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(Journal of Leukocyte Biology. 2001;70:969-976.)
© 2001 by Society for Leukocyte Biology

Mechanisms underlying reduced responsiveness of neonatal neutrophils to distinct chemoattractants

Barry Weinberger*, Debra L. Laskin{dagger}, Thomas M. Mariano{ddagger}, Vasanthi R. Sunil{dagger}, Christina J. DeCoste{dagger}, Diane E. Heck{dagger}, Carol R. Gardner{dagger} and Jeffrey D. Laskin{ddagger}

Departments of
* Pediatrics/Neonatology, and
{ddagger} Environmental and Community Medicine, UMDNJ-Robert Wood Johnson Medical School, and
{dagger} Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey

Correspondence: Barry Weinberger, M.D., Division of Neonatology, St. Peter’s University Hospital, 254 Easton Avenue, New Brunswick, NJ 08903. E-mail: barryw{at}pol.net

Potential mechanisms underlying impaired chemotactic responsiveness of neonatal neutrophils were investigated. Two distinct chemoattractants were compared: bacterially derived N-formyl-methionyl-leucyl-phenylalanine (fMLP) and a unique chemotactic monoclonal antibody, designated DL1.2, which binds to a neutrophil antigen with an apparent molecular mass of 120 kDa. Chemotaxis of neutrophils toward fMLP, as well as DL1.2, was reduced in neonates when compared with adult cells. This did not appear to be a result of decreased fMLP receptor or DL1.2 antigen expression by neonatal neutrophils. fMLP, but not DL1.2, induced a rapid increase in intracellular calcium in adult and neonatal cells, which reached a maximum within 30 s. The calcium response of cells from neonates to fMLP was reduced when compared with adult cells, and an unresponsive subpopulation of neonatal neutrophils was identified. NF-{kappa}B nuclear binding activity induced by fMLP and DL1.2, as well as expression of the p65 NF-{kappa}B subunit and I{kappa}B-{alpha}, was also significantly reduced in neonatal cells, when compared with adult cells. In contrast, although fMLP, but not DL1.2, activated p42/44 and p38 mitogen-activated protein (MAP) kinases in neutrophils, no differences were observed between adults and neonates. Chemotaxis of adult and neonatal neutrophils toward fMLP and DL1.2 was also blocked to a similar extent by inhibitors of phosphatidylinositol 3-kinase, as well as an inhibitor of NF-{kappa}B. These findings indicate that reduced chemotactic responsiveness in neonatal neutrophils is a result of, at least in part, aberrations in chemoattractant-induced signaling. However, the biochemical pathways mediating this defect appear to be related to the specific chemoattractant.

Key Words: neonates • chemotaxis • NF-{kappa}B




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