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Updated: Apr 21, 2026
Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
MLN4924 sensitizes monocytes and maturing dendritic cells for TNF-dependent and -independent necroptosis
Mohamed El-Mesery1, Axel Seher, Thorsten Stühmer
1Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
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.
Insights
MLN4924 inhibits NF-κB signaling and induces cell death in monocytes and dendritic cells (DCs) by affecting both apoptotic and necrotic pathways. This dual action suggests MLN4924 as a potential therapeutic for inflammatory diseases.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- MLN4924 inhibits the formation of active cullin-RING ubiquitin ligase complexes.
- This inhibition leads to the suppression of NF-κB signaling pathways.
Purpose of the Study:
- To evaluate the effects of MLN4924 on monocytes and dendritic cells (DCs).
- To investigate MLN4924's impact on cellular viability, pro-inflammatory gene induction, and DC maturation.
Main Methods:
- Monocytes and DCs were treated with TNF or LPS in the presence or absence of MLN4924.
- Cellular viability, gene induction, and DC maturation were assessed using MTT assays, ELISA, and FACS analysis.
- Mechanisms of cell death were studied using inhibitors of caspases, RIPK1, and MLKL.
Main Results:
- MLN4924 inhibited NF-κB activation and sensitized cells to TNFR1-induced cell death.
- MLN4924 induced cell death through combined apoptotic and necrotic pathways, as indicated by inhibitor studies.
- MLN4924 shifted LPS response from DC maturation to cell death, which was largely independent of endogenous TNF.
- MLN4924 strongly inhibited the maturation and activation of DCs that were rescued from cell death.
Conclusions:
- MLN4924 exhibits a dual suppressive effect on DC activity.
- Targeting NEDD8-activating enzyme (NAE) with MLN4924 presents a novel therapeutic strategy for inflammatory diseases.
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