Indoleamine 2,3-dioxygenase

• OMIM: 147 435
• UniProt: P14902

Indoleamine -2 ,3- dioxygenase ( IDO ) is the enzyme that degrades tryptophan to N- formylkynurenine. In contrast to the tryptophan -2 ,3- dioxygenase (TDO ) IDO is produced in all tissue types in the human body, but particularly in the tonsils and the placenta, where the degradation of tryptophan has a beyond the normal catabolism Purpose: To support the immune system in infection on the one hand, and prevent rejection of the fetus on the other hand. By their immunosuppressive activity, it is a promising target to achieve a prolonged acceptance of transplants. Conversely, could improve tumor control their inhibition.

The INDO gene probably arose by a copy of the TDO2 gene.

Catalyzed reaction

O2

L-tryptophan is oxidized to N- formyl-L- kynurenine. As substrate and D- tryptophan is accepted. Also, superoxide can act as oxygen donor.

Functions in the immune system

Both the immunosuppressive and immune- supportive function of IDO can be explained by the high value of the essential amino acid tryptophan, which is especially needed during the activation of T cells, but also by invading foreign cells. With the rapid degradation of tryptophan by IDO all protein synthesis is effectively paralyzed in the local environment. Additionally, enable the resulting degradation products, the production of regulatory T cells, which are ultimately responsible for the immunosuppression.

Immune tolerance in lymph nodes

Lymph nodes that are located downstream from a tumor are privileged, so to speak; they flow through a particularly large tumor antigens. It is important that in this area the immune response does not overshoot, otherwise would have to suffer much normal tissue underneath. For this reason, the production of IDO reinforced by the body in such a lymph nodes, in order to dampen the immune response. This may otherwise cause also in tumor tissue amplified IDO is produced and will no longer be presented and therefore is not detected in the course as foreign tumor antigens. IDO is actually over-expressed in several cancer cell lines. Therefore, one tries to achieve a better fight against cancer by inhibition of IDO.

The same mechanism is the cause, if chronic infections local tumor growth easier, because here produce the downstream lymph nodes below the infection site increased IDO and thereby prevent a full immune response by T cells. Mice with reduced IDO production did not show this phenomenon.

Immune tolerance in pregnancy

The original formulation of the paradox that the fetus is not rejected, goes back to Medawar. Munn was able to show the mouse model in 1998 that inhibition of IDO with 1-methyl tryptophan leads to a rejection of the conceptus.

Regulation

The production of IDO is stimulated by interferon-gamma and lipopolysaccharide. The anti-cancer activity of curcumin is at least partly due to the interruption of this signaling pathway and subsequent inhibition of IDO. The pathway also seems to play a role in the establishment of HIV infection.

As inhibitors of IDO are 1- methyl L- tryptophan, the known alkaloid Exiguamin A and derivatives of menadione.