Received for publication October 6, 2005.
Revised February 27, 2006.
Accepted for publication February 27, 2006.

IN VITRO AND IN VIVO NF-B INHIBITORY EFFECTS OF THE CELL-PENETRATING PENETRATIN PEPTIDE

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 NF-B in TNF- stimulated L929 fibroblasts and LPS-activated RAW 264.7 macrophages. Penetratin also inhibited TNF-induced ICAM- 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 of penetratin attenuated the severity of pancreatic inflammation by interfering with IB- 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.

Key words: Interleukins, Tumor necrosis factor, NFkappaB, Fluorescence techniques, Immunocytochemistry, Protein-binding, Oxidative stress, Peptide hormones

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