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O-065 Macrophage Migration Inhibitory Factor Balances Neonatal Innate Immune Responses
  1. T Roger1,
  2. M Weier2,
  3. A Schneider2,
  4. Fcgj Sweep3,
  5. J Bernhagen4,
  6. T Calandra1,
  7. E Giannoni2
  1. 1Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
  2. 2Service of Neonatology and Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
  3. 3Department of Laboratory Medicine, Radboud University, Nijmegen, Netherlands
  4. 4Institute of Biochemistry and Molecular Cell Biology, Aachen University, Aachen, Germany

Abstract

Background The vulnerability to infection observed in newborns is associated with a limited ability to mount efficient immune responses. Elevated circulating levels of anti-inflammatory mediators (adenosine, prostaglandins,...) reduce production of pro-inflammatory cytokines by newborn monocytes upon microbial challenge. We hypothesised that macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine constitutively expressed in blood and immune cells, counter-balances the anti-inflammatory milieu of newborns.

Methods MIF plasma levels were measured by ELISA in 200 healthy subjects, from birth to adulthood. Cord blood monocytes from term newborns were transfected with MIF siRNA, or were incubated with the MIF antagonist ISO-1, recombinant MIF, adenosine and prostaglandin E2 (PGE2) and then stimulated with endotoxin, bacterial lipopeptide, Escherichia coli and Group B Streptococcus (GBS). Intracellular proteins and cell-culture supernatants were collected to quantify MAPK phosphorylation by Western blot and cytokines by ELISA/Luminex.

Results Circulating MIF levels were 10-fold higher in newborns than adults, and decreased during infancy. Newborn monocytes expressed high MIF levels, and released MIF upon stimulation with Escherichia coli and GBS. Inhibition of MIF expression with MIF siRNA or MIF activity with ISO-1 reduced 1.5–5.7-fold microbial product-induced secretion of pro-inflammatory (TNF, IL-1β, IL-6, IL-8, IL-12p40, IL-12p70, IL-23) and anti-inflammatory (IL-10, IL-20, IL-27) cytokines and phosphorylation of p38 and ERK1/2 MAPKs. Recombinant MIF counter-regulated adenosine and PGE2-mediated inhibition of TNF production in Escherichia coli-stimulated newborn monocytes.

Conclusions MIF expression is developmentally regulated, with strikingly elevated levels in newborns compared to adults. High MIF levels at birth may act to balance pro/anti-inflammatory immune responses in newborns.

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