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Dimethyl‐ and monomethylfumarate regulate indoleamine 2,3‐dioxygenase ( IDO ) activity in human immune cells
Author(s) -
Eminel Sevgi,
Jin Na,
Rostami Martin,
Dibbert Stefan,
Mrowietz Ulrich,
Suhrkamp Ina
Publication year - 2017
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.13138
Subject(s) - indoleamine 2,3 dioxygenase , kynurenine , peripheral blood mononuclear cell , immune system , chemistry , psoriasis , metabolite , kynurenine pathway , pharmacology , in vitro , western blot , immunology , biochemistry , tryptophan , biology , amino acid , gene
Fumaric acid esters ( FAE s) are used as an oral treatment for psoriasis. Dimethylfumarate ( DMF ) and its metabolite monomethylfumarate ( MMF ) are regarded as the pharmacologically active moieties. Indoleamine 2,3‐dioxygenase ( IDO ) is the key enzyme for the metabolism of tryptophan. The kynurenine pathway is established as a major regulator of innate and adaptive immunity. Here, we investigated the effect of DMF and MMF on IDO activity and expression in human peripheral blood mononuclear cells ( PBMC s). IDO activity was determined by measuring the concentration of kynurenine in the culture medium using a HPLC technique. IDO and kynureninase protein expressions were analysed by Western blot. Our results demonstrated that DMF and MMF dose‐dependently reduced the levels of L‐kynurenine in PBMC s activated by interferon‐γ ( IFN ‐γ). Furthermore, MMF had an inhibitory effect on IDO activity in vitro with an ED 50 of 10 μmol/L, a value within the therapeutic concentration range for this molecule. We also observed that IDO and kynureninase expressions were reduced in PBMC s in a dose‐dependent manner by DMF and MMF . The results of our study show that DMF and MMF (in therapeutic concentrations) inhibited IDO and kynureninase activity and expression in a NF ‐κB‐dependent manner in PBMC s while also decreasing the level of L‐kynurenine in these cells. As we found that FAE s inhibit both IDO expression and enzymatic activity leading to a modulation of tryptophan degradation, we believe this effect may contribute to the clinical efficacy of this drug in psoriasis by downregulating pro‐inflammatory mediators generated by the kynurenine pathway.