title: Identification of genes particularly sensitive to lipopolysaccharide (LPS) in human monocytes induced by wild-type versus LPS-deficient Neisseria meningitidis strains.
abstract: Lipopolysaccharide (LPS) in the outer membrane of Neisseria meningitidis plays a dominant role as an inflammation-inducing molecule in meningococcal disease. We have used microarray analysis to study the global gene expression after exposure of human monocytes for 3 h to wild-type N. meningitidis (10(6)), LPS-deficient N. meningitidis (10(6) and 10(8)), and purified N. meningitidis LPS (1 ng [33 endotoxin units]/ml) to identify LPS-inducible genes. Wild-type N. meningitidis (10(6)) induced 4,689 differentially expressed genes, compared with 72 differentially expressed genes induced by 10(6) LPS-deficient N. meningitidis organisms. However, 10(8) LPS-deficient N. meningitidis organisms induced 3,905 genes, indicating a dose-response behavior of non-LPS cell wall molecules. A comparison of the gene expression patterns from 10(6) wild-type N. meningitidis and 10(8) LPS-deficient N. meningitidis organisms showed that 2,401 genes in human monocytes were not strictly LPS dependent. A list of "particularly LPS-sensitive" genes (2,288), differentially induced by 10(6) wild-type N. meningitidis but not by 10(8) LPS-deficient N. meningitidis organisms, showed an early expression of beta interferon (IFN-beta), most likely through the Toll-like receptor-MyD88-independent pathway. Subsequently, IFN-beta may activate the type I IFN signaling pathway, and an unknown number of IFN-beta-inducible genes, such as those for CXCL9, CXCL10, CXCL11, IFIT1, IFIT2, IFIT3, and IFIT5, are transcribed. Supporting this, human monocytes secreted significantly higher levels of CXCL10 and CXCL11 when stimulated by 10(6) wild-type N. meningitidis organisms than when stimulated by 10(8) LPS-deficient N. meningitidis organisms. Plasma CXCL10, but not CXCL11, was positively correlated (r = 0.67; P < 0.01) to LPS in patients (n = 24) with systemic meningococcal disease. Thus, new circulating biomarkers in meningococcal disease may be suggested through LPS-induced gene expression changes in human monocytes.
authors: Department of Clinical Chemistry, Ullevål University Hospital 0407, Oslo, Norway. reidun.ovstebo@medisin.uio.no
authors: Reidun
authors: R
authors: Ovstebø
authors: Ole Kristoffer
authors: OK
authors: Olstad
authors: Berit
authors: B
authors: Brusletto
authors: Anne Sophie
authors: AS
authors: Møller
authors: Audun
authors: A
authors: Aase
authors: Kari Bente Foss
authors: KB
authors: Haug
authors: Petter
authors: P
authors: Brandtzaeg
authors: Peter
authors: P
authors: Kierulf
mesh_terms: D054357:Chemokine CXCL10 / Q000097:blood; D054371:Chemokine CXCL11 / Q000097:blood; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology*; D008589:Meningococcal Infections / Q000097:blood; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D009154:Mutation; D009345:Neisseria meningitidis / Q000235:genetics* / Q000502:physiology; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation
chemical_list: C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D008070:Lipopolysaccharides; D050791:STAT Transcription Factors; D053612:Janus Kinases