Magnesium sulfate differentially modulates fetal membrane inflammation in a time-dependent manner

Problem: Chorioamnionitis and infection-associated inflammation are major causes of preterm birth. Magnesium sulfate (MgSO ₄ ) is widely used in obstetrics as a tocolytic; however, its mechanism of action is unclear. This study sought to investigate how MgSO ₄ modulates infection-associated inflammation in fetal membranes (FMs), and whether the response was time dependent. Method of Study: Human FM explants were treated with or without bacterial lipopolysaccharide (LPS); with or without MgSO ₄ added either: 1 hour before LPS; at the same time as LPS; 1 hour post-LPS; or 2 hours post-LPS. Explants were also treated with or without viral dsRNA and LPS, alone or in combination; and MgSO ₄ added 1 hour post-LPS After 24 hours, supernatants were measured for cytokines/chemokines; and tissue lysates measured for caspase-1 activity. Results: Lipopolysaccharide-induced FM inflammation by upregulating the secretion of a number of inflammatory cytokines/chemokines. Magnesium sulfate administered 1-hour post-LPS inhibited FM secretion of IL-1β, IL-6, G-CSF, RANTES, and TNFα. Magnesium sulfate administered 2 hours post-LPS augmented FM secretion of these factors as well as IL-8, IFNγ, VEGF, GROα and IP-10. Magnesium sulfate delivered 1- hour post-LPS inhibited LPS-induced caspase-1 activity, and inhibited the augmented IL-1β response triggered by combination viral dsRNA and LPS. Conclusion: Magnesium sulfate differentially modulates LPS-induced FM inflammation in a time-dependent manner, in part through its modulation of caspase-1 activity. Thus, the timing of MgSO ₄ administration may be critical in optimizing its anti-inflammatory effects in the clinical setting. MgSO ₄ might also be useful at preventing FM inflammation triggered by a polymicrobial viral-bacterial infection.