Cytokines activating the kynurenine pathway in schizophrenia?

I'm a bit of a fan of tryptophan biochemistry on this blog. This quite remarkable aromatic amino acid and it's off-shoot metabolites, which appear to have no end of biological uses, have taken quite a bit of my blogging time down the years. Most recently was the suggestion that a metabolite slotting in between serotonin (5-HT) and melatonin might require quite a bit more investigation when it comes to at least some cases of autism (see here).

See ya later, President Fartfeathers.

The findings reported by Lilly Schwieler and colleagues [1] (open-access here) add to the scientific interest and their assertion that: "IL-6 [interleukin-6] induces the KYN [kynurenine] pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA [kynurenic acid] in patients with schizophrenia." IL-6 by the way, is a cytokine (chemical messenger of the immune system) which is normally taken to be a pro-inflammatory cytokine (see here). Kynurenine and it's metabolic relations, are yet another set of compounds derived from tryptophan. The kynurenic hypothesis of schizophrenia (see here) hints at some of the research history this compound (and metabolites) has with the condition.

The Schwieler paper is open-access but a few pointers might be in order:

• Looking at a "well-characterized cohort of olanzapine-treated patients with chronic schizophrenia" researchers set about looking at cerebrospinal fluid (CSF) levels of various cytokines compared to a small participant group of asymptomatic controls "free from current signs of psychiatric morbidity or difficulties in social adjustment at the time of sampling".
• Previously measured levels of "tryptophan metabolites of the KYN pathway" were also included in the study bundle. Researchers also looked at a possible 'interplay' between IL-6 and kynurenic acid in human astrocyte cultures. This involved stimulation of said cultures with IL-6 and measuring KYNA using triple quadrupole mass spectrometry.
• Results: "The CSF IL-6 concentration was elevated in patients with chronic schizophrenia compared with controls." No real surprises there considering what has been reported previously in this area of schizophrenia research [2] and the growing idea of inflammation and psychiatry being linked. 
• CSF levels of kynurenine and kynurenic acid were also elevated in the schizophrenia group compared to controls, but no significant differences were noted in the starting material (tryptophan) between the groups. Authors also confirmed that IL-6 did indeed significantly raise levels of kynurenic acid (KYNA) in astrocyte cultures.
• They conclude that "The increased production of KYNA in fetal human astrocytes following exposure of IL-6 shows that this cytokine is able to induce the activity of the KYN pathway." This process may also pertain to schizophrenia.

Aside from the limitations already pointed out by the authors in terms of some analytical issues and the spot sampling methodology employed, I might also point out that whilst participants with schizophrenia were all taking olanzapine (and other meds in some cases), the asymptomatic controls were "free from medication for at least 1 month". Granted olanzapine is not generally thought to directly impact on levels of IL-6 for example [3] but one can't discount that other, more indirect effects might come into play. Indeed, I'm going to be talking about olanzapine, gut bacteria and weight gain (see here) early in the New Year.

I'd like to introduce the paper by Johansson and colleagues [4] at this point, and their observations related to kynurenic acid and related metabolites in "cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals." Looking at cells specifically from participants (with all their biological heterogeneity), they similarly concluded that there was an "increase in ratio between neurotoxic 3-HK [3-hydroxykynurenine] and neuroinhibitory/neuroprotective KYNA following exposure to cytokines" in the bipolar and schizophrenia groups compared to controls. The 3-HK finding might be of even greater interest to schizophrenia given the suggestion of a link with redox modulation [5] and the idea that oxidative stress might be a factor to the condition [6].

What's more to say on this topic? Well, not much more aside from the fact that there may be a complicated relationship between immune function - immune signalling - and amino acid biochemistry which may very well impinge on presented behaviour. Such links also offer some interesting prospects for potential intervention too...

And to some music: Lower Than Atlantis - Here We Go.

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[1] Schwieler L. et al. Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. J Psychiatry Neurosci. 2014 Dec 2;39(6):140126.

[2] Kunz M. et al. Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance. Rev Bras Psiquiatr. 2011 Sep;33(3):268-74.

[3] Hori H. et al. Effects of olanzapine on plasma levels of catecholamine metabolites, cytokines, and brain-derived neurotrophic factor in schizophrenic patients. Int Clin Psychopharmacol. 2007 Jan;22(1):21-7.

[4] Johansson AS. et al. Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: cytokine challenge increases production of 3-hydroxykynurenine. J Psychiatr Res. 2013 Nov;47(11):1815-23.

[5] Colín-González AL. et al. The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum. Brain Res. 2014 Nov 17;1589:1-14.

[6] Flatow J. et al. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013 Sep 15;74(6):400-9.

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Schwieler L, Larsson MK, Skogh E, Kegel ME, Orhan F, Abdelmoaty S, Finn A, Bhat M, Samuelsson M, Lundberg K, Dahl ML, Sellgren C, Schuppe-Koistinen I, Svensson C, Erhardt S, & Engberg G (2014). Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. Journal of psychiatry & neuroscience : JPN, 39 (6) PMID: 25455350