Cytokines, tryptophan metabolism

The production of KYNA is regulated by IDO and tryptophan 2,3-dioxygenase (TDO). Both enzymes catalyze the first step in the pathway, the degradation from tryptophan to kyn-urenine. Type-1 cytokines, such as IFN-y and IL-2 stimulate the activity of IDO (Grohmann etal., 2003). Figure 36.1 shows the relationship betw een cytokines, enzymes of the tryptophan metabolism, and formation of neuroactive intermediates. 

The enzyme indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine, kynurenine is then converted to quinolinic acid via the intermediate 3-HK by the enzyme kynurenine hydroxylase. Both IDO and kynurenine hydroxylase are induced by the type-1 cytokine IFN-y. The activity of IDO is an important regulatory component in the control of lymphocyte proliferation, the activation of the type-1 immune response and the regulation of the tryptophan metabolism (Mellor and Munn, 1999). It induces a halt in the lymphocyte cell cycle due to the catabolism of tryptophan (Munn et al., 1999). In contrast to the type-1 cytokines, the type-2 cytokines IL-4 and IL-10 inhibit the IFN-y-induced IDO-mediated tryptophan cataboUsm (Weiss et al., 1999). IDO is located in several cell types including monocytes and microglial cells (Alberati et al., 1996). An IFN-y-induced, IDO-mediated decrease of CNS... 

From 1978 to 1985 renewed interest in tryptophan metabolism via the kynurenine-niacin pathway was generated by the findings of Hayaishi et al. and others of a second enzyme, namely, indoleamine-2,3-dioxygenase (IDO).2 3 This enzyme was found to be present in several nonhepatic tissues (lung, intestine, brain, and epididymis) and cells (blood monocytes, macrophages, and eosinophils). The enzyme normally has very low activity but is induced to very high activity by stimulation of immune systems with interferon-y1-8 or interleukin-2 (cytokines).9 Thus, inflammatory processes, infections, and immune stimulation that induce interferon-y could lead to... 

Tryptophan dioxygenase (Section 8.3.2) is only found in the liver other tissues have an indoleamine dioxygenase, with lower specificity, that catalyzes the same reaction. However, the pathway for onward metabolism of kynure-nine is found only in liver and mononuclear phagocytes, and induction of indoleamine dioxygenase by cytokines, such as interferon-y, leads to increased circulating concentrations and urinary excretion of kynurenine, with litde or... 

Although IL-6 is not a type-1 cytokine, it may contribute to IDO activation by the stimulatory effect on PGE2, which acts as cofactor in the activation of IDO. This fits with a report on the correlation of increased IL-6 production in vitro with decreased tryptophan levels in depressed patients that emphasizes the influence of IL-6 on the serotonin metabolism in depressed patients (Maes et al., 1993). 

---