Innate immune response triggered by triacyl lipid A is dependent on phospholipid transfer protein (PLTP) gene expression.
Hexaacyl lipopolysaccharide (LPS) aggregates in aqueous media, but its partially deacylated lipid A moiety forms monomers with weaker toxicity. Because plasma phospholipid transfer protein (PLTP) transfers hexaacyl LPS, its impact on metabolism and biological activity of triacyl lipid A in mice was addressed. Triacyl lipid A bound readily to plasma high-density lipoproteins (HDLs) when active PLTP was expressed [HDL-associated lipid A after 4.5 h: 59.1+/-16.0% of total in wild-type (WT) vs. 32.5+/-10.3% in PLTP-deficient mice, P<0.05]. In the opposite to hexaacyl LPS, plasma residence time of lipid A was extended by PLTP, and proinflammatory cytokines were produced in higher amounts in WT than PLTP(-/-) mice (remaining lipid A after 8 h: 53+/-12 vs. 35+/-7%, and IL6 concentration after 4.5 h: 45.5+/-5.9 vs. 14.6+/-7.8 ng/ml, respectively; P<0.05 in all cases). After 1 wk, onset of B16-induced melanoma was observed in only 30% of lipid A-treated WT mice, whereas >80% of the untreated WT, untreated PLTP-deficient, or lipid A-treated PLTP-deficient animals bore tumors (P<0.05 in all cases). It is concluded that PLTP is essential in mediating the association of triacyl lipid A with lipoproteins, leading to extension of its residence time and to magnification of its proinflammatory and anticancer properties.
Gautier
Thomas
T
Centre de Recherche INSERM UMR866, Université de Bourgogne, Faculté de Médecine, 7 boulevard Jeanne d'Arc, BP87900, 21079 Dijon Cedex, France.
Paul
Catherine
C
Deckert
Valérie
V
Desrumaux
Catherine
C
Klein
Alexis
A
Labbé
Jérôme
J
Le Guern
Naig
N
Athias
Anne
A
Monier
Serge
S
Hammann
Arlette
A
Bettaieb
Ali
A
Jeannin
Jean-François
JF
Lagrost
Laurent
L
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood; D016207:Cytokines / Q000097:blood; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008050:Lipid A / Q000276:immunology* / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D018932:Chemokine CCL2; D016207:Cytokines; D015850:Interleukin-6; D008050:Lipid A; D049294:Phospholipid Transfer Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma