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Comparison of gene expression by sheep and human blood stimulated with the TLR4 agonists lipopolysaccharide and monophosphoryl lipid A

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Ovis aries Homo sapiens

PROVIDER: GSE72559 | GEO | 2015/12/16

SECONDARY ACCESSION(S): PRJNA294324

REPOSITORIES: GEO

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Comparison of gene expression by sheep and human blood stimulated with the TLR4 agonists lipopolysaccharide and monophosphoryl lipid A

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-12-16 | E-GEOD-72559 | biostudies-arrayexpress

Comparison of gene expression by sheep and human blood stimulated with the TLR4 agonists lipopolysaccharide and monophosphoryl lipid A [sheep]

2015-12-16 | GSE72558 | GEO

Comparison of gene expression by sheep and human blood stimulated with the TLR4 agonists lipopolysaccharide and monophosphoryl lipid A [sheep]

Project description:11,431 and 4,992 genes were determined in whole blood of healthy human volunteers and normal sheep, respectively following MPLA and LPS exposure Following the exposure 1,029 human and 175 sheep genes were differentially expressed. Of those 175 sheep genes, 54 had a known human ortolog. The major inflammatory mediators, such as IL-1-6-8, TNFa, NFkB, ETS2, PTGS2, PTX3, CXCL18, KYNU, and CLEC4E were similarly (>2-fold) upregulated in both human and sheep blood. Six healthy human volunteers and six normal sheep blood was incubated with LPS or MPLA for 90 minutes, then the blood was transferred to the Paxgene blood RNA tubes and the gene expression microarrays were scanned with G2556 Microaaray Scanner

2015-12-16 | E-GEOD-72558 | biostudies-arrayexpress

Comparison of gene expression by sheep and human blood stimulated with the TLR4 agonists lipopolysaccharide and monophosphoryl lipid A [human]

2015-12-16 | GSE72557 | GEO

Comparison of gene expression by sheep and human blood stimulated with the TLR4 agonists lipopolysaccharide and monophosphoryl lipid A [human]

2015-12-16 | E-GEOD-72557 | biostudies-arrayexpress

Comparison of gene expression by sheep and human blood stimulated with the TLR4 agonists lipopolysaccharide and monophosphoryl lipid A

Project description:Comparison of gene expression by sheep and human blood stimulated with the TLR4 agonists lipopolysaccharide and monophosphoryl lipid A

| PRJNA294324 | ENA

TLR4 ligands lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8+ T Cell differentiation.

Project description:Vaccines formulated with nonreplicating pathogens require adjuvants to help bolster immunogenicity. The role of adjuvants in Ab production has been well studied, but how they influence memory CD8(+) T cell differentiation remains poorly defined. In this study we implemented dendritic cell-mediated immunization to study the effects of commonly used adjuvants, TLR ligands, on effector and memory CD8(+) T cell differentiation in mice. Intriguingly, we found that the TLR4 ligand LPS was far more superior to other TLR ligands in generating memory CD8(+) T cells upon immunization. LPS boosted clonal expansion similar to the other adjuvants, but fewer of the activated CD8(+) T cells died during contraction, generating a larger pool of memory cells. Surprisingly, monophosphoryl lipid A (MPLA), another TLR4 ligand, enhanced clonal expansion of effector CD8(+) T cells, but it also promoted their terminal differentiation and contraction; thus, fewer memory CD8(+) T cells formed, and MPLA-primed animals were less protected against secondary infection compared with those primed with LPS. Furthermore, gene expression profiling revealed that LPS-primed effector cells displayed a stronger pro-memory gene expression signature, whereas the gene expression profile of MPLA-primed effector cells aligned closer with terminal effector CD8(+) T cells. Lastly, we demonstrated that the LPS-TLR4-derived "pro-memory" signals were MyD88, but not Toll/IL-1R domain-containing adapter inducing IFN-?, dependent. This study reveals the influential power of adjuvants on the quantity and quality of CD8(+) T cell memory, and that attention to adjuvant selection is crucial because boosting effector cell expansion may not always equate with more memory T cells or greater protection.

| S-EPMC4071140 | biostudies-literature

Monophosphoryl lipid A alleviated radiation-induced testicular injury through TLR4-dependent exosomes.

