title: Fumaric acid esters prevent the NLRP3 inflammasome-mediated and ATP-triggered pyroptosis of differentiated THP-1 cells.
abstract: Fumaric acid esters (FAEs) exert therapeutic effects in patients with psoriasis and multiple sclerosis, however their mode of action remains elusive. Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death, mediated by the activation of inflammasomes. To understand the pharmacological basis of the therapeutic effects of FAEs, the anti-pyroptotic activity of dimethyl fumarate (DMF) and its hydrolysis metabolite monomethyl fumarate (MMF) was studied in a model of NLRP3 inflammasome-mediated pyroptosis of human macrophages. Phorbol myristate acetate-differentiated THP-1 cells were exposed to lipopolysaccharide (5 μg/ml; 4h), then pulsed with ATP (5mM; 1h). MMF, DMF, or parthenolide (positive control) were added 1h before the ATP pulse. The pyroptotic cell death was evaluated by morphological examination and quantified by measuring the lactate dehydrogenase leakage. The ATP-triggered death of THP-1 cells (60.4 ± 4.0%) was significantly (P<0.01) prevented by DMF, in a time- and concentration-dependent manner (pIC50 and maximal effect were 6.6 and 67.6 ± 1.2%, respectively). MMF was less efficacious than DMF. These effects were accompanied by a decreased intracellular activation of caspase-1 and interleukin-1β release from ATP-treated cells, thus suggesting that FAEs antagonise the effects of ATP by preventing the activation of the pyroptotic molecular cascade leading to cell death. These results indicate that FAEs are endowed with anti-pyroptotic activity, which may contribute to their therapeutic effects.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Miglio
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Veglia
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects*; D020170:Caspase 1 / Q000187:drug effects; D002478:Cells, Cultured; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects*; D053583:Interleukin-1beta / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000069292:Pyroptosis / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D005650:Fumarates; C000594089:IL1B protein, rat; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D000255:Adenosine Triphosphate; D020170:Caspase 1; D013755:Tetradecanoylphorbol Acetate
keywords: Dimethyl fumarate; Macrophages; Pyroptosis