CETP Lowers TLR4 Expression Which Attenuates the Inflammatory Response Induced by LPS and Polymicrobial Sepsis.
Sepsis is a systemic inflammatory response to infection eliciting high mortality rate which is a serious health problem. Despite numerous studies seeking for therapeutic alternatives, the mechanisms involved in this disease remain elusive. In this study we evaluated the influence of cholesteryl ester transfer protein (CETP), a glycoprotein that promotes the transfer of lipids between lipoproteins, on the inflammatory response in mice. Human CETP transgenic mice were compared to control mice (wild type, WT) after polymicrobial sepsis induced by cecal ligation and puncture (CLP), aiming at investigating their survival rate and inflammatory profiles. Macrophages from the peritoneal cavity were stimulated with LPS in the presence or absence of recombinant CETP for phenotypic and functional studies. In comparison to WT mice, CETP mice showed higher survival rate, lower IL-6 plasma concentration, and decreased liver toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH) protein. Moreover, macrophages from WT mice to which recombinant human CETP was added decreased LPS uptake, TLR4 expression, NF-κB activation and IL-6 secretion. This raises the possibility for new therapeutic tools in sepsis while suggesting that lowering CETP by pharmacological inhibitors should be inconvenient in the context of sepsis and infectious diseases.
Lipids Laboratory (LIM 10), Faculty of Medical Sciences, The University of São Paulo, São Paulo, SP, Brazil.
Tatiana Martins
0000-0003-3739-8182
TM
Venancio
Lipids Laboratory (LIM 10), Faculty of Medical Sciences, The University of São Paulo, São Paulo, SP, Brazil.
Roberta Marcondes
0000-0003-0566-6410
RM
Machado
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Science IV, University of São Paulo, São Paulo, SP, Brazil.
Angela
A
Castoldi
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Science IV, University of São Paulo, São Paulo, SP, Brazil.
Mariane Tami
MT
Amano
Lipids Laboratory (LIM 10), Faculty of Medical Sciences, The University of São Paulo, São Paulo, SP, Brazil.
Valeria Sutti
VS
Nunes
Lipids Laboratory (LIM 10), Faculty of Medical Sciences, The University of São Paulo, São Paulo, SP, Brazil.
Eder Carlos Rocha
EC
Quintao
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Science IV, University of São Paulo, São Paulo, SP, Brazil.
Niels Olsen Saraiva
0000-0001-5436-1248
NO
Camara
Emergency Care Research Unit Laboratory (LIM 51), Faculty of Medical Sciences, The University of São Paulo, São Paulo, SP, Brazil.
Francisco Garcia
0000-0003-4898-0135
FG
Soriano
Lipids Laboratory (LIM 10), Faculty of Medical Sciences, The University of São Paulo, São Paulo, SP, Brazil.
Patrícia Miralda
PM
Cazita
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D053480:Cholesterol Ester Transfer Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D002265:Carboxylic Ester Hydrolases; C048964:acyloxyacyl hydrolase