Dimethyl- and monomethylfumarate regulate indoleamine 2,3-dioxygenase (IDO) activity in human immune cells.

Abstract

Fumaric acid esters (FAEs) 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 (PBMCs). 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 PBMCs activated by interferon-γ (IFN-γ). Furthermore, MMF had an inhibitory effect on IDO activity in vitro with an ED50 of 10μmol/L, a value within the therapeutic concentration range for this molecule. We also observed that IDO and kynureninase expressions were reduced in PBMCs 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 PBMCs while also decreasing the level of L-kynurenine in these cells. As we found that FAEs 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.