Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia

Abstract

Abnormalities in the kynurenine pathway (KP) of tryptophan degradation, leading to the dysfunction of neuroactive KP metabolites in the brain, have been implicated in the pathophysiology of schizophrenia (SZ). One plausible mechanism involves dysregulation of various pro-inflammatory cytokines associated with the disease, which affect indoleamine-2,3-dioxygenase (IDO), a key enzyme for tryptophan to kynurenine conversion. In order to test this hypothesis directly, we measured plasma levels of the major KP metabolites kynurenine and kynurenic acid (KYNA), as well as four major cytokines, in a sample of 106 SZ patients and 104 control participants. In contrast to the replicable findings of elevation of KYNA in the central nervous system in SZ, plasma levels of KYNA were significantly lower in SZ compared to controls (p = .004). Kynurenine levels were significantly correlated with levels of interferon-γ (p < .001), which is involved in the regulation of IDO, in both patients and controls. However, although patients had higher levels of interleukin-6 (IL-6) compared to controls (p = .012), IL-6 levels were not correlated with kynurenine or KYNA, and did not explain group differences in KYNA. Based on the lack of evidence that pro-inflammatory cytokines were significantly related to the KP abnormality in SZ despite an adequate sample size, further studies must consider alternative hypotheses to identify the origins of the KP abnormalities in SZ.

A mood state‐specific interaction between kynurenine metabolism and inflammation is present in bipolar disorder

“…This decrease in KYNA contrasts with previous reports in CSF and postmortem brain tissue where increased KYNA levels in patients with BD were related to manic episodes and psychotic symptoms . In line with our findings, studies using peripheral blood samples showed unchanged or decreased KYNA levels in patients with a history of mania or psychosis . Decreased peripheral KYNA levels have also been shown in euthymic and depressive patients with BD .…”

“…However, in patients with psychiatric disorders, the interaction between inflammation, kynurenine metabolism, and clinical symptoms is little investigated. In CSF of patients with schizophrenia, IL‐6 levels were negatively correlated with the TRP/KYNA ratio, however a study with larger sample size could not confirm an effect of cytokines levels on kynurenine metabolism disturbances . In depressive populations such a link between inflammation, kynurenine metabolism, and depressive symptoms has not yet been shown …”

“…In schizophrenia, studies in CSF and postmortem brain showed increased activation of astrocytes and elevated KYNA levels . Studies on peripheral levels of kynurenine metabolites in schizophrenia have yielded inconsistent results …”

“…8,9 Studies on peripheral levels of kynurenine metabolites in schizophrenia have yielded inconsistent results. 8,[10][11][12] In bipolar disorder (BD), the kynurenine pathway has been less studied. As in schizophrenia, elevated KYNA levels have been found in CSF, postmortem brain, and fibroblast cultures of patients with BD, and are mainly associated with a history of mania or psychosis.…”

“…In CSF of patients with schizophrenia, IL-6 levels were negatively correlated with the TRP/KYNA ratio, 29 however a study with larger sample size could not confirm an effect of cytokines levels on kynurenine metabolism disturbances. 12 In depressive populations such a link between inflammation, kynurenine metabolism, and depressive symptoms has not yet been shown. 6,30 The aim of this study was to further explore the relation between inflammation, kynurenine metabolism, and mood symptoms F I G U R E 1 The kynurenine pathway.…”