Magnesium Sulfate Increases Intracellular Magnesium Reducing Inflammatory Cytokine Release in Neonates Haruka Suzuki-Kakisaka 1 , Jun Sugimoto 1 , Manas Tetarbe 2 , Andrea M. Romani 2 , Christina M. Ramirez Kitchen 3 , Helene B. Bernstein 1,4 1 Department of Reproductive Biology, Case Western Reserve University School of Medicine, Cleveland, OH, USA; 2 Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA; 3 Department of Biostatistics, School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA; 4 Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, OH, USA Keywords IL-6, inflammation, magnesium, TNF-a Correspondence Helene B. Bernstein, Departments of Reproductive Biology, Molecular Biology and Microbiology, Case Western Reserve University, Wood Building, W210D, 10900 Euclid Avenue, Cleveland, OH 44106-4960, USA. E-mail: hbb22@case.edu Submission January 16, 2013; accepted March 1, 2013. Citation Suzuki-Kakisaka H, Sugimoto J, Tetarbe M, Romani AM, Ramirez Kitchen CM, Bernstein HB. Magnesium sulfate increases intracellular magnesium reducing inflammatory cytokine release in neonates. Am J Reprod Immunol 2013 doi:10.1111/aji.12118 Problem Magnesium sulfate (MgSO 4 ) exposure reduces the risk of cerebral palsy. As neonatal inflammatory cytokine levels strongly correlate with neuro- logic outcome, we hypothesize that MgSO 4 decreases inflammatory cytokine production. Method of study We assessed the effect of MgSO 4 on cellular magnesium levels, cytokine production, and release within THP-1 and cord blood mononuclear cells. Results MgSO 4 exposure increased intracellular magnesium levels, reducing the frequency of THP-1 cells producing IL-1b, IL-8, and TNF-a following LPS stimulation. Significant reductions in the frequency of neonatal monocytes producing TNF-a (48%) and IL-6 (37%) were seen following LPS stimula- tion, and MgSO 4 also significantly decreased the frequency of monocytes producing TNF-a (35%) under basal conditions. Decreased cytokine pro- duction was confirmed via ELISA, demonstrating a sustained effect and dose response. Magnesium also reduced cytokine production following stimulation with TLR ligands representing obstetrical infections (group B Streptococcus and Mycoplasma) and in preterm neonatal monocytes. Conclusion MgSO 4 increases intracellular magnesium, reducing inflammatory cyto- kine production and release, potentially elucidating the mechanism by which MgSO 4 prevents cerebral palsy, eclampsia, and preterm birth. Introduction Perinatal inflammation is associated with chorioam- nionitis, preterm birth, preeclampsia, and adverse neonatal outcome. Increased IL-1b, IL-6, IL-8, tumor necrosis factor-a (TNF-a), and RANTES levels are associated with preterm parturition, preeclampsia, and most importantly, cerebral palsy development. 1–4 Multiple epidemiologic studies have demonstrated that cord blood inflammatory cytokine levels are the best predictor of adverse neurologic outcome. 5 Magnesium sulfate (MgSO 4 ) is frequently utilized to treat preeclampsia and preterm labor, and recent ran- domized controlled clinical trials and meta-analyses establish that antepartum maternal MgSO 4 treatment reduces the risk of cerebral palsy and major motor dysfunction in preterm infants. 6–16 The Cochrane meta-analysis did not address whether magnesium American Journal of Reproductive Immunology (2013) ª 2013 John Wiley & Sons Ltd 1 ORIGINAL ARTICLE