In vitro and in vivo nuclear factor-κB inhibitory effects of the cell-penetrating penetratin peptide

Tamás Letoha, Erzsébet Kusz, Gábor Pápai, Annamária Szabolcs, József Kaszaki, Ilona Varga, Tamás Takács, Botond Penke, Erno Duda

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20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2027-2036
Number of pages10
JournalMolecular pharmacology
Volume69
Issue number6
DOIs
Publication statusPublished - Jun 22 2006

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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