TY - JOUR T1 - In Vitro and in Vivo Nuclear Factor-κB Inhibitory Effects of the Cell-Penetrating Penetratin Peptide JF - Molecular Pharmacology JO - Mol Pharmacol SP - 2027 LP - 2036 DO - 10.1124/mol.105.019653 VL - 69 IS - 6 AU - Tamás Letoha AU - Erzsébet Kusz AU - Gábor Pápai AU - Annamária Szabolcs AU - József Kaszaki AU - Ilona Varga AU - Tamás Takács AU - Botond Penke AU - Ernő Duda Y1 - 2006/06/01 UR - http://molpharm.aspetjournals.org/content/69/6/2027.abstract N2 - Penetratin is a cationic cell-penetrating peptide that has been frequently used for the intracellular delivery of polar bioactive compounds. Recent studies have just revealed the major role of polyanionic membrane proteoglycans and cholesterol-enriched lipid rafts in the uptake of the peptide. Both proteoglycans and lipid-rafts influence inflammatory processes by binding a wide array of proinflammatory mediators; thus, we decided to analyze the effect of penetratin on in vitro and in vivo inflammatory responses. Our in vitro luciferase gene assays demonstrated that penetratin decreased transcriptional activity of nuclear factor-κB (NF-κB) in tumor necrosis factor (TNF)-stimulated L929 fibroblasts and lipopolysaccharide-activated RAW 264.7 macrophages. Penetratin also inhibited TNF-induced intercellular adhesion molecule-1 expression in human endothelial HMEC-1 cells. Exogenous heparan sulfate abolished the in vitro NF-κB inhibitory effects of the peptide. Uptake experiments showed that penetratin was internalized by all of the above-mentioned cell lines in vitro and rapidly entered the cells of the lung and pancreas in vivo. In an in vivo rat model of acute pancreatitis, a disease induced by elevated activities of stress-responsive transcription factors like NF-κB, pretreatment with only 2 mg/kg penetratin attenuated the severity of pancreatic inflammation by interfering with IκB degradation and subsequent nuclear import of NF-κB, inhibiting the expression of proinflammatory genes and improving the monitored laboratory and histological parameters of pancreatitis and associated oxidative stress. ER -