Catechols in caffeic acid phenethyl ester are essential for inhibition of TNF-mediated IP-10 expression through NF-κB-dependent but HO-1- and p38-independent mechanisms in mouse intestinal epithelial cells.
METHODS
Caffeic acid phenethyl ester (CAPE) is an active constituent of honeybee propolis inhibiting nuclear factor (NF)-κB. The aims of our study were to provide new data on the functional relevance and mechanisms underlying the role of CAPE in regulating inflammatory processes at the epithelial interface in the gut and to determine the structure/activity relationship of CAPE.


RESULTS
CAPE significantly inhibited TNF-induced IP-10 expression in intestinal epithelial cells. Using various analogues, we demonstrated that substitution of catechol hydroxyl groups and addition of one extra hydroxyl group on ring B reversed the functional activity of CAPE to inhibit IP-10 production. The anti-inflammatory potential of CAPE was confirmed in ileal tissue explants and embryonic fibroblasts derived from TNF(ΔARE/+) mice. Interestingly, CAPE inhibited both TNF- and LPS-induced IP-10 production in a dose-dependent manner, independently of p38 MAPK, HO-1 and Nrf2 signaling pathways. We found that CAPE did not inhibit TNF-induced IκB phosphorylation/degradation or nuclear translocation of RelA/p65, but targeted downstream signaling events at the level of transcription factor recruitment to the gene promoter.


CONCLUSIONS
This study reveals the structure-activity effects and anti-inflammatory potential of CAPE in the intestinal epithelium.
ZIEL-Research Center for Nutrition and Food Sciences, CDD-Center for Diet and Disease, Technische Universität München, Freising-Weihenstephan, Germany.
Job O
JO
Mapesa
Nadine
N
Waldschmitt
Ingrid
I
Schmoeller
Carolin
C
Blume
Thomas
T
Hofmann
Symon
S
Mahungu
Thomas
T
Clavel
Dirk
D
Haller
D000818:Animals; D002109:Caffeic Acids / Q000737:chemistry*; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D002109:Caffeic Acids; D002396:Catechols; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; C000606205:Nfkbia protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol