Piscroside C inhibits TNF-α/NF-κB pathway by the suppression of PKCδ activity for TNF-RSC formation in human airway epithelial cells.

Abstract

BACKGROUND:

Piscroside C, isolated from Pseudolysimachion rotundum var. subintegrum, is a novel iridoid glycoside with therapeutic efficacy in a mouse model of chronic obstructive pulmonary disease (COPD). Piscroside C has been reported as a constituent of YPL-001 (under Phase 2a study, ClinicalTrials.gov identifier NCT02272634).

PURPOSE:

To investigate the mechanisms behind piscroside C therapeutic effects on COPD in human airway epithelial NCI-H292 cells.

METHODS:

We tested if piscroside C effectively suppresses MUC5AC gene expression and TNF-RSC/IKK/NF-κB cascades in TNF-α-stimulated NCI-H292 cells by employing, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, luciferase reporter assays, chromatin immunoprecipitation assays and immunoprecipitation.

RESULTS:

Piscroside C markedly suppressed the expression of TNF-α-induced MUC5AC mucus protein by inhibiting the transcriptional activity of NF-κB in NCI-H292 cells. Indeed, piscroside C negatively regulated the function of TNF receptor 1 signaling complex (TNF-RSC, an upstream regulator of the NF-κB pathway) without affecting its extracellular interaction with the TNF-α ligand. This inhibitory effect by piscroside C is mediated by the inactivation of protein kinase C (PKC), an essential regulator of TNF-RSC. PKC inactivation by piscroside C results in decreased PKCδ binding to a TRAF2 subunit of TNF-RSC and subsequent reduced IKK phosphorylation, resulting in NF-κB inactivation.

CONCLUSION:

We propose that piscroside C is a promising therapeutic constituent of YPL-001 through its inhibition of PKCδ activity in the TNF-RSC/IKK/NF-κB/MUC5AC signaling cascade.

• Authors: Su Ui Lee, Seoghyun Lee, Hyunju Ro, Ji-Hee Choi, Hyung Won Ryu, Mun-Ock Kim, Heung Joo Yuk, Jinhyuk Lee, Sung-Tae Hong, Sei-Ryang Oh
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 40 Pg. 148-157 (Feb 01 2018) ISSN: 1618-095X [Electronic] Germany
• PMID: 29496167 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier GmbH. All rights reserved.

Chemical References

• Iridoid Glycosides
• MUC5AC protein, human
• Mucin 5AC
• Multiprotein Complexes
• NF-kappa B
• PSMD2 protein, human
• Receptors, Tumor Necrosis Factor, Type I
• TNF Receptor-Associated Factor 2
• Tumor Necrosis Factor-alpha
• piscroside C
• Protein Kinase C-delta

Topics

• Bronchi (cytology)
• Cell Line
• Epithelial Cells (drug effects)
• Gene Expression (drug effects)
• Humans
• Iridoid Glycosides (pharmacology)
• Mucin 5AC (genetics, metabolism)
• Multiprotein Complexes
• NF-kappa B (metabolism)
• Phosphorylation (drug effects)
• Protein Kinase C-delta (antagonists & inhibitors, metabolism)
• Pulmonary Disease, Chronic Obstructive (drug therapy, pathology)
• Receptors, Tumor Necrosis Factor, Type I (metabolism)
• Signal Transduction (drug effects)
• TNF Receptor-Associated Factor 2 (metabolism)
• Tumor Necrosis Factor-alpha (metabolism, pharmacology)