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

Yan, Sen; Qing, Gefei; Byers, David M.; Stadnyk, Andrew W.; Al-Hertani, Walla; Bortolussi, Robert

doi:10.1128/iai.72.3.1223-1229.2004

Cited by 146 publications

(133 citation statements)

References 51 publications

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“…Whether and how the innate immune response in neonates contributes to their susceptibility to infection or TLR stimulation is still controversial. In human, it has been reported that mononuclear cells from cord blood secrete lower amounts of TNF than those from healthy adults in response to TLR agonists (10)(11)(12)(13), whereas other studies draw opposite conclusions (14)(15)(16). Results from studies in mice also conflict because neonates produce either lower (17,18) or higher (19) levels of TNF compared with adults.…”

contrasting

confidence: 38%

Hyper innate responses in neonates lead to increased morbidity and mortality after infection

Zhao

Kim

Yang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

146

129

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Neonates suffer high morbidity and mortality in infection, presumably because of the lack of a fully developed adaptive and innate immune system. Evidence of poor innate responses in neonates has been shown by using a model that sensitizes the host to Toll-like receptor (TLR)-mediated inflammation with D-galactosamine (DGalN). However, we show that neonatal mice demonstrate much stronger inflammatory responses than adult mice in response to LPS stimulation, and such hypersensitivity extends to other TLR agonists including actual viral infection. Our study reveals that the ensuing inflammatory reaction after D-GalN sensitization reflects preferential toxicity of D-GalN to adult liver cells, rather than accurately reflecting the TLR response to LPS. We show further that an uncontrolled proinflammatory innate response due to inadequate T cells makes neonates more vulnerable to TLR agonists or viral infection. Remarkably, through transfer of T cells into neonates or depletion of T cells in adult mice, we show that T cells are sufficient and necessary to control the early inflammatory response to LPS. Therefore, neonates might suffer from the unleashed innate responses caused by an insufficient number of T cells, which leads to increased morbidity and mortality.

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contrasting

confidence: 38%

Hyper innate responses in neonates lead to increased morbidity and mortality after infection

Zhao

Kim

Yang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

146

129

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“…Although neonatal monocytes express similar levels of mRNA for different TLRs than adult monocytes [20,19], these data do not exclude possible differences in the protein expression of such receptors. Some data also support a defect in TLR signaling: (1) the up-regulation of TLR4 and CD14 expression upon LPS stimulation is not observed in neonatal monocytes [19,21]; and (2) the protein expression of MyD88, an important adaptor molecule involved in TLR-mediated signaling, is decreased in neonatal monocytes [21], although MyD88 mRNA levels are similar in neonatal and adult monocytes [19]. It should be noted that the expression of several key molecules involved in TLR signaling, such as TIRAP and IRAK-4, has not been carefully examined.…”

Section: Neonatal Monocytes and Macrophagesmentioning

confidence: 99%

Defective antigen-presenting cell function in human neonates

Velilla¹,

Rugeles²,

Chougnet³

2006

Clinical Immunology

153

132

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Immaturity of the immune system has been suggested as an underlying factor for the high rate of morbidity and mortality from infections in newborns. Functional impairment of neonatal T cells is frequently quoted as the main underlying mechanism for such immaturity. However, recent studies suggest that neonatal antigen-presenting cells (APCs) also exhibit functional alterations, which could lead to secondary defects of adaptive T cell responses. In this review, we summarize what is known on the functionality of APC at birth and during early childhood. Compared to adults, neonatal APCs display markers of immaturity and produce low levels of cytokines. Multiple factors could be involved in neonatal APC alteration, such as intrinsic immaturity, defective interaction between APCs and T cells, and regulatory T cell-mediated inhibition. Characterization of the relative contribution of each mechanism is clearly needed to better understand the functional capability of the neonatal immune system.

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“…Even in the case of LPS, where several studies have explored the relative responses of newborn and adult cells (17), much of the published work was performed before the realization that commercial preparations of LPS are often contaminated with TLR2 ligands (18). A recent study described a correlation between reduced responsiveness of newborn mononuclear cells to LPS and reduced MyD88 expression (19). However, to our knowledge, there are no published reports of the activity of a range of well-defined TLR ligands and expression of their cognate receptors and signaling intermediates in newborn monocytes.…”

mentioning

confidence: 99%

Selective Impairment of TLR-Mediated Innate Immunity in Human Newborns: Neonatal Blood Plasma Reduces Monocyte TNF-α Induction by Bacterial Lipopeptides, Lipopolysaccharide, and Imiquimod, but Preserves the Response to R-848

Levy

Zarember²,

Roy

et al. 2004

The Journal of Immunology

341

330

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Newborns are at increased risk of overwhelming infection, yet the mechanisms underlying this susceptibility are incompletely defined. In this study we report a striking 1- to 3-log decrease in sensitivity of monocytes in human neonatal cord blood, compared with monocytes in adult peripheral blood, to the TNF-α-inducing effect of multiple TLR ligands, including bacterial lipopeptides (BLPs), LPS, and the imidazoquinoline compound, imiquimod. In marked contrast, TNF-α release in response to R-848, a TLR ligand that is a congener of imiquimod, was equivalent in newborn and adult blood. Differences in ligand-induced TNF-α release correlated with divergent ligand-induced changes in monocyte TNF-α mRNA levels. Newborn and adult monocytes did not differ in basal mRNA or protein expression of TLRs or mRNA expression of functionally related molecules. Newborn monocytes demonstrated diminished LPS-induced, but equivalent R-848-induced, phosphorylation of p38 mitogen-activated protein kinase and altered BLP- and LPS-induced acute modulation of cognate receptors, suggesting that the mechanism accounting for the observed differences may be localized proximal to ligand recognition by surface TLRs. Remarkably, newborn plasma conferred substantially reduced BLP-, LPS-, and imiquimod-induced TNF-α release on adult monocytes without any effect on R-848-induced TNF-α release, reflecting differences in a plasma factor(s) distinct from soluble CD14. Impaired response to multiple TLR ligands may significantly contribute to immature neonatal immunity. Conversely, relative preservation of responses to R-848 may present unique opportunities for augmenting innate and acquired immunity in the human newborn.

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

Cited by 146 publications

References 51 publications

Hyper innate responses in neonates lead to increased morbidity and mortality after infection

Hyper innate responses in neonates lead to increased morbidity and mortality after infection

Defective antigen-presenting cell function in human neonates

Selective Impairment of TLR-Mediated Innate Immunity in Human Newborns: Neonatal Blood Plasma Reduces Monocyte TNF-α Induction by Bacterial Lipopeptides, Lipopolysaccharide, and Imiquimod, but Preserves the Response to R-848

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