823: Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism

Abstract

ObjectiveTo determine if magnesium sulfate (MgSO4) influences inflammatory cytokine production.Study DesignMgSO4 exposure before preterm birth reduces the risk of cerebral palsy and major motor dysfunction. As neonatal inflammatory cytokine levels strongly correlate with neurologic outcome, we assessed the effect of MgSO4 on cytokine production within monocytic cell lines, cord blood mononuclear cells and maternal blood from women receiving parenteral magnesium sulfate for clinical indications.ResultsIn vivo MgSO4 treatment substantially reduced maternal TNF-α and IL-6 production. THP-1 cells exposed to TLR4 ligand in the presence of a clinically-effective MgSO4 concentration (6mg/dl) demonstrated reduced IL-1β, IL-6, IL-8 and TNF-α production. We next exposed term and preterm cord blood mononuclear cells to MgSO4 in vitro and found a significantly reduced frequency of neonatal monocytes producing cytokines under constitutive and TLR-stimulated conditions, as measured by intracellular cytokine staining. Total cellular magnesium content rapidly increased upon MgSO4 exposure, and the immunomodulatory effect was mediated by magnesium and not the sulfate moiety of the compound. Decreased cytokine production was linked to lower cytokine and IκBα gene expression and diminished NF-κB activation. Reduced cytokine production was seen following exposure to different TLR ligands, suggesting that magnesium acts intracellularly, directly influencing NF-κB or IκBα activity.ConclusionOur findings potentially elucidate the mechanism by which magnesium sulfate reduces the risk of cerebral palsy and establishes a new paradigm for innate immunoregulation, whereby magnesium plays a critical regulatory role in NF-κB activation, cytokine production, and disease pathogenesis. ObjectiveTo determine if magnesium sulfate (MgSO4) influences inflammatory cytokine production. To determine if magnesium sulfate (MgSO4) influences inflammatory cytokine production. Study DesignMgSO4 exposure before preterm birth reduces the risk of cerebral palsy and major motor dysfunction. As neonatal inflammatory cytokine levels strongly correlate with neurologic outcome, we assessed the effect of MgSO4 on cytokine production within monocytic cell lines, cord blood mononuclear cells and maternal blood from women receiving parenteral magnesium sulfate for clinical indications. MgSO4 exposure before preterm birth reduces the risk of cerebral palsy and major motor dysfunction. As neonatal inflammatory cytokine levels strongly correlate with neurologic outcome, we assessed the effect of MgSO4 on cytokine production within monocytic cell lines, cord blood mononuclear cells and maternal blood from women receiving parenteral magnesium sulfate for clinical indications. ResultsIn vivo MgSO4 treatment substantially reduced maternal TNF-α and IL-6 production. THP-1 cells exposed to TLR4 ligand in the presence of a clinically-effective MgSO4 concentration (6mg/dl) demonstrated reduced IL-1β, IL-6, IL-8 and TNF-α production. We next exposed term and preterm cord blood mononuclear cells to MgSO4 in vitro and found a significantly reduced frequency of neonatal monocytes producing cytokines under constitutive and TLR-stimulated conditions, as measured by intracellular cytokine staining. Total cellular magnesium content rapidly increased upon MgSO4 exposure, and the immunomodulatory effect was mediated by magnesium and not the sulfate moiety of the compound. Decreased cytokine production was linked to lower cytokine and IκBα gene expression and diminished NF-κB activation. Reduced cytokine production was seen following exposure to different TLR ligands, suggesting that magnesium acts intracellularly, directly influencing NF-κB or IκBα activity. In vivo MgSO4 treatment substantially reduced maternal TNF-α and IL-6 production. THP-1 cells exposed to TLR4 ligand in the presence of a clinically-effective MgSO4 concentration (6mg/dl) demonstrated reduced IL-1β, IL-6, IL-8 and TNF-α production. We next exposed term and preterm cord blood mononuclear cells to MgSO4 in vitro and found a significantly reduced frequency of neonatal monocytes producing cytokines under constitutive and TLR-stimulated conditions, as measured by intracellular cytokine staining. Total cellular magnesium content rapidly increased upon MgSO4 exposure, and the immunomodulatory effect was mediated by magnesium and not the sulfate moiety of the compound. Decreased cytokine production was linked to lower cytokine and IκBα gene expression and diminished NF-κB activation. Reduced cytokine production was seen following exposure to different TLR ligands, suggesting that magnesium acts intracellularly, directly influencing NF-κB or IκBα activity. ConclusionOur findings potentially elucidate the mechanism by which magnesium sulfate reduces the risk of cerebral palsy and establishes a new paradigm for innate immunoregulation, whereby magnesium plays a critical regulatory role in NF-κB activation, cytokine production, and disease pathogenesis. Our findings potentially elucidate the mechanism by which magnesium sulfate reduces the risk of cerebral palsy and establishes a new paradigm for innate immunoregulation, whereby magnesium plays a critical regulatory role in NF-κB activation, cytokine production, and disease pathogenesis.