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Toll-like receptor induced pro-interleukin-1? and interleukin-6 in monocytes are lower in healthy infants compared to adults.

ABSTRACT: Infants have long been known to have higher infectious diseases morbidity and mortality and suboptimal vaccination responses compared to older children and adults. A variety of differences in innate and adaptive immune responses have been described between these two groups. We compared Toll-like receptor (TLR)-induced production of pro-interleukin (IL)-1?, IL-6, and tumor necrosis factor (TNF)-? between 2-month-old infants and adults. TLR 7/8-induced production of pro-IL-1? and IL-6 in monocytes was lower in 2-month-old infants compared to adults. There was no difference in TLR 7/8-induced production of TNF-?. Lower TLR-induced production of pro-IL-1? and IL-6 in innate immune cells during early infancy likely contributes to suboptimal vaccine responses and infectious diseases susceptibility.

SUBMITTER: Libraty DH

PROVIDER: S-EPMC3808280 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Toll-like receptor induced pro-interleukin-1β and interleukin-6 in monocytes are lower in healthy infants compared to adults.

Libraty Daniel H DH Zhang Lei L Woda Marcia M Acosta Luz P LP Obcena Anamae A Brion Job D JD Capeding Rosario Z RZ

PloS one 20131025 10

Infants have long been known to have higher infectious diseases morbidity and mortality and suboptimal vaccination responses compared to older children and adults. A variety of differences in innate and adaptive immune responses have been described between these two groups. We compared Toll-like receptor (TLR)-induced production of pro-interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α between 2-month-old infants and adults. TLR 7/8-induced production of pro-IL-1β and IL-6 in monocytes ...[more]

PMID: 24205068

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Decreased Toll-like receptor 8 expression and lower TNF-? synthesis in infants with acute RSV infection.

Project description:BackgroundToll-like receptors (TLRs) are part of the innate immune system, able to recognize pathogen-associated molecular patterns and activate immune system upon pathogen challenge. Respiratory syncytial virus (RSV) is a RNA virus particularly detrimental in infancy. It could cause severe lower respiratory tract disease and recurrent infections related to inadequate development of anti-viral immunity. The reason could be inadequate multiple TLRs engagement, including TLR8 in recognition of single-stranded viral RNA and diminished synthesis of inflammatory mediators due to a lower expression.MethodsIntracellular TLR8 expression in peripheral blood monocytes from RSV-infected infants was profiled and compared to healthy adults and age matched controls. Whether the observed difference in TLR8 expression is a transitory effect, infants in convalescent phase (4-6 weeks later) were retested. Specific TLR8-mediated TNF-? production in monocytes during an acute and convalescent phase was analyzed.ResultsRSV-infected and healthy infants had lower percentage of TLR8-expressing monocytes than healthy adults whereas decreased of TLR8 protein levels were detected only for RSV-infected infant group. Lower protein levels of TLR8 in monocytes from RSV-infected infants, compared to healthy infants, negatively correlated with respiratory frequency and resulted in lower TNF-? synthesis upon a specific TLR8 stimulation. In the convalescent phase, levels of TLR8 increased, accompanied by increased TNF-? synthesis compared to acute infection.ConclusionsLower TLR8 expression observed in monocytes, during an acute RSV infection, might have a dampening impact on early anti-viral cytokine production necessary to control RSV replication, and subsequently initiate an adaptive Th1 type immune response leading to severe disease in infected infants.

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Fish oil supplementation does not lower C-reactive protein or interleukin-6 levels in healthy adults.

Project description:BackgroundThe n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may prevent a range of chronic conditions through anti-inflammatory actions. However, as clinical trials using these fatty acids for primary prevention are yet unavailable, their putative role in disease prevention rests, in part, on evidence of anti-inflammatory actions in healthy individuals.ObjectiveTo investigate in a double-blind, placebo-controlled clinical trial whether supplementation with a moderate dose of EPA+DHA reduces common biomarkers of chronic, systemic inflammation in healthy individuals.MethodsA total of 261 healthy individuals aged 30-54 years who were free of inflammatory conditions and consumed ≤ 300 mg per day EPA+DHA were included in the study. Participants were randomly assigned to 18 weeks of either fish oil supplementation providing 1400 mg per day EPA+DHA or matching placebo. Outcome measures were serum levels of C-reactive protein (CRP) and interleukin (IL)-6. In a substudy, ex vivo cytokine production was measured. Missing data for CRP and IL-6 were estimated using regression imputation. Data analyses conformed to intention-to-treat principles.ResultsParticipant blinding was verified. Red blood cell EPA+DHA increased by 64% in the active treatment group, but serum CRP and IL-6 were not affected by supplementation (P ≥ 0.20). Findings were consistent with and without imputed values and across subgroups. Similarly, EPA+DHA supplementation did not alter ex vivo production of four pro-inflammatory cytokines (P ≥ 0.20).ConclusionsSupplementation with 1400 mg EPA+DHA did not reduce common markers of systemic inflammation in healthy adults. Whether this or a higher dose affects other measures of inflammation, oxidative stress or immune function warrants examination.

