.
 Results MES suppressed the overproduction of IL-2 and TNF-α in PMA/Io-treated Jurkat cells. Interestingly, we found that MES produced hydrogen peroxide (H2O2) in the culture media, which was shown to have anti-inflammatory effect. Moreover, MES inhibited the nuclear translocation of NFAT and NF-κB in PMA/Io-treated Jurkat cells. MES also affected other signaling pathways, such as Nrf2 and MAPK. The effects of MES were inhibited by catalase, indicating that H2O2 is the key molecule that mediates the effects of MES. MES also suppressed the overproduction of inflammatory cytokines and reduced mouse spleen enlargement in ConA-treated BALB/c mice, indicating the potential of MES to inhibit excessive inflammation in vivo.
 Conclusion Our results demonstrate that MES modulates the excessive inflammatory cytokine production via multiple signaling pathways by inducing hydrogen peroxide. These findings shed light on the mechanism of MES and may be considered as a new therapeutic approach to immune diseases.
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