title: Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A.
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.
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Luan
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Naeem K
authors.initials: NK
authors.lastname: Patil
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Bohannon
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fensterheim
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jingbin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Yaomin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, the University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Stark
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sherwood
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D007155:Immunologic Factors / Q000096:biosynthesis; D007962:Leukocytes / Q000187:drug effects*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D046228:Microarray Analysis; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D000276:Adjuvants, Immunologic; D007155:Immunologic Factors; D008050:Lipid A; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; C048436:monophosphoryl lipid A