Evaluation of Tryptophan Metabolism in Chronic Immune Activation

Abstract

Chronic immune activation is encountered in different pathologies including granulomatous and functional bowel diseases, cancer, aging, atherosclerosis, and obesity. Persistence of chronic infl ammatory stimuli over time creates a biologic background for immunosenescence and favors neopterin formation with the enhanced tryptophan (Trp) degradation in diseases concomitant with cellular immune activation. Trp degradation leads to the generation of several neuroactive compounds by three distinct pathways.Indoleamine 2,3-dioxygenase (IDO) induction leads to many complex changes within the affected cells resulting in immunosuppression through breakdown of Trp. Thus, neopterin concentrations as well as IDO expression signifi cantly increase in infl ammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease.However, irritable bowel syndrome (IBS) is linked with abnormal serotonin functioning and immune activation. In this case, enteric serotonin (5-HT) signaling may be defective and inactivated by the serotonin-selective reuptake transporter (SERT) in the enterocytes. A positive correlation is evident between IBS severity and kynurenine (Kyn) to Trp ratio which is signifi cantly correlated with the rise of interferon (IFN)-gamma.The dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. IDO-reactive T cells are able to recognize and kill tumor cells as well as IDO-expressing dendritic cells (DCs). IDO activation leads to immunosuppression through breakdown of Trp in the tumor microenvironment and tumor-draining lymph nodes. C-C chemokine receptor type 4 (CCR4)+ forkhead boxp3(Foxp3)+ regulatory T (Treg) cells create a favorable environment for tumor escape from host immune responses. Thus, Foxp3+/IDO+ tumors are associated with more advanced disease.Age-related changes in the immune system are known as immunosenescence. A causal relationship is evident between the Trp metabolism and immune defi ciency in elderly. Eventually, the reduced serum Trp concentrations and increased Kyn levels indicate increased chronic low-grade infl ammation in elderly. In this case,

Aspects of Tryptophan and Nicotinamide Adenine Dinucleotide in Immunity: A New Twist in an Old Tale

“…The kynurenine pathway is a major route for the catabolism of tryptophan and has an important role in the immune system. 17 , 21 , 32 , 44 The kynurenine pathway is initiated by cleavage of the indole ring, which is initiated by tryptophan 2,3-dioxygenase 2 (TDO-2), indoleamine 2,3-dioxygenase 1 (IDO-1), or IDO-2, which shares similarities with IDO-1 but has limited catabolic activity compared with TDO-2 and IDO-1. 22 , 45 – 47 TDO-2 has been found primarily in the liver and central nervous system (CNS), but recent publications have identified TDO-2 in different types of cancer.…”

“… 60 More importantly, tumors expressing Foxp3 + /IDO + are associated with more advanced disease. 44 Interestingly, therapies targeting IDO have been shown to be effective against different types of cancer by measuring messenger RNA. 12 , 61 , 62 Similar interactions between IDO and other cells of the immune system have been described.…”