An expanding role for apolipoprotein E in sepsis and inflammation.
BACKGROUND
Apolipoprotein E (apoE), a component of plasma lipoproteins, plays an important, but poorly defined role in sepsis. We have shown that injecting apoE increases septic mortality in a rat model of gram-negative bacterial sepsis, with concomitant hepatic natural killer T (NKT) cell proliferation and activation. The presumed mechanism for this apoE-mediated mortality is that apoE can bind and traffic antigens, presumed to include lipopolysaccharide (LPS), and promote activation of dendritic cells (DC) with subsequent NKT activation and cytokine release. Thus, we sought to prove that LPS was the antigen responsible for the increased NKT activation enhanced by the presence of apoE.


METHODS
We isolated murine marrow-derived DCs, pulsed them with lipid antigen (LPS, and positive controls alpha-galactosylceramide [alpha-GalCer] and isoglobotrihexosylceramide 3 [iGb3]) with or without apoE, and then cocultured the DCs with hybridoma NKTs. NKT activation was measured by interleukin-2 (IL-2) supernatant levels using enzyme-linked immunosorbent assay (ELISA).


RESULTS
LPS at different concentrations was a weak stimulus for NKT activation regardless of apoE presence. When apoE was present, iGb3, an endogenous ligand analog, elicited more than a 2-fold increase in IL-2 response when compared with iGb3 alone (P < .05).


CONCLUSIONS
These results indicate an endogenous ligand, not LPS, may be responsible for NKT activation. A molecular remnant similar to iGb3 could act as a damage-associated molecular pattern and play a prominent role in animal models of sepsis.
Chuang
Kelley
K
Department of Surgery, University of California, San Francisco, East Bay, Oakland, USA.
Elford
Erica L
EL
Tseng
Jill
J
Leung
Briana
B
Harris
Hobart W
HW
D000818:Animals; D001057:Apolipoproteins E / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005915:Globosides / Q000276:immunology; D016905:Gram-Negative Bacterial Infections / Q000276:immunology / Q000401:mortality*; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000401:mortality; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D051381:Rats; D018805:Sepsis / Q000276:immunology / Q000401:mortality*; D014281:Trihexosylceramides / Q000276:immunology
D001057:Apolipoproteins E; D005915:Globosides; D007376:Interleukin-2; D014281:Trihexosylceramides; C514781:isoglobotrihexosylceramide
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