Biochemical and Biophysical Research Communications
Celastrol inhibits pro-inflammatory cytokine secretion in Crohn’s disease biopsies
Section snippets
Materials and methods
Reagents and compounds. β-Mercaptoethanol, dexamethasone, glutamine, Hanks’ balanced salt solution (HBSS), heparin, Histopaque-1077, lipopolysaccharide (LPS) from Salmonella abortus equi, mifepristone (RU486), MTT, RPMI 1640, and SigmaFast OPD substrate were purchased from Sigma–Aldrich (Saint-Quentin Fallavier, France). Celastrol was a generous gift of Dr. A.C. Allison (SurroMed, Mountain View, California, USA). Twenty-four-well tissue culture treated plates and 96-well polyvinyl chloride
Celastrol inhibits pro-inflammatory cytokine production by LPS-activated human peripheral blood mononuclear cells and human whole blood
Since various antioxidants have been described to potently inhibit production of several pro-inflammatory cytokines or chemokines, we measured Celastrol’s potential to inhibit IL-1β, -6, -8, and TNF-α production in vitro by human LPS-activated PBMCs. Celastrol inhibits in a dose-dependant way the production of these four cytokines, with IC50’s ranging from 3 to 30 nM (Fig. 1 and Table 1A). The similar activity profile is found for human whole blood, with, as expected, IC50 values approximately
Discussion
Celastrol has been previously described as a potent inhibitor of various inflammatory mediators (NO, IL-1β) in different in vitro models [20]. Here, we focused initially on four cytokines (IL-1β, IL-6, IL-8, and TNF-α) believed to play a key role in chronic immune diseases, particularly Crohn’s disease [8] and overproduced in various immune-mediated pathologies. We then enlarged our study to a panel of cytokines involved in the Th1/Th2 balance and to inflammatory intestinal mucosal biopsies
Acknowledgments
The authors thank Dr. Kenneth TAKEDA (UMR 7034 CNRS) for critical reviewing of the manuscript. Financial support: The Région Alsace, and FORENAP, FRANCE equally supported G.F. Pinna. Y. Arondel thanks the laboratoires FERRING for their financial assistance.
References (38)
New biological therapies in inflammatory bowel disease
Best Pract. Res. Clin. Gastroenterol.
(2003)- et al.
Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn’s disease
Lancet
(1999) - et al.
Recombinant interleukin-1 receptor antagonist blocks the proinflammatory activity of endogenous interleukin-1 in rabbit immune colitis
Gastroenterology
(1992) Strategies for targeting tumour necrosis factor in IBD
Best Pract. Res. Clin. Gastroenterol.
(2003)- et al.
An engineered human antibody to TNF (CDP571) for active Crohn’s disease: a randomized double-blind placebo-controlled trial
Gastroenterology
(2001) - et al.
Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial
Lancet
(2002) Redox regulation of pro-inflammatory cytokines and IkappaB-alpha/NF-kappaB nuclear translocation and activation
Biochem. Biophys. Res. Commun.
(2002)- et al.
Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer’s disease
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2001) - et al.
Prostaglandin E(2) upregulates cyclooxygenase-2 expression in lipopolysaccharide-stimulated RAW 264.7 macrophages
Biochem. Biophys. Res. Commun.
(2000) - et al.
Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method
Methods
(2001)
The Rel/NF-kappa B family: friend and foe
Trends Biochem. Sci.
Lipopolysaccharide induces phosphorylation of MAD3 and activation of c-Rel and related NF-kappa B proteins in human monocytic THP-1 cells
J. Biol. Chem.
Post-transcriptional regulation of gene expression by mitogen-activated protein kinase p38
FEBS Lett.
TNF-R1 signaling: a beautiful pathway
Science
Pathogenesis of bone and cartilage destruction in rheumatoid arthritis
Rheumatology (Oxford)
Genes, microbes, and T cells—new therapeutic targets in Crohn’s disease
N. Engl. J. Med.
The role of Th1/Th2 polarization in mucosal immunity
Nat. Med.
Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn’s disease
J. Clin. Immunol.
Enhanced production of IL-8 in chronic but not in early ileal lesions of Crohn’s disease (CD)
Clin. Exp. Immunol.
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