Project description:Radiation protection on male testis is an important task for ionizing radiation-related workers or people who receive radiotherapy for tumours near the testicle. In recent years, Toll-like receptors (TLRs), especially TLR4, have been widely studied as a radiation protection target. In this study, we detected that a low-toxicity TLR4 agonist monophosphoryl lipid A (MPLA) produced obvious radiation protection effects on mice testis. We found that MPLA effectively alleviated testis structure damage and cell apoptosis induced by ionizing radiation (IR). However, as the expression abundance differs a lot in distinct cells and tissues, MPLA seemed not to directly activate TLR4 singling pathway in mice testis. Here, we demonstrated a brand new mechanism for MPLA producing radiation protection effects on testis. We observed a significant activation of TLR4 pathway in macrophages after MPLA stimulation and identified significant changes in macrophage-derived exosomes protein expression. We proved that after MPLA treatment, macrophage-derived exosomes played an important role in testis radiation protection, and specially, G-CSF and MIP-2 in exosomes are the core molecules in this protection effect.

| S-EPMC7171420 | biostudies-literature

Endothelial cell tolerance to lipopolysaccharide challenge is induced by monophosphoryl lipid A.

Project description:Prior exposure to lipopolysaccharide (LPS) produces a reduced or "tolerant" inflammatory response to subsequent challenges with LPS, however the potent pro-inflammatory effects of LPS limit its clinical benefit. The adjuvant monophosphoryl lipid A (MPLA) is a weak toll-like receptor 4 (TLR4) agonist that induces negligible inflammation but retains potent immunomodulatory properties. We postulated that pre-treatment with MPLA would inhibit the inflammatory response of endothelial cells to secondary LPS challenge. Human umbilical vein endothelial cells (HUVECs), were exposed to MPLA (10 ?g/ml), LPS (100 ng/ml) or vehicle control. HUVECs were then washed and maintained in culture for 24 h before being challenged with LPS (100 ng/ml). Supernatants were collected and examined for cytokine production in the presence or absence of siRNA inhibitors of critical TLR4 signalling proteins. Pre-treatment with MPLA attenuated interleukin (IL)-6 production to secondary LPS challenge to a similar degree as LPS. The application of myeloid differentiation primary response gene 88 (MyD88) siRNA dramatically reduced MPLA-induced tolerance while TIR-domain-containing adapter-inducing interferon-? (TRIF) siRNA had no effect. The tolerant phenotype in endothelial cells was associated with reduced I?B kinase (IKK), p38 and c-Jun N-terminal kinase (JNK) phosphorylation and enhanced IL-1 receptor associated kinase-M (IRAK-M) expression for LPS-primed HUVECs, but less so in MPLA primed cells. Instead, MPLA-primed HUVECs demonstrated enhanced p-extracellular-signal-regulated kinase (ERK) phosphorylation. In contrast with leucocytes in which tolerance is largely TRIF-dependent, MyD88 signalling mediated endotoxin tolerance in endothelial cells. Most importantly, MPLA, a vaccine adjuvant with a wide therapeutic window, induced tolerance to LPS in endothelial cells.

| S-EPMC4744094 | biostudies-literature

Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A.

Project description:Monophosphoryl lipid A (MPLA), a less toxic derivative of lipopolysaccharide (LPS), is employed as a vaccine adjuvant and is under investigation as a non-specific immunomodulator. However, the differential response of human leukocytes to MPLA and LPS has not been well characterized. The goal of this study was to compare the differential transcriptomic response of human blood to LPS and MPLA. Venous blood from human volunteers was stimulated with LPS, MPLA or vehicle. Gene expression was determined using microarray analysis. Among 21,103 probes profiled, 136 and 130 genes were differentially regulated by LPS or MPLA, respectively. Seventy four genes were up-regulated and 9 were down-regulated by both ligands. The remaining genes were differentially induced by either agent. Ingenuity Pathway Analysis predicted that LPS and MPLA share similar upstream regulators and have comparable effects on canonical pathways and cellular functions. However, some pro-inflammatory cytokine and inflammasome-associated transcripts were more strongly induced by LPS. In contrast, only the macrophage-regulating chemokine CCL7 was preferentially up-regulated by MPLA. In conclusion, LPS and MPLA induce similar transcriptional profiles. However, LPS more potently induces pro-inflammatory cytokine and inflammasome-linked transcripts. Thus, MPLA is a less potent activator of the pro-inflammatory response but retains effective immunomodulatory activity.

| S-EPMC5215261 | biostudies-literature

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