AUTHOR=Rao Zebing , Zhang Na , Xu Ning , Pan Ying , Xiao Mengjun , Wu Junxian , Zhou Hong , Yang Shuo , Chen Yunzi 

TITLE=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

JOURNAL=Frontiers in Immunology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01308

DOI=10.3389/fimmu.2017.01308

ISSN=1664-3224

ABSTRACT=<p>1,25-Dihydroxyvitamin D [1,25(OH)<sub>2</sub>D<sub>3</sub>] is recognized as a key mediator of inflammatory diseases, including sepsis. Clinical studies demonstrate that 1,25 (OH)<sub>2</sub>D<sub>3</sub> protects patients from sepsis, but clinical treatment with 1,25(OH)<sub>2</sub>D<sub>3</sub> is rare. In this study, we report that 1,25(OH)<sub>2</sub>D<sub>3</sub> 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)<sub>2</sub>D<sub>3</sub><italic>via</italic> blocking HMGB1 translocation from the nucleus to the cytoplasm in macrophages. 1,25(OH)<sub>2</sub>D<sub>3</sub> 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)<sub>2</sub>D<sub>3</sub> 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)<sub>2</sub>D<sub>3</sub> upon LPS exposure. Together, we provide evidence that 1,25(OH)<sub>2</sub>D<sub>3</sub> attenuates LPS-induced HMGB1 secretion <italic>via</italic> the Nrf2/HO-1 pathway in macrophages.</p>