Chronic Immune Stimulation Correlates with Reduced Phenylalanine Turnover

G.      Neurauter; K.      Schrocksnadel; S.      Scholl-Burgi; B.      Sperner-Unterweger; C.      Schubert; M.      Ledochowski; D.      Fuchs

Abstract

Neurospychiatric symptoms like mood changes and depression are common in patients with chronic inflammatory disorders such as infections, autoimmune diseases or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic, but also with those of the adrenergic system. The proinflammatory cytokine interferon-γ stimulates the biosynthesis of 5,6,7,8-tetrahydrobiopterin (BH4), which is cofactor for several aromatic amino acid monooxygenases and thus is strongly involved in the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). In macrophages, interferon-γ also triggers the high output of reactive oxygen species, which can destroy the oxidation-labile BH4. Recent data suggest that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients.

Keywords: Phenylalanine, phenylalanine 4-hydroxylase (PAH), tetrahydrobiopterin (BH4), inflammation, immune activation, interferon-γ, oxidative stress

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