title: Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism.
abstract: MgSO(4) exposure before preterm birth is neuroprotective, reducing the risk of cerebral palsy and major motor dysfunction. Neonatal inflammatory cytokine levels correlate with neurologic outcome, leading us to assess the effect of MgSO(4) on cytokine production in humans. We found reduced maternal TNF-α and IL-6 production following in vivo MgSO(4) treatment. Short-term exposure to a clinically effective MgSO(4) concentration in vitro substantially reduced the frequency of neonatal monocytes producing TNF-α and IL-6 under constitutive and TLR-stimulated conditions, decreasing cytokine gene and protein expression, without influencing cell viability or phagocytic function. In summary, MgSO(4) reduced cytokine production in intrapartum women, term and preterm neonates, demonstrating effectiveness in those at risk for inflammation-associated adverse perinatal outcomes. By probing the mechanism of decreased cytokine production, we found that the immunomodulatory effect was mediated by magnesium and not the sulfate moiety, and it was reversible. Cellular magnesium content increased rapidly upon MgSO(4) exposure, and reduced cytokine production occurred following stimulation with different TLR ligands as well as when magnesium was added after TLR stimulation, strongly suggesting that magnesium acts intracellularly. Magnesium increased basal IĸBα levels, and upon TLR stimulation was associated with reduced NF-κB activation and nuclear localization. These findings establish a new paradigm for innate immunoregulation, whereby magnesium plays a critical regulatory role in NF-κB activation, cytokine production, and disease pathogenesis.
authors.affiliation: Department of Reproductive Biology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Sugimoto
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Romani
authors.forename: Alice M
authors.initials: AM
authors.lastname: Valentin-Torres
authors.forename: Angel A
authors.initials: AA
authors.lastname: Luciano
authors.forename: Christina M
authors.initials: CM
authors.lastname: Ramirez Kitchen
authors.forename: Nicholas
authors.initials: N
authors.lastname: Funderburg
authors.forename: Sam
authors.initials: S
authors.lastname: Mesiano
authors.forename: Helene B
authors.initials: HB
authors.lastname: Bernstein
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005312:Fetal Blood / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology*; D056747:Immunomodulation / Q000276:immunology*; D007231:Infant, Newborn; D007234:Infant, Premature / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D008278:Magnesium Sulfate / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D008278:Magnesium Sulfate