Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections.

Abstract

Lipoproteins can bind lipopolysaccharide (LPS) and decrease the LPS-stimulated production of pro-inflammatory cytokines. We investigated the effect of increased plasma concentrations of low-density-lipoproteins (LDL) on survival and cytokine production after a lethal challenge with either LPS or live Gram-negative bacteria in LDL receptor deficient mice (LDLR Ϫ / Ϫ ). The LDLR Ϫ / Ϫ mice challenged with LPS had an eightfold increased LD 50 when compared with the wild type controls (C57Bl/6J), while tumor necrosis factor ␣ (TNF ␣ ) and interleukin-1 ␣ (IL-1 ␣ ) plasma concentrations were decreased twofold. LDLR Ϫ / Ϫ mice had significantly lower and delayed mortality than control mice after infection with Klebsiella pneumoniae. No differences in the outgrowth of bacteria in the organs were present between the two groups, while circulating cytokine concentrations were decreased twofold in LDLR Ϫ / Ϫ mice. In contrast, the LPS-stimulated in vitro production of cytokines by peritoneal macrophages of LDLR Ϫ / Ϫ mice was significantly increased compared with controls. This increase was associated with enhanced specific binding of LPS to the macrophages of LDLR Ϫ / Ϫ mice. In conclusion, endogenous LDL can protect against the lethal effects of endotoxin and Gram-negative infection. At least part of this protection is achieved through decreased in vivo production of pro-inflammatory cytokines, in spite of increased cytokine production capacity. ( J. Clin. Invest. 1996. 97:1366-1372). Key words: lipopolysaccharide • gram-negative infection • tumor necrosis factor • interleukin-1 • low-density lipoproteins.

Cholesterol supplementation prevents necrosis and inflammation but enhances fibrosis in alcoholic liver disease in the rat

“…The present study showed that the degree of fibrosis was creased in vivo production of cytokines in response to endotoxin. 39 Minimally oxidized LDLs are also known to decrease enhanced by dietary cholesterol supplementation. Because of the observed relationship between TGF-b 1 and fibrosis in lipopolysaccharide-induced TNF-a expression in macrophages.…”

Hypercholesterolemia Exacerbates Virus-Induced Immunopathologic Liver Disease Via Suppression of Antiviral Cytotoxic T Cell Responses

“…Furthermore, modified LDL increases macrophage chemotaxis (4) and may stimulate T cells in atheromatous lesions (5). However, high lipoprotein levels in plasma diminish systemic cytokine responses (6,7). Furthermore, high plasma cholesterol levels can result in impaired antibacterial immune responses, as shown by the failure of genetically hypercholesterolemic apolipoprotein E (ApoE) 3 -deficient (ApoE Ϫ/Ϫ ) mice to rapidly clear Listeria monocytogenes (8) or Klebsiella pneumoniae infection (9).…”

Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection

“…Lipoproteins may be involved in the redistribution of nutrients, neutralisation, binding or lysis of viruses and the binding of endotoxins and other biological agents. 44 Indeed, it has been shown that high lipoprotein levels reduce cytokine responses, 45 increase macrophage chemotaxis 46 and impair antiviral T cell immunity in hypercholcholesterolemic LDLR deficient mice. 47 It is hence plausible that genetic variation in the LDLR gene could affect the immune responses in HCV infection.…”