title: Identification of high and low responders to lipopolysaccharide in normal subjects: an unbiased approach to identify modulators of innate immunity.
abstract: LPS stimulates a vigorous inflammatory response from circulating leukocytes that varies greatly from individual to individual. The goal of this study was to use an unbiased approach to identify differences in gene expression that may account for the high degree of interindividual variability in inflammatory responses to LPS in the normal human population. We measured LPS-induced cytokine production ex vivo in whole blood from 102 healthy human subjects and identified individuals who consistently showed either very high or very low responses to LPS (denoted lps(high) and lps(low), respectively). Comparison of gene expression profiles between the lps(high) and lps(low) individuals revealed 80 genes that were differentially expressed in the presence of LPS and 21 genes that were differentially expressed in the absence of LPS (p < 0.005, ANOVA). Expression of a subset of these genes was confirmed using real-time RT-PCR. Functional relevance for one gene confirmed to be expressed at a higher level in lps(high), adipophilin, was inferred when reduction in adipophilin mRNA by small interfering RNA in the human monocyte-like cell line THP-1 resulted in a modest but significant reduction in LPS-induced MCP-1 mRNA expression. These data illustrate a novel approach to the identification of factors that determine interindividual variability in innate immune inflammatory responses and identify adipophilin as a novel potential regulator of LPS-induced MCP-1 production in human monocytes.
authors.affiliation: Medical Research Service, Veterans Affairs Puget Sound Medical Center and Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle 98105, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Wurfel
authors.forename: William Y
authors.initials: WY
authors.lastname: Park
authors.forename: Frank
authors.initials: F
authors.lastname: Radella
authors.forename: John
authors.initials: J
authors.lastname: Ruzinski
authors.forename: Andrew
authors.initials: A
authors.lastname: Sandstrom
authors.forename: Jeanna
authors.initials: J
authors.lastname: Strout
authors.forename: Roger E
authors.initials: RE
authors.lastname: Bumgarner
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Martin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000502:physiology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology; D008875:Middle Aged; D000070780:Perilipin-2; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; D012333:RNA, Messenger; C085483:Re lipopolysaccharide