title: Kavain Inhibition of LPS-Induced TNF-α via ERK/LITAF.
abstract: Kavain, an extract from the shrubPiper Methysticum,was recently reported to modulate TNF-α expression in both human and mouse cells via regulation of LPS-Induced TNF-Alpha Factor (LITAF). The purpose of the present study was to define the molecular pathway(s) associated with Kavain effects on TNF modulation. In vitro studies using WT mouse primary macrophages showed that Kavain significantly reducedE.coliLPS-induced TNF-α production but this effect was almost abrogated in LITAF-/-and ERK2-/-cells. Therefore we reintroduced the ERK2 gene in ERK2-/-cells and partially restoredE.coliLPS-induced LITAF-mediated TNF-α production. The translocation of LITAF into to nucleus was found to be dependent on ERK2 S206 residue. Kavain inhibits LITAF/TNF-α expression via dephosphorylation of ERK2 in response toE.coliLPS. Finally,in vivo,Kavain had a significant anti-inflammatory effect on wild type mice that developed Collagen Antibody Induced Arthritis (CAIA), but only a minor effect in ERK2-/-mice also affected by CAIA. Based on these findings, we concluded that ERK2 may be the kinase upstream of LITAF with its Serine residue 206 being crucial for the regulation of LPS-induced TNF-α.
authors.affiliation: Center for Anti-Inflammatory Therapeutics, Molecular & Cell Biology Department, Boston University Goldman School of Dental Medicine, Boston, MA, 02118 USA.
authors.forename: Xiaoren
authors.initials: X
authors.lastname: Tang
authors.affiliation: Center for Anti-Inflammatory Therapeutics, Molecular & Cell Biology Department, Boston University Goldman School of Dental Medicine, Boston, MA, 02118 USA.
authors.forename: Salomon
authors.initials: S
authors.lastname: Amar
keywords: E. coli LPS; ERK2; Kavain; TNF; amino acid; lentivirus