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Low dose endotoxin induces inflammation by selectively removing nuclear receptors and activating C/EBP‐delta
Author(s) -
Li Liwu,
Maitra Urmila,
Gan Lu,
Chang Samantha
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.116.10
Subject(s) - inflammation , receptor , nuclear receptor , chemistry , delta , pharmacology , endocrinology , medicine , physics , biochemistry , transcription factor , gene , astronomy
Subclinical levels of circulating endotoxin are associated with the pathogenesis of diverse human inflammatory diseases, by mildly inducing the expression of pro‐inflammatory mediators. In this report, 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 pro‐inflammatory mediators, we observed that low dose LPS fails to activate NF‐kappa‐B. Instead, low dose LPS selectively activates C/EBP‐delta and removes nuclear repressors including PPAR‐alpha and RAR‐alpha, enabling a mild and leaky expression of pro‐inflammatory mediators. The effect of low dose LPS requires the interleukin‐1 receptor associated kinase 1 (IRAK‐1). IRAK‐1 interacts with and acts upstream of IKK‐epsilon in contributing to LPS‐mediated induction of C/EBP‐delta and pro‐inflammatory mediators. Additionally, mice fed with a high fat diet acquire elevated levels of endotoxin and pro‐inflammatory mediators in an IRAK‐1 dependent fashion. Taken together, these data reveal a distinct pathway preferentially utilized by low dose endotoxin in initiating low grade inflammation.