Magnesium sulfate enhances lipopolysaccharide tolerance

Lipopolysaccharide (LPS) tolerance is the downregulation of LPS signaling after pre-exposure to LPS, and it provides protection against hyperactive inflammation. Cytokine production decreases during LPS tolerance, and the phenotype of LPS-tolerant monocytes shifts toward M2 (anti-inflammatory) type. Magnesium sulfate (MgSO4) is a widely used anti-inflammatory agent. Although MgSO4 inhibits LPS signaling, the effect of MgSO4 on LPS tolerance is unknown. In the present study, we investigated the in vitro effects of MgSO4 on LPS tolerance. To induce LPS tolerance, THP-1 cells were stimulated with LPS (200 ng/mL, 2 h) after pre-exposure to LPS (200 ng/mL, 24 h) with or without pre-treatment of MgSO4 (20 mM, 24 h). Our results revealed that MgSO4 enhanced LPS tolerance by downregulating nuclear factor-κB (NF-κB)-induced tumor necrosis factor-α or interleukin-6, and upregulating cluster of differentiation 163 (a M2-associated marker). Furthermore, the LPS-triggered upregulation of phosphoinositide 3-kinase (PI3K) was significantly increased during LPS tolerance. MgSO4 activated PI3K, but inhibited NF-κB in LPS-stimulated cells. Notably, MgSO4 mitigated the signaling of both PI3K and NF-κB in LPS-tolerant cells, suggesting the effect of MgSO4 on LPS tolerance relies on the modulation of the crosstalk between PI3K and NF-κB. MgSO4 enhanced LSP tolerance, thus providing evidence for a novel underlying mechanism of the anti-inflammatory effects of MgSO4.