Cells (Treg) [4]. Lipopolysaccharide (LPS) is an important virulence factor of Gram-negative bacteria responsible for septic shock in mammals. LPS is the major molecule of the bacterial outer membrane and can be massively released into the host during the course of infection [5,6]. LPS consists of the O-polysaccharide chain, the oligosaccharide core region and the lipid A. Typical LPS such as those of E. coli and most enteric bacteria express a lipid A composed of a bisphosphorylated glucosamine disaccharidecarrying two amide- and two ester-linked acyl and hydroxyacyl chains. Additional acyloxyacyl chains are commonly present, resulting in penta or hexa-acyl lipid A, the dominant molecular lipid A species in most wild type enterobacteria [7,8]. It has been shown that variations of structural arrangements of lipid A 23115181 such as a reduction in the number of charges or the number of acyl chains or a change in their distribution or saturation degree result in a dramatic reduction in endotoxicity. For instance, the synthetic precursor tetracyl lipid IVa has been described as a non-endotoxic molecule and proposed as an antagonist of hexa-acyl endotoxic LPS [9,10]. Moreover, some pathogens like the yersiniae modulate the degree of acylation of the lipid A depending upon the environmental conditions. Most notably, growth at 37uC causes Yersinia pestis to synthesize tri- and dominant Title Loaded From File tetra-acyl lipid A, with no hexa-acyl and only small amounts of penta-acyl 1527786 molecules. Since these bacteria move from 20?5uC to 37uC when transmitted from the flea to the mammal host, Y. pestis express tetra-acyl lipid A which displays low immunostimulatory Title Loaded From File properties in mammals. This change has been described as a mark of pathogen adaptation to the host environment [7]. In this study, we investigated the relationship between lipid A acylation and the immunostimulatory properties of LPS in the context of mouse and human DC activation. We show that LPS with acylation defects described as not endotoxic are capable of inducing a strong and early TLR4-dependent cell activation. This leads to the activation of the proteasome machinery and theTetraacyl LPS Potentiate Intracellular Signallingdegradation of newly synthetized pro-inflammatory cytokines. Mouse and human DC activated by tetra-acyl LPS trigger CD4+ and CD8+ T cell responses. Moreover, human DC activated by LPS with acylation defects display a semi-mature phenotype and induce high levels of regulatory T cells (Treg).Materials and Methods Ethics StatementAnimal experimentation was conducted in strict accordance with good animal practice as defined by the French animal welfare bodies (Law 87?48 dated 19 October 1987 modified by Decree 2001?64 and Decree 2001?31 relative to European Convention, EEC Directive 86/609). All animal work was approved by the Direction Departmentale des Services Veterinaires des ???Bouches du Rhone (authorization number 13.118). INSERM ^ guidelines have been followed regarding animal experimentation (authorization No. 02875 for mouse experimentation). Blood from healthy adult donors were collected at the Baylor Hospital Liver Transplant Clinic (Dallas, TX) after obtaining written informed consent. This study, including the consent form, was approved by the Institutional Review Board (IRB) of the Baylor Research Institute (BRI) (Dallas, TX). Any medical issue during blood collection from healthy donors was written and reported to the IRB at BRI.AAD was used to exclude dead cells. For intracell.Cells (Treg) [4]. Lipopolysaccharide (LPS) is an important virulence factor of Gram-negative bacteria responsible for septic shock in mammals. LPS is the major molecule of the bacterial outer membrane and can be massively released into the host during the course of infection [5,6]. LPS consists of the O-polysaccharide chain, the oligosaccharide core region and the lipid A. Typical LPS such as those of E. coli and most enteric bacteria express a lipid A composed of a bisphosphorylated glucosamine disaccharidecarrying two amide- and two ester-linked acyl and hydroxyacyl chains. Additional acyloxyacyl chains are commonly present, resulting in penta or hexa-acyl lipid A, the dominant molecular lipid A species in most wild type enterobacteria [7,8]. It has been shown that variations of structural arrangements of lipid A 23115181 such as a reduction in the number of charges or the number of acyl chains or a change in their distribution or saturation degree result in a dramatic reduction in endotoxicity. For instance, the synthetic precursor tetracyl lipid IVa has been described as a non-endotoxic molecule and proposed as an antagonist of hexa-acyl endotoxic LPS [9,10]. Moreover, some pathogens like the yersiniae modulate the degree of acylation of the lipid A depending upon the environmental conditions. Most notably, growth at 37uC causes Yersinia pestis to synthesize tri- and dominant tetra-acyl lipid A, with no hexa-acyl and only small amounts of penta-acyl 1527786 molecules. Since these bacteria move from 20?5uC to 37uC when transmitted from the flea to the mammal host, Y. pestis express tetra-acyl lipid A which displays low immunostimulatory properties in mammals. This change has been described as a mark of pathogen adaptation to the host environment [7]. In this study, we investigated the relationship between lipid A acylation and the immunostimulatory properties of LPS in the context of mouse and human DC activation. We show that LPS with acylation defects described as not endotoxic are capable of inducing a strong and early TLR4-dependent cell activation. This leads to the activation of the proteasome machinery and theTetraacyl LPS Potentiate Intracellular Signallingdegradation of newly synthetized pro-inflammatory cytokines. Mouse and human DC activated by tetra-acyl LPS trigger CD4+ and CD8+ T cell responses. Moreover, human DC activated by LPS with acylation defects display a semi-mature phenotype and induce high levels of regulatory T cells (Treg).Materials and Methods Ethics StatementAnimal experimentation was conducted in strict accordance with good animal practice as defined by the French animal welfare bodies (Law 87?48 dated 19 October 1987 modified by Decree 2001?64 and Decree 2001?31 relative to European Convention, EEC Directive 86/609). All animal work was approved by the Direction Departmentale des Services Veterinaires des ???Bouches du Rhone (authorization number 13.118). INSERM ^ guidelines have been followed regarding animal experimentation (authorization No. 02875 for mouse experimentation). Blood from healthy adult donors were collected at the Baylor Hospital Liver Transplant Clinic (Dallas, TX) after obtaining written informed consent. This study, including the consent form, was approved by the Institutional Review Board (IRB) of the Baylor Research Institute (BRI) (Dallas, TX). Any medical issue during blood collection from healthy donors was written and reported to the IRB at BRI.AAD was used to exclude dead cells. For intracell.
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