Effects of bilirubin on neutrophil responses in newborn infants.

Abstract:

BACKGROUND:Newborns are susceptible to inflammatory diseases due to defects in clearing activated immune cells from tissues. Therefore, mechanisms have likely evolved to protect neonates from leukocyte-mediated cytotoxicity. Bilirubin has antioxidant activity, and it is possible that it also exerts effects on cellular immune responses in jaundiced infants. OBJECTIVES:We hypothesize that bilirubin increases expression of antioxidant genes and decreases production of inflammatory proteins in neonatal neutrophils. METHODS:Neutrophils were isolated from umbilical cord blood, and from adults for comparison, and treated with bilirubin (10-300 µmol/l, equivalent to unbound bilirubin 3-40 nmol/l), in the presence or absence of lipopolysaccharide (LPS). Expression of genes for antioxidant enzymes [superoxide dismutase (SOD), heme-oxygenase-1 (HO-1)] and heme-dependent enzymes involved in inflammation [NADPH oxidase-1 (NOX-1), cyclooxygenase-2 (COX-2)] was measured by PCR. Inflammatory cytokines were measured by bead array analysis using flow cytometry. RESULTS:We found that LPS induced production of interleukin (IL)-8, IL-1β, and macrophage inhibitory protein-1β (MIP-1β). Bilirubin increased basal production of IL-8 and IL-1β, but downregulated LPS-induced generation of IL-8 and MIP-1β. It also upregulated SOD and HO-1 gene expression. We observed an unexpected bilirubin-induced increase in gene expression of NOX-1 in LPS-activated cells, and of COX-2 in both resting and activated cells. CONCLUSIONS:These findings suggest that bilirubin suppresses inflammation and increases antioxidant enzyme generation in activated neonatal neutrophils. The unexpected increases in NOX-1 and COX-2 expression may represent an early response, with physiologic effects mitigated by increased antioxidant activity. Further studies will be needed to define levels of bilirubin that optimize its protective effects, while minimizing potential inflammatory toxicity.

journal_name

Neonatology

journal_title

Neonatology

authors

Weinberger B,Archer FE,Kathiravan S,Hirsch DS,Kleinfeld AM,Vetrano AM,Hegyi T

doi

10.1159/000343097

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

105-11

issue

2

eissn

1661-7800

issn

1661-7819

pii

000343097

journal_volume

103

pub_type

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