Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide
Liming Luan1, Naeem K Patil1, Yin Guo2
1Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
Abstract:
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.
Insights
Monophosphoryl lipid A (MPLA) and lipopolysaccharide (LPS) activate similar gene expression profiles in human leukocytes. However, LPS more potently induces pro-inflammatory responses, while MPLA retains immunomodulatory activity with less inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Transcriptomics
Background:
- Monophosphoryl lipid A (MPLA) is a less toxic derivative of lipopolysaccharide (LPS).
- MPLA is used as a vaccine adjuvant and immunomodulator.
- Differential leukocyte responses to MPLA and LPS require characterization.
Purpose of the Study:
- To compare the differential transcriptomic response of human blood to LPS and MPLA.
- To elucidate the distinct immune activation pathways triggered by LPS and MPLA.
Main Methods:
- Human venous blood from volunteers was stimulated with LPS, MPLA, or vehicle.
- Gene expression profiling was performed using microarray analysis.
- Ingenuity Pathway Analysis (IPA) was used to interpret transcriptomic data.
Main Results:
- LPS and MPLA differentially regulated 136 and 130 genes, respectively.
- Both ligands shared 74 up-regulated and 9 down-regulated genes.
- LPS more potently induced pro-inflammatory cytokine and inflammasome-associated transcripts.
- CCL7, a macrophage-regulating chemokine, was preferentially up-regulated by MPLA.
Conclusions:
- LPS and MPLA induce largely similar transcriptional profiles in human blood.
- LPS is a more potent activator of pro-inflammatory and inflammasome responses.
- MPLA demonstrates effective immunomodulatory activity with a less potent pro-inflammatory profile.
More Related Videos
07:58Quantitative Imaging of Lineage-specific Toll-like Receptor-mediated Signaling in Monocytes and Dendritic Cells from Small Samples of Human Blood
Published on: April 16, 2012
08:34Legionella pneumophila Outer Membrane Vesicles: Isolation and Analysis of Their Pro-inflammatory Potential on Macrophages
Published on: February 22, 2017
Related Concept Videos
01:19Formation of Lipopolysaccharides
01:26Signal Transduction: Overview
Typically, signal transduction involves three...