Activation of nuclear factor-kappaB and its suppression by dexamethasone in polymorphonuclear leukocytes: newborn versus adult.
Polymorphonuclear leukocytes (PMN) of the newborn, to a greater extent than those of the adult, have the ability to amplify PMN recruitment to an inflammatory site by their own release of IL-8, and this process is inhibited by dexamethasone. The aim of the present study was to determine whether the regulation of nuclear factor-kappaB (NF-kappaB) could explain the previous observations. NF-kappaB is a transcription factor pivotal for expression of genes encoding inflammatory cytokines such as IL-8, but NF-kappaB has not been previously studied in the PMN of the newborn. NF-kappaB activation was measured by an electrophoretic mobility shift assay in nuclear extracts prepared from PMN isolated from adults and cord blood from newborns. Two distinct molecular forms of NF-kappaB were identified after tumor necrosis factor-alpha stimulation; this included the previously characterized p50/65 heterodimer and a newly identified p50/50 homodimer. Both NF-kappaB dimers were activated by tumor necrosis factor-alpha to significantly higher levels in the neutrophil of the newborn versus adult. An additional new finding was that pretreatment of PMN with dexamethasone (10(-7) M, therapeutic range) inhibited activation of both NF-kappaB complexes in both the newborn and the adult PMN. We conclude that the increased activation of NF-kappaB by the PMN of the newborn may play an important role in neonatal inflammatory reactions. Eventually, specific targeting of NF-kappaB activation in the neutrophil may be an effective molecular approach for the treatment of neutrophil-mediated disorders in the newborn.
Vancurova
I
I
Division of Neonatal-Perinatal Medicine, Schneider Children's Hospital, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.
Bellani
P
P
Davidson
D
D
D000328:Adult; D001483:Base Sequence; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism
D017931:DNA Primers; D016328:NF-kappa B; D003907:Dexamethasone