Low-Dose Endotoxin Induces Inflammation by Selectively Removing Nuclear Receptors and Activating CCAAT/Enhancer-Binding Protein δ

Subclinical levels of circulating endotoxin are associated with the pathogenesis of diverse human inflammatory diseases, by mildly inducing the expression of proinflammatory mediators. In this study, we examined the molecular mechanism responsible for the effect of low-dose LPS in macrophages. In contrast to high-dose LPS, which activates NF-kappa B and induces the robust expression of proinflammatory mediators, we observed that low-dose LPS failed to activate NF-kappa B. Instead, it selectively activated C/EBP delta and removed nuclear repressors, including peroxisome proliferator-activated receptor a and retinoic acid receptor alpha, enabling a mild and leaky expression of proinflammatory mediators. The effect of low-dose LPS required IRAK-1, which interacts with and acts upstream of I kappa B kinase epsilon to contribute to LPS-mediated induction of C/EBP delta and proinflammatory mediators. Additionally, mice fed a high-fat diet acquired elevated levels of endotoxin and proinflammatory mediators in an IRAK-1-dependent fashion. Taken together, these data reveal a distinct pathway preferentially used by low-dose endotoxin in initiating low-grade inflammation. The Journal of Immunology, 2011, 186: 4467-4473.