Endotoxin tolerance: Selective alterations in gene expression and protection against lymphocyte death

Edielle S. Melo, Tatiana Goloubkova, Denise F. Barbeiro, Renata Gorjão, Dewton Vasconcelos, Csaba Szabo, Rui Curi, Thais Martins de Lima Salgado, Irineu T. Velasco, Francisco G. Soriano

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Extensive lymphocyte apoptosis may be an important cause of immune suppression in sepsis. Here we investigated the effect of LPS tolerance on lymphocyte apoptosis in an experimental model of polymicrobial infection. Tolerance was induced by the injection of lipopolysaccharide (1.0mg/kg/subcutaneously) once a day for 5 days. Macroarray analysis of mRNA isolated from T-(CD4) lymphocytes was used to identify genes that are differentially expressed during LPS tolerance. In addition, assessment of the expression of apoptosis-associated lymphocyte gene products and apoptotic events was performed on the 8th day; 6h after the terminal challenge with polymicrobial infection or high-dose LPS administration. Survival studies with polymicrobial infection were also conducted. LPS tolerance induced a broad reprogramming of cell death pathways, including a suppression of receptor-mediated and mitochondrial apoptotic pathways, inflammatory caspases, alternate apoptotic pathways, as well as reduced expression of genes involved in necrosis. These alterations led to a marked resistance of lymphocytes against cell death during the subsequent period of sepsis. In addition, LPS tolerance produced an increased differentiation of T-lymphocytes to TH1 and TH2, with a TH1 differentiation predominance. Thus, in the current study we provide an evidence for a marked reprogramming of gene expression of multiple cell death pathways during LPS tolerance. These alterations may play a significant role in the observed protection of the animals from a subsequent lethal polymicrobial sepsis challenge.

Original languageEnglish (US)
Pages (from-to)435-442
Number of pages8
Issue number6
StatePublished - Jun 2010
Externally publishedYes


  • Apoptosis
  • Cytokines
  • Inflammation
  • Necrosis
  • Sepsis
  • Shock
  • T-cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Hematology


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