TAT cell-penetrating peptide modulates inflammatory response and apoptosis in human lung epithelial cells

Abstract

Cell-penetrating peptides (CPPs) are commonly used as delivery vehicles for the introduction of a variety of macromolecules into cells. Trans-activator of transcription (TAT) is the most commonly used CPP and, as a delivery vehicle, is assumed to be biologically inert. In this study, we pretreated human lung epithelial cells with TAT prior to stimulation with phorbol 12,13-dibutyrate (PDBu), a protein kinase C (PKC) activator. Surprisingly, TAT alone inhibited the production of multiple cytokines induced by PKC activation. Furthermore, PKC activation-induced IκBα degradation was partially reduced by TAT. Moreover, TAT treatment alone induced apoptosis in a dose-dependent manner, influenced expression of several B cell lymphoma 2 (Bcl-2) family members and increased caspase 3 cleavage at a high dose. These findings suggest that TAT as a delivery vehicle should be used cautiously, as it may affect the inflammatory response, as well as signals related to apoptosis.

δV1-1 Reduces Pulmonary Ischemia Reperfusion-Induced Lung Injury by Inhibiting Necrosis and Mitochondrial Localization of PKCδ and p53

“…In the present study, the cell penetration peptide, TAT, was used as a delivery vehicle for dV1-1 with noted nonspecific, inhibitory effects of TAT on cytokine production. Similar and additional nonspecific effects of TAT have been reported (40,41). To overcome this effect, a gold nanoparticle-based formulation strategy has been developed (58,59).…”

“…dV1-1 also inhibited IL-8 and GRO1a production in human primary airway epithelial cells ( Figure S2D). TAT alone also reduced IL-6 production in BEAS-2B cells ( Figure 5A), and IL-8 and GRO-1a production in human primary airway epithelial cells ( Figure S2D), through its nonspecific effects (40,41). The 18-h CIT-induced morphological changes and cell loss were partially prevented by dV1-1 ( Figure 5B).…”

Synthetic Nucleic Acid Analogues in Gene Therapy: An Update for Peptide–Oligonucleotide Conjugates

“…On the other hand, the trans ‐activator of transcription (TAT), which is one of the most common CPPs, recently showed undesirable biological effects. It was reported that TAT induced apoptosis of human lung epithelial BEAS‐2B cells and an inflammatory response . Prior to stimulation with protein kinase C activator (PKC) of BEAS‐B cells, they were pretreated with TAT.…”

“…The results were inhibition of activity of the PKC. Conspicuously, TAT inhibited the production of multiple cytokines induced by PCK and the PCK activation‐induced degradation of IkBα (alpha‐nuclear factor of kappa light polypeptide gene enhancer in B‐cell inhibitor) …”

Effective delivery of a rationally designed intracellular peptide drug with gold nanoparticle–peptide hybrids

“…δV1-1 interferes in RACK-PKCδ interaction, thereby preventing PKCδ translocation to the subcellular compartments. 20 Considering that the clinical trial was unsuccessful 21 and Tat's application as a delivery motif is limited due to non-specific effects, 3,22 we examined whether δV1-1 can be effectively delivered using the 95P2P4-GNP hybridization strategy. 16,17 Both activated and inactivated PKCδ can translocate to the nucleus and cause a number of changes including caspase-3mediated DNA fragmentation and degradation of nuclear proteins, eventually leading to cell death.…”