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B Inhibitory Effects of the Cell-Penetrating Penetratin Peptide
DudaDepartments of Medical Chemistry (T.L., B.P.), Genetics and Molecular Biology (I.V.), and Medical Biology (E.D.), and First Department of Medicine (A.S., T.T.), University of Szeged, Szeged, Hungary; Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary (E.K., G.P.); and Institute of Surgical Research, University of Szeged, Szeged, Hungary (J.K.)
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-
B (NF-
B) 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-
B 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-
B, pretreatment with only 2 mg/kg penetratin attenuated the severity of pancreatic inflammation by interfering with I
B degradation and subsequent nuclear import of NF-
B, inhibiting the expression of proinflammatory genes and improving the monitored laboratory and histological parameters of pancreatitis and associated oxidative stress.
Received for publication October 6, 2005.
Accepted for publication February 27, 2006.
Address correspondence to: Dr. Tamás Letoha, Department of Medical Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. E-mail: tletoha{at}yahoo.com
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