Identification of high and low responders to lipopolysaccharide in normal subjects: An unbiased approach to identify modulators of innate immunity

Mark M. Wurfel, William Y. Park, Frank Radella, John Ruzinski, Andrew Sandstrom, Jeanna Strout, Roger E. Bumgarner, Thomas R. Martin

Research output: Contribution to journalArticlepeer-review

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 lpshigh and lpslow, respectively). Comparison of gene expression profiles between the lps high and lpslow 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.

Original languageEnglish (US)
Pages (from-to)2570-2578
Number of pages9
JournalJournal of Immunology
Volume175
Issue number4
DOIs
StatePublished - Aug 15 2005
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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