Celastrol inhibits pro-inflammatory cytokine secretion in Crohn's disease biopsies.
Crohn's disease is a chronic intestinal inflammatory process. In modern therapy, TNF-alpha inhibition is the main goal. The aim here is to characterize the effects of Celastrol, a pentacyclic-triterpene, on the secretion of inflammatory cytokines by LPS-activated human cells. Celastrol dose-dependently inhibited the secretion of all tested pro-inflammatory cytokines with IC(50) in the nanomolar range. Effect not related to glucocorticoid receptor activity is shown by competition experiments with the steroid antagonist RU486. Celastrol inhibited the pro-inflammatory cytokine secretion from mucosal inflammatory biopsies from Crohn's disease patients. Cytometry emphasized that for all tested pro-inflammatory cytokines, CD33(+) cells are the most sensitive. Quantitative-PCR and confocal analysis on a human monocytic cell line indicated that Celastrol acts at the transcriptional level by inhibiting LPS-induced NF-kappaB translocation. Celastrol might be a putative anti-inflammatory drug in the treatment of inflammatory diseases, given its inhibition of cytokine production by intestinal biopsies from Crohn's disease patients.
Pinna
Guillaume F
GF
UMR 7034 du CNRS (Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires), Université Louis Pasteur de Strasbourg, UFR de Sciences Pharmaceutiques, Illkirch, France.
Fiorucci
Marc
M
Reimund
Jean-Marie
JM
Taquet
Nathalie
N
Arondel
Yves
Y
Muller
Christian D
CD
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003106:Colon / Q000187:drug effects / Q000473:pathology*; D003424:Crohn Disease / Q000473:pathology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D009000:Monocytes; D053978:Pentacyclic Triterpenes; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology; D014315:Triterpenes / Q000494:pharmacology*
D016207:Cytokines; D008070:Lipopolysaccharides; D053978:Pentacyclic Triterpenes; D011965:Receptors, Glucocorticoid; D014315:Triterpenes; C050414:celastrol