Interferon‐β affects the tryptophan metabolism in multiple sclerosis patients

Abstract

Tryptophan and its metabolites are of great interest in understanding the pathogenesis of multiple sclerosis (MS). The total levels of tryptophan and its metabolites, kynurenine and kynurenic acid were determined in plasma by capillary liquid chromatography electrospray ionisation tandem mass spectrometry. This is the first report of the plasma levels of these analytes in healthy controls and relapsing-remitting MS patients receiving long-term and acute interferon-beta (IFN-beta) treatment. Twenty-four hours post-administration increased kynurenine levels (first IFN MS versus healthy, P = 0.042) and kynurenine/tryptophan ratio (K/T; first IFN MS versus healthy, P =0.027; first IFN MS versus long-term IFN MS, P = 0.036) were found. The long-term IFN MS group had higher K/T ratios at 4 and 12 h post-administration (P = 0.015 and 0.009, respectively). The increase of K/T ratio in the first IFN MS group indicate an induction of the enzyme indolamine-2,3-dioxygenase (IDO), as reported earlier in experimental allergic encephalomyelitis. As IDO is participating in both inflammatory and neurodegenerative processes, further knowledge of its involvement in the pathogenesis of MS is of great importance.

IDO expression in the brain: a double-edged sword

“…Interestingly, IFN-β induces the kynurenine pathway and the synthesis of QUIN in human macrophages, although to a lesser extent than IFN-γ [5]. This is in line with the observation that treatment with IFN-β increased the relative IDO activity in blood serum samples (Kyn/Trp) from MS patients [85]. However, increased IDO activity was not found in specimens deriving from patients who received long-term treatment with IFN-β.…”

Tryptophan degradation in autoimmune diseases

“…Plasma levels of kynurenic acid were not changed in MS patients after initial treatment with IFN-b or after long-term IFN-b treatment [116]. In contrast, after initiation of IFN-b1a/b treatment, there was an increase in the kynurenine/tryptophan (K/T) ratio, indicating an induction of IDO [116]. However, in patients receiving long-term IFN-b, the K/T ratio did not differ from the healthy control group [116].…”

“…In contrast, after initiation of IFN-b1a/b treatment, there was an increase in the kynurenine/tryptophan (K/T) ratio, indicating an induction of IDO [116]. However, in patients receiving long-term IFN-b, the K/T ratio did not differ from the healthy control group [116]. At present the impact of IFN-b-mediated induction of Trp catabolism in patients with autoimmune diseases remains elusive.…”

“…More recently, concentrations of IFN-b1b comparable to those found in the sera of MS patients were shown to increase IDO mRNA expression and quinolinic acid production in human macrophages [115]. Plasma levels of kynurenic acid were not changed in MS patients after initial treatment with IFN-b or after long-term IFN-b treatment [116]. In contrast, after initiation of IFN-b1a/b treatment, there was an increase in the kynurenine/tryptophan (K/T) ratio, indicating an induction of IDO [116].…”

“…At present the impact of IFN-b-mediated induction of Trp catabolism in patients with autoimmune diseases remains elusive. As the inhibition of Trp catabolism exacerbates EAE [91], induction of Trp catabolism by IFN-b could be beneficial in MS but does not appear to be involved in the long-term effects of IFN-b treatment [116]. On the other hand, induction of quinolinic acid production by IFN-b could also account for toxic effects on neurons or oligodendrocytes [115].…”