Biologically active 1,25-dihydroxyvitamin D3 protects against experimental sepsis by negatively regulating the Toll-like receptor 4/myeloid differentiation primary response gene 88/Toll-IL-1 resistance-domain-containing adapter-inducing interferon-β signaling pathway.

Abstract

The hormonally active form of vitamin D (VD), 1,25‑dihydroxyvitamin D3, has been reported to be a key immunoregulator in the reduction of inflammation. In this study, we investigated the effects of VD in an experimental sepsis cell model, and the underlying mechanisms. The sepsis cell model was first established in monocytes, isolated from newborns and healthy adults, which were stimulation with lipopolysaccharide (LPS). We observed that cell viability was significantly impaired in the monocytes after LPS stimulation, using a Cell Counting Kit‑8 and trypan blue assays. Additionally, ELISA revealed that LPS stimulation significantly elevated the expression of interleukin 6 (IL‑6), IL‑10 and tumor necrosis factor‑α (TNF‑α). The expression levels of Toll‑like receptor (TLR4), myeloid differentiation primary response gene 88 (MyD88), and Toll‑IL‑1 resistance‑domain‑containing adapter‑inducing interferon‑β (TRIF) mRNA were also significantly elevated under LPS stimulation using reverse transcription‑quantitative PCR and western blot analysis. VD treatment could significantly suppress the effects of LPS simulation on monocytes by negatively regulating inflammatory cytokines and TLR4/MyD88/TRIF signaling. Furthermore, a regulatory feedback mechanism was proposed to involve TLR4, MyD88 and TRIF in the sepsis cell model. In conclusion, VD may effectively decrease the release of inflammatory cytokines by inhibiting the TLR4/MyD88/TRIF signaling pathway, could be considered as a potential therapeutic agent for the treatment of sepsis.