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


METHODS
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.


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
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.
Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, Korea; Department of Food and Nutrition, Kyung Hee University, Seoul, Korea.
Se-Eun
SE
Jang
Supriya R
SR
Hyam
Jin-Ju
JJ
Jeong
Myung Joo
MJ
Han
Dong-Hyun
DH
Kim
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D047348:Hydrolyzable Tannins / Q000008:administration & dosage / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014162:Transfection; D014302:Trinitrobenzenesulfonic Acid
D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D047348:Hydrolyzable Tannins; D018836:Inflammation Mediators; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C435084:pentagalloylglucose; D014302:Trinitrobenzenesulfonic Acid; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D020928:Mitogen-Activated Protein Kinases
MyD88; NF-κB; inflammation; macrophage; penta-O-galloyl-β-D-glucose