The sirtuin inhibitor cambinol impairs MAPK signaling, inhibits inflammatory and innate immune responses and protects from septic shock.

Details

Serval ID
serval:BIB_0F6F53429C86
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The sirtuin inhibitor cambinol impairs MAPK signaling, inhibits inflammatory and innate immune responses and protects from septic shock.
Journal
Biochimica et Biophysica Acta
Author(s)
Lugrin J., Ciarlo E., Santos A., Grandmaison G., dos Santos I., Le Roy D., Roger T.
ISSN
0167-4889 (Print)
ISSN-L
0167-4889
Publication state
Published
Issued date
2013
Volume
1833
Number
6
Pages
1498-1510
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish. PDF type: Review
Abstract
Sirtuins (SIRT1-7) are NAD(+)-dependent histone deacetylases (HDACs) that play an important role in the control of metabolism and proliferation and the development of age-associated diseases like oncologic, cardiovascular and neurodegenerative diseases. Cambinol was originally described as a compound inhibiting the activity of SIRT1 and SIRT2, with efficient anti-tumor activity in vivo. Here, we studied the effects of cambinol on microbial sensing by mouse and human immune cells and on host innate immune responses in vivo. Cambinol inhibited the expression of cytokines (TNF, IL-1β, IL-6, IL-12p40, and IFN-γ), NO and CD40 by macrophages, dendritic cells, splenocytes and whole blood stimulated with a broad range of microbial and inflammasome stimuli. Sirtinol, an inhibitor of SIRT1 and SIRT2 structurally related to cambinol, also decreased macrophage response to TLR stimulation. On the contrary, selective inhibitors of SIRT1 (EX-527 and CHIC-35) and SIRT2 (AGK2 and AK-7) used alone or in combination had no inhibitory effect, suggesting that cambinol and sirtinol act by targeting more than just SIRT1 and SIRT2. Cambinol and sirtinol at anti-inflammatory concentrations also did not inhibit SIRT6 activity in in vitro assay. At the molecular level, cambinol impaired stimulus-induced phosphorylation of MAPKs and upstream MEKs. Going well along with its powerful anti-inflammatory activity, cambinol reduced TNF blood levels and bacteremia and improved survival in preclinical models of endotoxic shock and septic shock. Altogether, our data suggest that pharmacological inhibitors of sirtuins structurally related to cambinol may be of clinical interest to treat inflammatory diseases.
Keywords
Animals, Apoptosis, Benzamides/pharmacology, Blotting, Western, Cell Proliferation, Cells, Cultured, Cytokines/metabolism, Flow Cytometry, Humans, Immunity, Innate/immunology, Inflammation/immunology, Inflammation/microbiology, Klebsiella Infections/immunology, Klebsiella Infections/microbiology, Klebsiella pneumoniae, Macrophages/drug effects, Macrophages/immunology, Mice, Mice, Inbred BALB C, Mitogen-Activated Protein Kinases/genetics, Mitogen-Activated Protein Kinases/metabolism, Naphthalenes/pharmacology, Naphthols/pharmacology, Pyrimidinones/pharmacology, RNA, Messenger/genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Shock, Septic/immunology, Shock, Septic/microbiology, Sirtuins/antagonists & inhibitors
Pubmed
Web of science
Open Access
Yes
Create date
06/05/2013 14:13
Last modification date
20/08/2019 12:36
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