1,25-Dihydroxyvitamin D Inhibits Lps-Induced High-Mobility Group Box 1 (Hmgb1) Secretion Via Targeting The Nf-E2-Related Factor 2-Hemeoxygenase-1-Hmgb1 Pathway In Macrophages

1,25-Dihydroxyvitamin D [1,25(OH)(2)D3] is recognized as a key mediator of inflammatory diseases, including sepsis. Clinical studies demonstrate that 1,25 (OH)(2)D-3 protects patients from sepsis, but clinical treatment with 1,25(OH)(2)D-3 is rare. In this study, we report that 1,25(OH)(2)D-3 treatment has beneficial effects and improves the survival rate in LPS-induced mouse sepsis model by blocking the secretion of high-mobility group box 1 (HMGB1), a key late regulator of sepsis. LPS-induced HMGB1 secretion is attenuated by 1,25(OH)(2)D-3 via blocking HMGB1 translocation from the nucleus to the cytoplasm in macrophages. 1,25(OH)(2)D-3 can induce the expression of hemeoxygenase-1 (HO-1), which is essential for blocking HMBG1 nuclear translocation and its secretion. When siHO-1 or an HO-1 inhibitor are used, the effect of 1,25(OH)(2)D-3 on inhibition of HMGB1 secretion is suppressed. Considering that HO-1 is a downstream gene of NF-E2-related factor 2 (Nrf2), we further confirm that Nrf2 activation can be activated by 1,25(OH)(2)D-3 upon LPS exposure. Together, we provide evidence that 1,25(OH)(2)D-3 attenuates LPSinduced HMGB1 secretion via the Nrf2/HO-1 pathway in macrophages.