LOW-DENSITY-LIPOPROTEIN RECEPTOR-DEFICIENT MICE ARE PROTECTED AGAINSTLETHAL ENDOTOXEMIA AND SEVERE GRAM-NEGATIVE INFECTIONS

Lipoproteins can bind lipopolysaccharide (LPS) and decrease the LPS-st imulated 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 wi th either LPS or live Gram-negative bacteria in LDL receptor deficient mice (LDLR-/-). The LDLR-/- mice challenged with LPS had an eightfold increased LD(50) when compared with the wild type controls (C57BI/6J) , while tumor necrosis factor alpha (TNF alpha) and interleukin-l alph a (IL-1 alpha) plasma concentrations were decreased twofold. LDLR-/- m ice had significantly lower and delayed mortality than control mice af ter infection with Klebsiella pneumoniae. No differences in the outgro wth of bacteria in the organs were present between the two groups, whi le circulating cytokine concentrations were decreased twofold in LDLR- /- mice. In contrast, the LPS-stimulated in vitro production of cytoki nes by peritoneal macrophages of LDLR-/- mice was significantly increa sed compared with controls. This increase was associated with enhanced specific binding of LPS to the macrophages of LDLR-/- mice. In conclu sion, endogenous LDL can protect against the lethal effects of endotox in and Gram-negative infection. At least part of this protection is ac hieved through decreased in vivo production of pro-inflammatory cytoki nes, in spite of increased cytokine production capacity.