Enhancement of Neonatal Innate Defense: Effects of Adding an N-Terminal Recombinant Fragment of Bactericidal/Permeability-Increasing Protein on Growth and Tumor Necrosis Factor-Inducing Activity of Gram-Negative Bacteria Tested in Neonatal Cord Blood Ex Vivo

Levy, Ofer; Sisson, Richard B.; Kenyon, J P; Eichenwald, Eric C.; Macone, Ann B.; Goldmann, Donald A.

doi:10.1128/iai.68.9.5120-5125.2000

Cited by 49 publications

(42 citation statements)

References 37 publications

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“…Perhaps one of the most instructive aspects of our study is the description of yet another noninducible immunomodulatory mechanism in the human amniotic fluid. This is in sharp contrast with the existence of other "acute" phase innate immune systems (defensins, calgranulins, amniotic fluid peptide-1, lactoferrin, bactericidal permeability increasing protein) that seem to be suppressed in the absence of infection (20,43,44,57,58). When one considers the role of the innate immune system as microbes make their way into the amniotic cavity, the value of a temporal reaction becomes obvious.…”

Section: Discussionmentioning

confidence: 48%

Soluble TLR2 Is Present in Human Amniotic Fluid and Modulates the Intraamniotic Inflammatory Response to Infection

Dulay

Buhimschi

Zhao

et al. 2009

The Journal of Immunology

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TLRs are pattern recognition transmembrane receptors that play key roles in innate immunity. A recently discovered soluble truncated form of TLR2 (sTLR2) acts as a decoy receptor, down-regulating the host inflammatory response to bacteria. To identify the presence and functional role of sTLR2 in modulating the intraamniotic inflammatory response to infection, we studied 109 amniotic fluid samples of women with normal pregnancy outcomes (n ‫؍‬ 28) and women with (n ‫؍‬ 39) and without (n ‫؍‬ 42) intraamniotic infection. We sought to demonstrate a functional role of the amniotic fluid sTLR2 in modulating the TLR2 inflammatory signaling in vitro by using a villous explant system. Two sTLR2 forms were identified, and specificity was confirmed with neutralizing peptides. We showed that sTLR2 is present constitutively in amniotic fluid, its levels are gestational age dependent, and we determined that the sTLR2 quantity and functional engagement modulates the intensity of the intraamniotic inflammation elicited by Gram-positive bacteria. In vitro, we demonstrated that challenging placental villous explants with a specific TLR2 agonist (Pam3Cys) induced a significant cytokine response. Notably, preincubation of the preterm, but not near-term, amniotic fluid with Pam3Cys significantly inhibited the ability of this TLR2 agonist to elicit a cytokine reaction. Moreover, depletion of sTLR2 from preterm amniotic fluid removed its neutralizing property. Monensin significantly diminished sTLR2 immunoreactivity, indicating that sTLR2 is the result of intracellular posttranslational processing of TLR2. We conclude that sTLR2 is part of the amniotic fluid innate immune system and participates in regulating the inflammatory response to microbial pathogens. The Journal of Immunology, 2009, 182: 7244 -7253.T he innate immune system is an archaic defense mechanism, phylogenetically preserved to be at the forefront of resistance to microbial infections (1). The human TLRs are essential for triggering an inflammatory innate immune response (2). To date, 13 mammalian TLRs have been identified and 10 of these are present in humans (3). At the maternal-fetal interface, TLRs are expressed not only in immune cells, but also in the trophoblast and decidual cells (4, 5). Moreover, their expression pattern varies according to the stage of pregnancy (5). Such findings provide evidence that during pregnancy, placental TLRs may play a key role in modulating the inflammatory response triggered by infection.TLRs are transmembrane receptors that mediate host defense through the engagement of pathogen-associated molecular patterns (PAMPs) 3 , which are ubiquitous constituents of the bacterial wall (6). TLR2 was the first of 10 human TLRs, proven to be precisely involved in recognition of PAMPs (lipoproteins, peptidoglycan, glycolipids, nucleic acids), representing broad groups of microbial species such as Gram-positive bacteria, Mycobacteria, spirochetes, and Mycoplasmataceae (7,8,9). Traditionally, it has been thought that the extracellular recepto...

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Section: Discussionmentioning

confidence: 48%

Soluble TLR2 Is Present in Human Amniotic Fluid and Modulates the Intraamniotic Inflammatory Response to Infection

Dulay

Buhimschi

Zhao

et al. 2009

The Journal of Immunology

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“…Recently, administration of recombinant BPI to newborn cord blood showed beneficial effects (37), raising the possibility that supplementing BPI may be of benefit to premature newborns with Gram-negative bacteremia, endotoxemia, or both.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Release of Bactericidal/Permeability-Increasing Protein in Newborn Infants

