Deficient Priming Activity of Newborn Cord Blood–Derived Polymorphonuclear Neutrophilic Granulocytes with Lipopolysaccharide and Tumor Necrosis Factor-α Triggered with Formyl-Methionyl-Leucyl-Phenylalanine

Bortolussi, Robert; Howlett, Susan E.; Rajaraman, K.; Halperin, Scott A.

doi:10.1203/00006450-199309000-00001

Cited by 33 publications

(24 citation statements)

References 13 publications

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“…Labor is associated with the generation of inflammatory cytokines, including IL-6 and IL-8, which are known to stimulate the production of ROIs in neutrophils (33). These findings are consistent with previous reports that the oxidative response to inflammatory mediators is impaired in term neonatal neutrophils (34,35). Decreased responsiveness to inflammatory stimuli may be related to defects in the activation of signaling via the nuclear transcription factors STAT-1 and NF-B in neonatal cells (36).…”

Section: Discussionsupporting

confidence: 89%

Influence of Labor on Neonatal Neutrophil Apoptosis, and Inflammatory Activity

et al. 2007

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Section: Discussionsupporting

confidence: 89%

Influence of Labor on Neonatal Neutrophil Apoptosis, and Inflammatory Activity

et al. 2007

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“…We have shown previously that PMNs from newborns are primed less effectively in vitro with LPS compared to PMNs from adults (7,38). Similarly, some authors have found that monocytes from newborns have a lower response than adult monocytes in the secretion of cytokines, such as TNF-␣, after LPS stimulation (11,36).…”

mentioning

confidence: 93%

Role of MyD88 in Diminished Tumor Necrosis Factor Alpha Production by Newborn Mononuclear Cells in Response to Lipopolysaccharide

Yan¹,

Qing²,

Byers³

et al. 2004

Infect Immun

144

115

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Human newborns are more susceptible than adults to infection by gram-negative bacteria. We hypothesized that this susceptibility may be associated with a decreased response by leukocytes to lipopolysaccharide (LPS). In this study, we compared LPS-induced secretion of tumor necrosis factor alpha (TNF-␣) by mononuclear cells (MNC) from adult peripheral blood and newborn umbilical cord blood in vitro and attempted to determine the mechanisms involved in its regulation. At a high concentration of LPS (10 ng/ml) and in the presence of autologous plasma, MNC from adults and newborns secreted similar amounts of TNF-␣. However, in the absence of plasma, MNC from newborns secreted significantly less TNF-␣ compared to MNC from adults. Moreover, at a low concentration of LPS (0.1 ng/ml) and in the presence of plasma, TNF-␣ secretion was significantly lower for newborn MNC compared to adult MNC. Adults and newborns had similar numbers of CD14 and Toll-like receptor 4 (TLR-4)-positive cells as measured by flow cytometry. However, the intensity of the CD14 marker was greater for adult than for newborn cells. Incubation of cells with LPS led to an increase in CD14 and TLR-4 intensity for adult cells but not for newborn cells. The effect of LPS stimulation of adult or newborn cells was similar for ERK, p38, and IB␣ phosphorylation, as well as IB␣ degradation. Finally, we assessed levels of the TLR-4 adapter protein, the myeloid differentiation antigen 88 (MyD88). We found a direct relation between adult and newborn TNF-␣ secretion and MyD88, which was significantly decreased in newborn monocytes. Since TLR-4 signals intracellularly through the adapter protein, MyD88, we hypothesize that MyD88-dependent factors are responsible for delayed and decreased TNF-␣ secretion in newborn monocytes.

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“…Although neutrophils from newborns exhibit defects in chemotaxis, phagocytosis, and oxidative metabolism (1)(2)(3)(4), infants are at high risk for neutrophil-mediated tissue injury. Activated neutrophils are cleared from inflamed sites by the process of apoptosis, followed by macrophage phagocytosis.…”

mentioning

confidence: 99%

Mechanisms Underlying Reduced Apoptosis in Neonatal Neutrophils

et al. 2005

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Apoptosis, which leads to phagocytosis by mononuclear cells, represents the primary mechanism for removing neutrophils from inflamed tissues and minimizing injury. The present studies show that membrane phosphatidylserine turnover and permeability, as well as DNA fragmentation, were reduced in neutrophils from neonates when compared with adults. The activity of caspase 3 and expression of the proapoptotic proteins Bax, Bad, and Bak were also decreased in neonatal relative to adult neutrophils. These findings are consistent with impaired apoptosis in neonatal cells, which may contribute to prolonged inflammation in infants after oxidative stress or infection. Neutrophil apoptosis is induced by endogenous ligands such as Fas (FasL), which engage death receptors of the tumor necrosis factor/nerve growth factor superfamily, including Fas receptor (FasR). We found that expression of FasR was decreased in neonatal when compared with adult cells. Moreover, neonatal neutrophils did not undergo apoptosis in response to anti-FasR antibody and exhibited impaired chemotaxis to soluble FasL. However, in both adult and neonatal cells, p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase inhibitors blocked Fas-induced activity. These data suggest that prolonged survival of neonatal neutrophils at injured sites is due, in part, to reduced responsiveness to FasL. This may be related to decreased expression of both FasR and Bcl-2-family proteins that mediate neutrophil apoptosis. Human neutrophils are the primary effector cells in acute inflammation and are rapidly recruited from the bloodstream to injured sites. Although neutrophils from newborns exhibit defects in chemotaxis, phagocytosis, and oxidative metabolism (1-4), infants are at high risk for neutrophil-mediated tissue injury. Activated neutrophils are cleared from inflamed sites by the process of apoptosis, followed by macrophage phagocytosis. This promotes resolution rather than persistence of tissue injury (5,6). Attenuation of neutrophil apoptosis in neonates may contribute to severe and prolonged inflammatory responses. In premature infants, this may play a role in conditions such as bronchopulmonary dysplasia and necrotizing enterocolitis, which result in significant mortality and morbidity.Neutrophil longevity and functional activity are regulated by inflammatory mediators present in the microenvironment.Whereas proinflammatory cytokines, such as interferon-␥ (IFN-␥), granulocyte-monocyte colony-stimulating factor (GM-CSF), and bacterial-derived lipopolysaccharide (LPS), promote neutrophil activation and survival, anti-inflammatory mediators, such as IL-10 (IL-10) and Fas ligand (FasL), are proapoptotic (7-10). These mediators regulate the expression of pro-and antiapoptotic mitochondrial proteins, including Bak, Bad, Bax, and A1, as well as the proapoptotic effector protease caspase 3 (10 -14). Previous studies have demonstrated that the rate of apoptosis is reduced in peripheral blood neutrophils from neonates relative to adult cells (15,16). W...

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Deficient Priming Activity of Newborn Cord Blood–Derived Polymorphonuclear Neutrophilic Granulocytes with Lipopolysaccharide and Tumor Necrosis Factor-α Triggered with Formyl-Methionyl-Leucyl-Phenylalanine

Cited by 33 publications

References 13 publications

Influence of Labor on Neonatal Neutrophil Apoptosis, and Inflammatory Activity

Influence of Labor on Neonatal Neutrophil Apoptosis, and Inflammatory Activity

Role of MyD88 in Diminished Tumor Necrosis Factor Alpha Production by Newborn Mononuclear Cells in Response to Lipopolysaccharide

Mechanisms Underlying Reduced Apoptosis in Neonatal Neutrophils

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