Proinflammatory Cytokines and Oxidative Stress Decrease the Transport of Dopamine Precursor Tyrosine in Human Fibroblasts

Abstract

Background: Proinflammatory cytokines and oxidative stress responses have been extensively implicated in the pathophysiology of neuropsychiatric disorders over the past 2 decades. Moreover, disturbed transport of the dopamine precursor (i.e., the amino acid tyrosine) has been demonstrated, in different studies, across fibroblast cell membranes obtained from neuropsychiatric patients. However, the role and influences of proinflammatory cytokines and oxidative stress, and the reasons for disturbed tyrosine transport in neuropsychiatric disorders, are still not evaluated. Aims: The present study aimed to assess the role of proinflammatory cytokines and oxidative stress, indicated in many neuropsychiatric disorders, in tyrosine transportation, by using human skin-derived fibroblasts. Methods: Fibroblasts obtained from a healthy control were used in this study. Fibroblasts were treated with proinflammatory cytokines (IL-1β, IFN-γ, IL-6, TNF-α), their combinations, and oxidative stress, optimized for concentrations and incubation time, to analyze the uptake of ¹⁴C-tyrosine compared to untreated controls. Results and Conclusion: This study demonstrates that proinflammatory cytokines and oxidative stress decrease the transport of tyrosine (47% and 33%, respectively), which can alter dopamine synthesis. The functionality of the tyrosine transporter could be a new potential biomarker to target for discovering new drugs to counteract the effects of proinflammatory cytokines and oxidative stress in the pathophysiology of neuropsychiatric disorders.

Butyrate Rescues Oxidative Stress-Induced Transport Deficits of Tryptophan: Potential Implication in Affective or Gut-Brain Axis Disorders

“…The data from this study indicated that oxidative stress induced by H 2 O 2 significantly decreased the transport of the serotonin precursor tryptophan across the fibroblast membranes. These results are in line with our previous findings, showing that oxidative stress decreased the transport of the dopamine precursor tyrosine across the fibroblast membranes [8]. Transport of tryptophan and tyrosine are shared by LAT1 and LAT2 isoforms of system-L in fibroblast cells and also at the BBB.…”

Pretreatment Effect of Inflammatory Stimuli and Characteristics of Tryptophan Transport on Brain Capillary Endothelial (TR-BBB) and Motor Neuron Like (NSC-34) Cell Lines

“…The elevated influx of [ 3 H] l -tryptophan transport might have been the result of alterations in the transport mechanisms due to induction of free radicals and oxidative stress by the pro-inflammatory cytokines [ 29 ] ( Figure 4 A,B). An increase in oxidative stress triggers an increased production of pro-inflammatory cytokines, which affect the expression of lipid membrane components and the transport function of tryptophan in the BBB [ 45 ]. On the other hand, inflammatory stimuli-treated NSC-34 WT and MT cell lines demonstrated significantly reduced tryptophan uptake ( Figure 7 ).…”

Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

“…However, tyrosine transport related to dopamine metabolism has been investigated in HDF from patients with other psychiatric diseases such as schizophrenia [ 133 ], bipolar disorder [ 134 ], and autism [ 135 ], as mentioned above. HDF express D1 and D2 dopaminergic receptors and tyrosine transporter (tyrosine being the dopamine precursor) [ 85 - 87 ] (Table 3 ). Moreover, HDF express several important proteins characteristic of the dopaminergic pathway such as the COMT [ 43 ], one of the main enzymes involved in catecholamine catabolism, which has been related to MDD pathophysiology [ 136 ].…”