Document Detail

Inhibition of neddylation represses lipopolysaccharide-induced proinflammatory cytokine production in macrophage cells.
MedLine Citation:
PMID:  22927439     Owner:  NLM     Status:  MEDLINE    
Cullin-RING E3 ligases (CRLs) are a class of ubiquitin ligases that control the proteasomal degradation of numerous target proteins, including IκB, and the activity of these CRLs are positively regulated by conjugation of a Nedd8 polypeptide onto Cullin proteins in a process called neddylation. CRL-mediated degradation of IκB, which normally interacts with and retains NF-κB in the cytoplasm, permits nuclear translocation and transactivation of the NF-κB transcription factor. Neddylation occurs through a multistep enzymatic process involving Nedd8 activating enzymes, and recent studies have shown that the pharmacological agent, MLN4924, can potently inhibit Nedd8 activating enzymes, thereby preventing neddylation of Cullin proteins and preventing the degradation of CRL target proteins. In macrophages, regulation of NF-κB signaling functions as a primary pathway by which infectious agents such as lipopolysaccharides (LPSs) cause the up-regulation of proinflammatory cytokines. Here we have analyzed the effects of MLN4924, and compared the effects of MLN4924 with a known anti-inflammatory agent (dexamethasone), on certain proinflammatory cytokines (TNF-α and IL-6) and the NF-κB signaling pathway in LPS-stimulated macrophages. We also used siRNA to block neddylation to assess the role of this molecular process during LPS-induced cytokine responsiveness. Our results demonstrate that blocking neddylation, either pharmacologically or using siRNA, abrogates the increase in certain proinflammatory cytokines secreted from macrophages in response to LPS. In addition, we have shown that MLN4924 and dexamethasone inhibit LPS-induced cytokine up-regulation at the transcriptional level, albeit through different molecular mechanisms. Thus, neddylation represents a novel molecular process in macrophages that can be targeted to prevent and/or treat the LPS-induced up-regulation of proinflammatory cytokines and the disease processes associated with their up-regulation.
Fang-Mei Chang; Sara M Reyna; Jose C Granados; Sung-Jen Wei; Wendy Innis-Whitehouse; Shivani K Maffi; Edward Rodriguez; Thomas J Slaga; John D Short
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Publication Detail:
Type:  Journal Article     Date:  2012-08-27
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-15     Completed Date:  2012-12-31     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  35756-67     Citation Subset:  IM    
Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio, Edinburg, Texas 78541, USA.
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MeSH Terms
Anti-Inflammatory Agents / pharmacology
Cell Line, Tumor
Cyclopentanes / pharmacology
Dexamethasone / pharmacology
Inflammation Mediators / metabolism*
Interleukin-6 / biosynthesis*
Lipopolysaccharides / pharmacology
Macrophages / cytology,  metabolism*
NF-kappa B / metabolism
Protein Processing, Post-Translational / drug effects,  physiology*
Pyrimidines / pharmacology
Transcription, Genetic / drug effects,  physiology
Tumor Necrosis Factor-alpha / biosynthesis*
Ubiquitin-Activating Enzymes
Ubiquitins / metabolism*
Up-Regulation / drug effects,  physiology
Reg. No./Substance:
0/((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo(2,3-d)pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulphamate; 0/Anti-Inflammatory Agents; 0/Cyclopentanes; 0/IL6 protein, human; 0/Inflammation Mediators; 0/Interleukin-6; 0/Lipopolysaccharides; 0/NEDD8 protein, human; 0/NF-kappa B; 0/Nedd8 protein, mouse; 0/Pyrimidines; 0/Tumor Necrosis Factor-alpha; 0/Ubiquitins; 50-02-2/Dexamethasone; EC Enzymes

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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