Abstract：
BACKGROUND AND PURPOSE:MLN4924 prevents the formation of active cullin-RING ubiquitin ligase complexes and thus inhibits NF-κB signalling. Here, we evaluated the effects of this compound on monocytes and dendritic cells (DCs). EXPERIMENTAL APPROACH:Monocytes and DCs were challenged with TNF or LPS in the presence and absence of MLN4924. The effects of MLN4924 on cellular viability, pro-inflammatory gene induction and DC maturation were investigated using the MTT assay, elisa and FACS analysis. Mechanisms of cell death induction were evaluated by using inhibitors of caspases, RIPK1 and MLKL. KEY RESULTS:MLN4924 inhibited NF-κB activation and sensitized monocytes and immature DCs (iDCs) for TNFR1-induced cell death. Neither the caspase inhibitor zVAD-fmk, the RIPK1 inhibitor necrostatin-1 (nec-1) nor the MLKL inhibitor necrosulfonamide (NSA) alone prevented TNF-induced cell death. A combination of zVAD-fmk and nec-1 or NSA, however, rescued monocytes and iDCs from MLN4924/TNF-induced cell death indicating that MLN4924 affects anti-apoptotic and anti-necrotic activities in TNFR1 signalling. MLN4924 also converted the response of iDCs to LPS from maturation to cell death. LPS-induced cell death in MLN4924-treated iDCs was again only effectively blocked by cotreatment with zVAD-fmk and nec-1 or NSA. Noteworthy, MLN4924/LPS-induced cell death was almost completely independent of endogenous TNF. MLN4924 also strongly inhibited maturation and activation of iDCs that were rescued from cell death by zVAD-fmk and nec-1. CONCLUSIONS AND IMPLICATIONS:Our data reveal a strong dual suppressive effect of MLN4924 on DC activity. The targeting of NAE by MLN4924 could be a new way to treat inflammatory diseases.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
El-Mesery M,Seher A,Stühmer T,Siegmund D,Wajant Hdoi
10.1111/bph.12998subject
Has Abstractpub_date
2015-03-01 00:00:00pages
1222-36issue
5eissn
0007-1188issn
1476-5381journal_volume
172pub_type
杂志文章abstract：:1. The effect of the nitro-derivative of aspirin, NCX4016, was assessed on ischaemic ventricular arrhythmias and myocardial infarct size in anaesthetized pigs in comparison to native aspirin. 2. Pigs were given aspirin (10 mg kg(-1); n=6), low dose NCX4016 (18.4 mg kg(-1); n=6) or high dose NCX4016 (60 mg kg(-1); n=7)...
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journal_title：British journal of pharmacology
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doi：10.1038/sj.bjp.0706224
更新日期：2005-08-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
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abstract：:Using an in vitro mouse cerebellar slice preparation and whole-cell electrophysiological recording techniques we have characterized Purkinje and basket cell inhibitory post-synaptic currents (IPSCs), and examined the effects of a number of selective peptidergic K+ channel blockers. Spontaneous IPSC amplitude ranged fr...
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更新日期：1998-11-01 00:00:00
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doi：10.1111/bph.13250
更新日期：2015-10-01 00:00:00
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pub_type： 杂志文章
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