title: Gene- and exon-expression profiling reveals an extensive LPS-induced response in immune cells in patients with cirrhosis.
abstract: OBJECTIVE
  Lipopolysaccharide (LPS)-expressing bacteria cause severe inflammation in cirrhotic patients. The global gene response to LPS is unknown in cirrhotic immune cells.
  
  
  METHODS
  Gene-expression profiling using Affymetrix Human Exon Array analyzed the expression of 14,851 genes in LPS-stimulated peripheral blood mononuclear cells (PBMCs) from 4 patients with cirrhosis and 4 healthy subjects. We performed validation studies using RT-qPCR in LPS-stimulated PBMCs from 52 patients and 9 healthy subjects and investigated the association of gene induction with mortality in 26 patients.
  
  
  RESULTS
  Gene-expression profiling of LPS-stimulated cirrhotic cells showed 509 upregulated genes and 1588 downregulated genes. In LPS-stimulated "healthy" cells, 952 genes were upregulated and 838 genes downregulated. The 741 LPS-regulated genes shared by cirrhotic and "healthy" cells were involved in cytokine production/activity and induction of "immune paralysis". Comparison of functions associated with the 1356 genes, specifically regulated by LPS in cirrhotic cells, to functions of the 1049 genes, specifically regulated in "healthy" cells, allowed to define a cirrhosis-specific phenotype. Unlike in "healthy" cells, LPS failed to induce an interferon-mediated program in cirrhotic cells. In cirrhotic PBMCs, LPS specifically induced certain molecules involved in apoptosis and downregulated molecules involved in endocytic trafficking. RT-qPCR experiments showed that LPS-stimulated cirrhotic PBMCs had an enhanced induction of certain proinflammatory cytokines and chemokines. In the prognosis study, higher ex vivo LPS-induction of the inflammatory genes IL6 and CXCL5 was a significant predictor of mortality.
  
  
  CONCLUSIONS
  Our results show that LPS-stimulated cirrhotic PBMCs exhibit an extensive and often unexpected transcriptional response.
authors: INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Clichy and Paris, France.
authors: Sonia
authors: S
authors: Gandoura
authors: Emmanuel
authors: E
authors: Weiss
authors: Pierre-Emmanuel
authors: PE
authors: Rautou
authors: Magali
authors: M
authors: Fasseu
authors: Thierry
authors: T
authors: Gustot
authors: Frédéric
authors: F
authors: Lemoine
authors: Margarita
authors: M
authors: Hurtado-Nedelec
authors: Caroline
authors: C
authors: Hego
authors: Nathalie
authors: N
authors: Vadrot
authors: Laure
authors: L
authors: Elkrief
authors: Philippe
authors: P
authors: Lettéron
authors: Zéra
authors: Z
authors: Tellier
authors: Marie-Anne
authors: MA
authors: Pocidalo
authors: Dominique
authors: D
authors: Valla
authors: Didier
authors: D
authors: Lebrec
authors: André
authors: A
authors: Groyer
authors: Renato C
authors: RC
authors: Monteiro
authors: Pierre
authors: P
authors: de la Grange
authors: Richard
authors: R
authors: Moreau
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D054365:Chemokine CXCL5 / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D015996:Survival Rate
chemical_list: D015415:Biomarkers; D054365:Chemokine CXCL5; D015850:Interleukin-6; D008070:Lipopolysaccharides