Tryptophan, in addition to be a constituent of proteins, is also substratum of three important biosynthetic pathways:
- formation of serotonin by tryptophan 5-hydroxylase
- formation of kynurenine derivates, that allow to remove tryptophan from circulation and to redirect it to other biosynthetic pathways
- NAD's formation from kynurenine.
Some studies observed that there is a considerable production of inflammatory cytokines during cerebral ischaemia. This cytokines could amplify inflammation process, expecially in limbic areas, with activation of an enzyme (indoleamine 2,3-dioxygenase,IDO) and subsequent serotonin's depletion in particular cerebral areas. That pro-inflammatory molecules are released by macrophages as a result of neuroinflammatory processes and could indirectly induce a state of depression in the patient caused by a deficit of serotonin.
Considerations: May inflammation produce a state of depression in patients? Which mechanisms are involved? Why organism increase tryptophan catabolism during infections?
The second way of tryptophan's biosynthesis is started by tryptophan 2,3dioxygenase (TDO) and IDO. TDO is placed in liver cells, while IDO is expresses by different cells, e.g. monocyte-derived macrophages and dendritic cells, and is induced by interferon-gamma (produced by Th1 linphocytes).
Low levels of tryptophan serum are observed in infections caused by an immune activation of Th1, because IFN-gamma's production stimulates macrophages activating tryptophan's catabolic pathways.
This tryptophan's deplection affects serotonin's biosynthesis and thus contributes to undermine patient's quality of life contributing to a state of depression. It has also been verified that stimulation with IFN-gamma leads to activation of IDO in all human cells. This enzyme is responsible for antibacterial effects (caused by production of ROS) on different micro-organism's species (e.g. Toxoplasma and Chlamydia). Particularly induction of IDO in Chlamydia infected macrophages explains the production of cytokines in response to infection and this fact constitutes one of the systems of reply and control of intracellular infections due to micro-organisms. It has further been proved that IDO's action could act as a mechanism of defence in fibroblasts' and macrophages' infection due to beta haemolytic-streptococcus.
This elements lead to other analysis of tryptophan's metabolism. Tryptophan metabolic pathway, that leads to formation of kyurenine, could also prodce NAD and 3-OH-anthranilate: witch is very important in immune response during bacterial infections because its formation allows to use tryptophan serum. In this way tryptophan serum couldn't be used by bacteria as element of synthesis.
Furthermore has been recently proved that macrophages, in particular culture's conditions, could express IDO ex novo. Through this enzyme (particularly by formation of kinurenine and picolinic acid from tryptophan's catabolism) macrophages could be able to carry out an anti-proliferative acion towards T cells and Natular Killers. This phenomenon allows to observe a negative control action on NK's action by other immune cells.
Research projects are in progress in order to discover more about this phenomenon.
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- IFN-gamma-activated indoleamine2,3-dioxygenase activity in human cells is an antiparasitic and antibacterial effector mechanism
- expression of indoleamine2,3-dioxygenase, tryptophan degradation, and kynurenine formation during in vivo infection with toxoplasma gondii: induction by endogenous gamma interferon and requirement of interferon regulatory factor 1