3rd Annual BMRP Investigator Meeting - Abstract

The Flavonoid Luteolin Prevents LPS-Induced NF-kB Signaling and Gene Expression by Blocking IkB Kinase Activity in Intestinal Epithelial Cells and Bone Marrow-Derived Dendritic Cells

Joo Sung Kim and Christian Jobin^a

Departments of Medicine, Microbiology and Immunology and the Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill (Chapel Hill, North Carolina, U.S.A.)

The NF-kB transcriptional system is a major effector pathway involved in inflammation and innate immune responses.  The flavonoid luteolin is found in various herbal extracts and has shown anti-inflammatory properties.  However, the mechanism of action and impact of luteolin on innate immunity is still unknown.

We report that luteolin significantly blocks LPS-induced IkB phosphorylation/degradation, NF-kB transcriptional activity and ICAM-1 gene expression in rat IEC-18 cells.  Using chromatin immunoprecipitation, we demonstrate that LPS-induced RelA recruitment to the ICAM-1 gene promoter is significantly reduced in luteolin-treated cells.  Moreover, in vitro kinase assays show that luteolin directly inhibits LPS-induced IkB kinase (IKK) activity in IEC-18 cells.  Using bone marrow-derived dendritic cells (BMDCs) isolated from IL-10^-/- mice or from recently engineered transgenic mice expressing the enhanced green fluorescent protein (EGFP) under the transcriptional control of NF-kB cis-elements (cis-NF-kB^EGFP), we found that luteolin blocks LPS-induced IkB phosphorylation and IKK activity and decreases EGFP, IL-12 and TNF-a gene expression.  Moreover, intraperitoneal administration of luteolin significantly inhibited LPS-induced EGFP expression in both peripheral blood mononuclear cells and splenocytes isolated from cis-NF-kB^EGFP mice.

These results indicate that luteolin blocks LPS-induced NF-kB signaling and pro-inflammatory gene expression in intestinal epithelial cells and dendritic cells.  Modulation of innate immunity by natural plant products may represent an attractive strategy to prevent intestinal inflammation associated with dysregulated innate immune responses.

^aPrincipal Investigator