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Ulvan Activates Chicken Heterophils and Monocytes Through Toll-Like Receptor 2 and Toll-Like Receptor 4.

Project description:Responsiveness to invasive pathogens, clearance via the inflammatory response, and activation of appropriate acquired responses are all coordinated by innate host defenses. Toll-like receptor (TLR) ligands are potent immune-modulators with profound effects on the generation of adaptive immune responses. This property is being exploited in TLR-based vaccines and therapeutic agents in chickens. However, for administering the TLR agonist, all previous studies used in ovo, intra-muscular or intra-venous routes that cannot be performed in usual farming conditions, thus highlighting the need for TLR ligands that display systemic immune effects when given orally (per os). Here we have demonstrated that an ulvan extract of Ulva armoricana is able to activate avian heterophils and monocytes in vitro. Using specific inhibitors, we have evidenced that ulvan may be a new ligand for TLR2 and TLR4; and that they regulate heterophil activation in slightly different manner. Moreover, activation of heterophils as well as of monocytes leads to release pro-inflammatory cytokines, including interleukin1-?, interferon ? and interferon ?, through pathways that we partly identified. Finally, when given per os to animals ulvan induces heterophils and monocytes to be activated in vivo thus leading to a transient release of pro-inflammatory cytokines with plasma concentrations returning toward baseline levels at day 3.

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Circulating interleukin-38 concentrations in healthy adults.

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| S-EPMC9396651 | biostudies-literature

Transcripts differentially expressed in healthy blood mDCs compared to healthy monocytes

Project description:To directly compare the SLE monocyte transcriptional program with that of blood mDC precursors, we purified lineage HLA-DRhighCD11chigh mDCs and CD14+ monocytes from the blood of five healthy donors. Their gene expression profiles were then compared to those of blood SLE monocytes. An unsupervised clustering analysis of transcripts present in >20% of the samples classified healthy monocytes, SLE monocytes and healthy mDCs into three well defined groups. A supervised analysis was then performed to find genes: 1) differentially expressed in healthy mDCs compared to monocytes; 2) shared by healthy blood mDCs and SLE blood monocytes.

2014-06-03 | GSE46913 | GEO

Toll/interleukin-1 receptor domain dimers as the platform for activation and enhanced inhibition of Toll-like receptor signaling.

Project description:TIR (Toll/IL-1 receptor) domains mediate interactions between TLR (Toll-like) or IL-1 family receptors and signaling adapters. While homotypic TIR domain interactions mediate receptor activation they are also usurped by microbial TIR domain containing proteins for immunosuppression. Here we show the role of a dimerized TIR domain platform for the suppression as well as for the activation of MyD88 signaling pathway. Coiled-coil dimerization domain, present in many bacterial TCPs, potently augments suppression of TLR/IL-1R signaling. The addition of a strong coiled-coil dimerization domain conferred the superior inhibition against the wide spectrum of TLRs and prevented the constitutive activation by a dimeric TIR platform. We propose a molecular model of MyD88-mediated signaling based on the dimerization of TIR domains as the limiting step.

| S-EPMC3438932 | biostudies-literature

Properties of human blood monocytes. II. Monocytes from healthy adults are highly heterogeneous within and among individuals.

Project description:BackgroundHuman blood monocytes are known to include subsets defined by the expression of CD14 and CD16 but otherwise are often assumed to be relatively homogeneous. However, we had observed additional heterogeneity that led us to a more extensive examination of monocytes.MethodsBlood samples from 200 healthy adults without known immunological abnormalities were examined by analysis with a hematology analyzer and by flow cytometry (FCM) to determine leukocyte differential counts, to identify subsets and to measure expression of monocyte-associated molecules.ResultsThe estimated cell counts of monocytes, neutrophils, total lymphocytes, and T cells all varied to a similar extent, that is, ±30-35%. The fractions of monocyte subsets defined by CD14 and CD16 or by CD163 expression also varied among individuals. FCM examinations showed that all the monocyte-associated molecules that were examined varied in expression in this increasing order-CD244, CD4, CD38, CD91, CD11b, toll-like receptor 2 (TLR2), TIA-1, CD14 (on CD14(Br+) cells), CD86, CD80, HLA-DQ, CD33, and HLA-DR.ConclusionsHuman blood monocytes are heterogeneous among healthy adults with respect to cell counts, subsets, and the levels of expression of monocyte-associated molecules. An increase in the "non-classical" (CD14(Lo/Neg) /CD16(+) ) monocyte subset or in the expression of CD11b or TLR2 have known diagnostic/prognostic implications. CD244 and CD4 have well-defined functions on lymphocytes but perform unknown activities on monocytes although their expression appears more narrowly controlled. Together, these data suggest that monocytes should be more extensively examined in both clinical and basic contexts.

| S-EPMC4854626 | biostudies-literature

Interaction between interleukin-1 receptor 2 and Toll-like receptor 4, and cervical cytokines.

