Penta-O-galloyl-β-D-glucose ameliorates inflammation by inhibiting MyD88/NF-κB and MyD88/MAPK signalling pathways.

Abstract

BACKGROUND AND PURPOSE:

The gallnut of Rhus chinensis MILL and its main constituent penta-O-galloyl-β-D-glucose (PGG) inhibited NF-κB activation in LPS-stimulated peritoneal and colonic macrophages. Here we have investigated PGG mechanisms underlying anti-inflammatory effects of PGG in vitro and in vivo.

EXPERIMENTAL APPROACH:

Male C57BL/6 mice (18-22 g, 6 weeks old) were used to prepare peritoneal and colonic macrophages and for the induction of colitis by intrarectal administration of 2,3,4-trinitrobenzene sulphonic acid (TNBS). A range of inflammatory markers and transcription factors were evaluated by elisa, immunoblotting, flow cytometry and confocal microscopy.

KEY RESULTS:

Expression of Toll-like receptor (TLR)-4 or Lipopolysaccharide (LPS) binding to TLR-4 in LPS-stimulated peritoneal macrophages was not affected by PGG. However PGG inhibited binding of an anti-MyD88 antibody to peritoneal macrophages, but did not reduce binding of anti-IL-1 receptor-associated kinase (IRAK1) and IRAK4 antibodies to the macrophages with or without transfection with MyD88 siRNA. PGG potently reduced the activation of IRAK1, NF-κB, and MAPKs in LPS- or pepetidoglycan-stimulated peritoneal and colonic macrophages. PGG suppressed IL-1β, TNF-α and IL-6 in LPS-stimulated peritoneal macrophages, while increasing expression of the anti-inflammatorycytokine IL-10. Oral administration of PGG inhibited colon shortening and myeloperoxidase activity in mice with TNBS-induced colitis, along with reducing NF-κB activation and IL-1β, TNF-α, and IL-6 levels, whereas it increased IL-10.

CONCLUSIONS AND IMPLICATIONS:

PGG reduced activation of NF-κB and MAPK signalling pathways by directly interacting with the MyD88 adaptor protein. PGG may ameliorate inflammatory diseases such as colitis.

• Authors: Se-Eun Jang, Supriya R Hyam, Jin-Ju Jeong, Myung Joo Han, Dong-Hyun Kim
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 170 Issue 5 Pg. 1078-91 (Nov 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 23941302 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• Anti-Inflammatory Agents
• Gastrointestinal Agents
• Hydrolyzable Tannins
• Inflammation Mediators
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• NF-kappa B
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• pentagalloylglucose
• Trinitrobenzenesulfonic Acid
• Interleukin-1 Receptor-Associated Kinases
• Irak1 protein, mouse
• Mitogen-Activated Protein Kinases

Topics

• Administration, Oral
• Animals
• Anti-Inflammatory Agents (administration & dosage, pharmacology)
• Cells, Cultured
• Colitis (chemically induced, enzymology, immunology, prevention & control)
• Colon (drug effects, enzymology, immunology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gastrointestinal Agents (administration & dosage, pharmacology)
• Hydrolyzable Tannins (administration & dosage, pharmacology)
• Inflammation Mediators (metabolism)
• Interleukin-1 Receptor-Associated Kinases (metabolism)
• MAP Kinase Signaling System (drug effects)
• Macrophages, Peritoneal (drug effects, enzymology, immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Molecular Sequence Data
• Myeloid Differentiation Factor 88 (antagonists & inhibitors, genetics, metabolism)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Phosphorylation
• RNA Interference
• Toll-Like Receptor 4 (metabolism)
• Transfection
• Trinitrobenzenesulfonic Acid