Gene expression reprogramming protects macrophage from septic-induced cell death.
Sepsis induces a systemic inflammatory response leading to tissue damage and cell death. LPS tolerance affects inflammatory response. To comprehend potential new mechanisms of immune regulation in endotoxemia, we examined macrophage mRNA expression by macroarray affected by LPS tolerance. LPS tolerance was induced with subcutaneous administration of 1 mg/kg/day of LPS over 5 days. Macrophages were isolated from the spleen and the expression of 1200 genes was quantitatively analyzed by the macroarray technique. The tolerant group displayed relevant changes in the expression of 84 mRNA when compared to naïve mice. A functional group of genes related to cell death regulation was identified. PARP-1, caspase 3, FASL and TRAIL genes were confirmed by RT-PCR to present lower expression in tolerant mice. In addition, reduced expression of the pro-inflammatory genes TNF-α and IFN-γ in the tolerant group was demonstrated. Following this, animals were challenged with polymicrobial sepsis. Flow cytometry analysis showed reduced necrosis and apoptosis in macrophages from the tolerant group compared to the naïve group. Finally, a survival study showed a significant reduction in mortality in the tolerant group. Thus, in the current study we provide evidence for the selective reprogramming of the gene expression of cell death pathways during LPS tolerance and link these changes to protection from cell death and enhanced survival rates.
Melo
Edielle Sant'Anna
ES
Emergency Medicine Department, Medical School, University of São Paulo, São Paulo, Brazil.
Barbeiro
Denise F
DF
Gorjão
Renata
R
Rios
Ester Correia Sarmento
EC
Vasconcelos
Dewton
D
Velasco
Irineu T
IT
Szabo
Csaba
C
Curi
Rui
R
de Lima-Salgado
Thais Martins
TM
Soriano
Francisco Garcia
FG
D000818:Animals; D017209:Apoptosis; D019070:Cell Lineage; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018805:Sepsis / Q000235:genetics / Q000276:immunology*
D016207:Cytokines; D008070:Lipopolysaccharides