Project description:The objective was to assess the impact of genetic variation on cervical cytokine concentrations of interleukin (IL)-1?, IL-1?, IL-6, IL-8 and tumor necrosis factor alpha (TNF-?), and first, to determine if these variants interact with polymorphisms in Toll-like receptor 4 (TLR4) that were previously shown to associate with pro-inflammatory cervical cytokine concentrations, and second, to determine if findings are affected by bacterial vaginosis (BV). We examined 183 single nucleotide polymorphisms (SNPs) in 13 cytokine genes and receptors for associations with cervical cytokine levels in 188 African American and European American women. We tested for associations of gene-gene interactions between SNPs in TLR4 and cytokine gene and receptor polymorphisms with cervical pro-inflammatory cytokines. None of the single locus associations were significant after correction for multiple testing in either European Americans or African Americans. However, there were significant gene-gene interactions between IL-1R2 rs485127 and two SNPs in TLR4 (rs1554973 and rs7856729) with IL-1? after correction for multiple testing. Our study demonstrates that interactions between TLR4 and IL-1R2 are associated with cervical pro-inflammatory cytokine concentrations. These results provide important insights into the possible regulatory mechanisms of the inflammatory response in the presence and absence of microbial disorders such as BV. Additionally, the observed differences in allele frequencies between African Americans and those of European descent may partially explain population disparity in pregnancy-related phenotypes that are cytokine concentration-dependent.

| S-EPMC3147278 | biostudies-literature

Reduced brain resting-state network specificity in infants compared with adults.

Project description:PurposeInfant resting-state networks do not exhibit the same connectivity patterns as those of young children and adults. Current theories of brain development emphasize developmental progression in regional and network specialization. We compared infant and adult functional connectivity, predicting that infants would exhibit less regional specificity and greater internetwork communication compared with adults.Patients and methodsFunctional magnetic resonance imaging at rest was acquired in 12 healthy, term infants and 17 adults. Resting-state networks were extracted, using independent components analysis, and the resulting components were then compared between the adult and infant groups.ResultsAdults exhibited stronger connectivity in the posterior cingulate cortex node of the default mode network, but infants had higher connectivity in medial prefrontal cortex/anterior cingulate cortex than adults. Adult connectivity was typically higher than infant connectivity within structures previously associated with the various networks, whereas infant connectivity was frequently higher outside of these structures. Internetwork communication was significantly higher in infants than in adults.ConclusionWe interpret these findings as consistent with evidence suggesting that resting-state network development is associated with increasing spatial specificity, possibly reflecting the corresponding functional specialization of regions and their interconnections through experience.

| S-EPMC4114919 | biostudies-literature

Lipopolysaccharide decreases single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR) expression by suppressing specificity protein 1 (Sp1) via the Toll-like receptor 4 (TLR4)-p38 pathway in monocytes and neutrophils.

Project description:Single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR) is one of the immunoglobulin-like membrane proteins that is crucial for negative regulation of toll-like receptor 4 (TLR4) and interleukin-1 receptor. Despite the importance of understanding its expression and function, knowledge is limited on the regulatory mechanism in the epithelial tissues, such as the liver, lung, and gut, where its predominant expression is originally described. Here, we found expression of SIGIRR in non-epithelial innate immune cells, including primary peripheral blood monocytes, polymorphonuclear neutrophils, monocytic RAW264 cells, and neutrophilic-differentiated HL-60 cells. Consistent with previous findings in epithelial tissues, SIGIRR gene and protein expression were also down-regulated by LPS treatment in a time-dependent manner in primary blood monocytes and polymorphonuclear neutrophils. A reduction was also observed in RAW264 and differentiated HL-60 cells. Notably, exogenous introduction of the dominant negative form of TLR4 and siRNA of p38 resulted in inhibition of LPS-induced SIGIRR down-regulation, whereas treatment with p38 activator anisomycin showed a dose-dependent decrease in SIGIRR expression, suggesting TLR4-p38 signal as a critical pathway for LPS-induced SIGIRR down-regulation. Finally, reporter gene and chromatin immunoprecipitation assays demonstrated that Sp1 is a key factor that directly binds to the proximal promoter of SIGIRR gene and consequently regulates basal SIGIRR expression, which is negatively regulated by the LPS-dependent TLR4-p38 pathway. In summary, the data precisely demonstrate how LPS down-regulates SIGIRR expression and provide a role of LPS signal that counteracts Sp1-dependent basal promoter activation of SIGIRR gene via TLR4-p38 pathway in non-epithelial innate immune cells.

| S-EPMC4140261 | biostudies-literature

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