Nupponen

2002

Pediatric Research

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Upon activation, polymorphonuclear leucocytes (PMN) release bactericidal/permability-increasing protein, (BPI) from their azurophil granules. BPI selectively binds to the lipopolysaccharide (LPS) on gram-negative bacteria and induces their death. This study examined plasma BPI concentration levels in healthy newborns and in newborns with clinical sepsis, and the ability of PMN from preterm and term infants to release BPI. We also studied the release of myeloperoxidase (MPO), and the surface expression of adhesion molecule CD11b on PMN. In infants with clinical sepsis, plasma BPI concentration was higher, 27.8 g/L [8.6 -883; median (range)] (n ϭ 11), than in healthy term infants 8.9 g/L (3.9 -179) (n ϭ 17), and in adults 7.3 g/L (0.7 -18.4) (n ϭ 15); p ϭ 0.014, Kruskal-Wallis. In preterm infants (n ϭ 8), the ability of PMN to release BPI in vitro after stimulation with PMA was 8.8, in term infants it was 15.9 (n ϭ 29; p Ͼ 0.05 vs. preterm infants) and in adults 23.4 ng/10 6 PMN (n ϭ 15; p ϭ 0.024 and p Ͼ 0.05 vs. preterm and term infants, respectively Newborn infants, especially those born prematurely, are at risk for overwhelming bacterial infections. A number of immaturities in the host defense system have been reported in newborn infants. Among the immune mechanisms that apparently function suboptimally are the PMN (1). PMN contain multiple antibiotic proteins such as BPI, which is found in human PMN and eosinophils. BPI selectively binds to the LPS on the outer membrane of Gramnegative bacteria, causing immediate growth arrest followed by irreversible damage and then the death of the bacterium (2). BPI also blocks the endotoxic effects of LPS and promotes phagocytosis of BPI-coated bacteria (3, 4).BPI has been localized to azurophil granules, where its hydrophobic C-terminal end is believed to anchor it to the granule membrane. Studies of PMN conducted in vitro suggest that BPI is capable of acting against Gram-negative bacteria in the intracellular environment. Data on isolated cells stimulated to secrete granule contents in vitro and on plasma derived from animals and humans with sepsis in vivo have demonstrated that a portion of cellular BPI stores is released from stimulated PMN (5-9

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“…E. coli K1/r, a bacteremic isolate, was a gift from Dr. A. Cross (University of Maryland, College Park, MD) and was grown as previously described (24). L. monocytogenes serotype 4b (isolated from the cerebrospinal fluid of a child with meningitis; ATCC strain 13932; American Type Culture Collection) was grown in brain heart infusion broth (BD Biosciences) overnight and then in subculture to an OD 650 of 0.5 then resuspended in sterile saline to 3 ϫ 10 9 /ml.…”

Section: Tlr Agonistsmentioning

confidence: 99%

The Adenosine System Selectively Inhibits TLR-Mediated TNF-α Production in the Human Newborn

Levy

Coughlin

Cronstein

et al. 2006

The Journal of Immunology

Self Cite

214

220

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Human newborns are susceptible to microbial infection and mount poor vaccine responses, yet the mechanisms underlying their susceptibility are incompletely defined. We have previously reported that despite normal basal expression of TLRs and associated signaling intermediates, human neonatal cord blood monocytes demonstrate severe impairment in TNF-α production in response to triacylated (TLR 2/1) and diacylated (TLR 2/6) bacterial lipopeptides (BLPs). We now demonstrate that in marked contrast, BLP-induced synthesis of IL-6, a cytokine with anti-inflammatory and Th2-polarizing properties, is actually greater in neonates than adults. Remarkably, newborn blood plasma confers substantially reduced BLP-induced monocyte synthesis of TNF-α, while preserving IL-6 synthesis, reflecting the presence in neonatal blood plasma of a soluble, low molecular mass inhibitory factor (<10 kDa) that we identify as adenosine, an endogenous purine metabolite with immunomodulatory properties. The neonatal adenosine system also inhibits TNF-α production in response to whole microbial particles known to express TLR2 agonist activity, including Listeria monocytogenes, Escherichia coli (that express BLPs), and zymosan particles. Selective inhibition of neonatal TNF-α production is due to the distinct neonatal adenosine system, including relatively high adenosine concentrations in neonatal blood plasma and heightened sensitivity of neonatal mononuclear cells to adenosine A3 receptor-mediated accumulation of cAMP, a second messenger that inhibits TLR-mediated TNF-α synthesis but preserves IL-6 production. We conclude that the distinct adenosine system of newborns polarizes TLR-mediated cytokine production during the perinatal period and may thereby modulate their innate and adaptive immune responses.

show abstract

Enhancement of Neonatal Innate Defense: Effects of Adding an N-Terminal Recombinant Fragment of Bactericidal/Permeability-Increasing Protein on Growth and Tumor Necrosis Factor-Inducing Activity of Gram-Negative Bacteria Tested in Neonatal Cord Blood Ex Vivo

Cited by 49 publications

References 37 publications

Soluble TLR2 Is Present in Human Amniotic Fluid and Modulates the Intraamniotic Inflammatory Response to Infection

Soluble TLR2 Is Present in Human Amniotic Fluid and Modulates the Intraamniotic Inflammatory Response to Infection

Extracellular Release of Bactericidal/Permeability-Increasing Protein in Newborn Infants

The Adenosine System Selectively Inhibits TLR-Mediated TNF-α Production in the Human Newborn

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