Interferon-γ-induzierter Tryptophanabbau: Bedeutung für Immunologie und Psychiatrie

Zusammenfassung

Tryptophan, eine essenzielle Aminosäure und Bestandteil von Proteinen, ist auch Substrat für 2 wichtige biochemische Stoffwechselwege: Die Bildung des Neurotransmitters Serotonin (5-Hydroxytryptamin) durch die Tryptophan-(5)-Hydroxylase sowie die Bildung von Kynureninderivaten und Nikotinamidadenindinukleotiden über die Enzyme Tryptophanpyrrolase (Tryptophan-2,3-Dioxygenase, TDO) und Indolamin-2,3-Dioxygenase (IDO). TDO ist in Leberzellen lokalisiert, während IDO von einer Vielzahl von Zellen nach Induktion durch das Zytokin Interferon-γ exprimiert wird. Der durch Induktion von IDO durchgeführte Tryptophanabbau ist einerseits Teil des antimikrobiellen und antiproliferativen Repertoirs von Zellen, kann aber auch zur Suppression der T-Zellantwort beitragen. Für die Abschätzung einer Aktivierung der IDO in vivo kann das Verhältnis von Kynurenin zu Tryptophan (= Kyn/Trp) bestimmt und gleichzeitig zu Immunaktivierungsparametern wie Neopterin in Beziehung gesetzt werden. Verstärkter Tryptophankatabolismus wird bei Erkrankungen beobachtet, die mit einer zellulären (= Th1-Typ) Immunantwort einhergehen, wie Virusinfektionen (z. B. mit dem humanen Immunodefizienz Virus = HIV), Autoimmunkrankheiten, aber auch Krebserkrankungen und während einer Schwangerschaft. Bei diesen Prozessen könnte der Tryptophanabbau eine Rolle bei der Entwicklung einer Immundefizienz spielen. Außerdem kann besonders bei chronischen Krankheiten die reduzierte Verfügbarkeit des freien Tryptophan im Serum auch zu einer unzureichenden Synthese von Serotonin führen. So können serotonerge Funktionen gestört werden und der gesteigerte Tryptophanabbau zur Entstehung von neuropsychiatrischen Symptomen beitragen. Störungen des Serotoninstoffwechsels sind in der Pathogenese von Depressionen von besonderer Bedeutung. Analog dazu wurde z. B. ein Zusammenhang zwischen verstärktem Tryptophanabbau und verminderter Lebensqualität bei Patienten mit malignen Erkrankungen nachgewiesen. Die Aktivierung der IDO kann eine Verbindung zwischen dem immunologischen Netzwerk und neuroendokrinen Funktionen mit weit reichenden Konsequenzen für den psychischen Status von Patienten darstellen. Diese Zusammenhänge könnten auch eine neue Basis für ein besseres Verständnis für die Entstehung von Gemütsveränderungen bei chronisch Kranken darstellen.

Abstract

The essential amino acid tryptophan is constituent of proteins and also substrate for two important metabolic pathways, namely the formation of neurotransmitter serotonin (5-hydroxytryptamine) by tryptophan-(5)-hydroxylase and the production of kynurenine derivatives and nicotinamide-adenine-dinucleotides via enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-diooxygenase (IDO). TDO is localized in liver, whereas IDO is expressed in a variety of cells upon induction with Th1-type cytokine interferon-y. IDO-induced tryptophan degradation is part of the antimicrobial and antiproliferative repertoire of cells, accordingly it also can contribute to the suppression of T-cell response. Enhanced tryptophan catabolism coinciding with immune activation is commonly observed during diseases, which go along with cell-mediated (= Th1-type) immune response, such as virus infections including human immunodeficiency virus infection, autoimmune disorders and cancer and also during pregnancy. In these conditions, tryptophan degradation may be involved in the development of immunodeficiency, however, the limited availability of serum tryptophan may also lead to an insufficient biosynthesis of serotonin especially in chronic situations. Consequently serotonergic functions can be disturbed, and accelerated tryptophan catabolism may thus contribute to neuropsychiatric symptoms in patients. Disturbed serotonin metabolism is of particular relevance in the pathogenesis of depression, and an association between enhanced tryptophan degradation and reduced quality of life has already been observed in patients with malignant diseases. In conclusion, activation of IDO may represent a link between the immunologic network and neuroendocrine functions with far-reaching consequences for the neuropsychiatrie status of patients. Results provide a basis for a better understanding of the development of mood disturbances in patients with chronic diseases.

Tryptophan - Serotonin - Interferon-γ - Indolamin-(2,3)-dioxygenase - Depression

Tryptophan - serotonin - interferon-γ - indoleamine (2,3)-dioxygenase - depression

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