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2015 ; 172
(5
): 1222-36
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MLN4924 sensitizes monocytes and maturing dendritic cells for TNF-dependent and
-independent necroptosis
#MMPMID25363690
El-Mesery M
; Seher A
; Stühmer T
; Siegmund D
; Wajant H
Br J Pharmacol
2015[Mar]; 172
(5
): 1222-36
PMID25363690
show ga
BACKGROUND AND PURPOSE: MLN4924 prevents the formation of active cullin-RING
ubiquitin ligase complexes and thus inhibits NF-?B 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-?B 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.
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