Molecular Mechanisms Governing Persistent Induction of Pro-Inflammatory Genes by Lipopolysaccharide

Low dose endotoxemia is caused by several health conditions including smoking, alcohol abuse, high fat diets, and aging. Several studies have correlated low dose endotoxemia with increased risks of atherosclerosis, diabetes, and Parkinson's disease. Unlike high doses of endotoxin which induce a strong but transient induction of pro-inflammatory mediators, low doses of endotoxin result in a mild but chronic induction of pro-inflammatory genes. The central hypothesis of our study was that if low doses of endotoxin are capable of inducing mild prolonged inflammation, then a unique signaling circuit must be utilized.

In the first study, the molecular mechanisms for the persistent induction of lipocalin 2 (LCN2) in response to 100 ng/mL of lipopolysaccharide (LPS) in kidney fibroblasts was examined. It appears that the intracellular signaling network responsible for the persistent induction of LCN2 requires both activator protein-1 (AP-1) and CCAAT/enhancer binding protein delta (C/ebpδ). Interleukin-1 receptor-associated kinase 1 (IRAK-1) is critical for LCN2 expression.

In the second study, the molecular mechanisms governing the persistent induction of interleukin 6 (IL-6) upon a 50 pg/mL challenge of LPS in macrophages was examined. At this dose, only the persistent activation of cJun N-terminal kinase (JNK) and C/ebpδ was observed. IL-6 transcription requires the transient recruitment of activating transcription factor 2 (ATF2) and the persistent recruitment of C/ebpδ to the IL-6 promoter.

In the third study, the molecular mechanisms that mediate LPS-induced priming was examined. The results demonstrate that macrophages are able to sense their prior history of exposure to LPS that result in either a priming or tolerance phenotype upon a secondary challenge of LPS. Results suggest that this sensing mechanism involves cross-talk between IRAK-1 and phosphoinositide-3-kinase (PI3K).

Collectively, these studies indicate that JNK and C/ebpδ are the primary players responsible for the persistent expression of pro-inflammatory genes during low dose endotoxemia. IRAK-1 is a key intracellular signaling kinase that mediates signaling at low doses of LPS. IRAK-1 is not only critical for low dose induced expression, but also for LPS-induced priming. This research has revealed a novel signaling pathway that could provide new molecular targets for drug development against chronic inflammatory diseases.