Dimethyl sulfoxide induces heme oxygenase-1 expression via JNKs and Nrf2 pathways in human umbilical vein endothelial cells.

Dimethyl sulfoxide (DMSO) has recently been proposed as an anti-inflammatory and free radical scavenging agent. However, the mechanisms by which DMSO mediates its therapeutic effects are unclear. In this paper, we investigated the capability of DMSO to up-regulate heme oxygenase-1(HO-1) expression, as well as the possible underlying mechanisms in human umbilical vein endothelial cells (HUVECs). DMSO induced HO-1 expression both at the level of mRNA and protein in dose-and time-dependent manners in HUVECs, resulting in increased HO-1 activity. The pharmacological inhibition of cJun-N-terminal kinases (JNKs) blocked the DMSO-induced HO-1 up-regulation, while inhibition of extracellular regulated kinase and p38-MAPK did not block heme oxygenase-1 up-regulation. In addition, the phosphorylation of JNKs was initiated by DMSO, indicating the involvement of this kinase in the observed response. DMSO increased the nuclear translocation of NF-E2-related factor 2 (Nrf2) and enhanced its binding to the anti-oxidant response element. Inhibition of Nrf2 synthesis by small interfering RNA molecules subsequently inhibited HO-1 expression induced by DMSO, indicating DMSO's role in inducing HO-1 expression via Nrf2 activation. Utilizing these findings, the present study identified DMSO as a novel inducer of HO-1 expression and identified the underlying mechanisms involved in this process.