The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall

2019 ◽  
Vol 115 (9) ◽  
pp. 1408-1415 ◽  
Author(s):  
Daniel F J Ketelhuth
Keyword(s):  
Current Knowledge ◽  
Large Body ◽  
Vascular Wall ◽  
Kynurenine Pathway ◽  
Atherosclerotic Cardiovascular Disease ◽  
Artery Wall ◽  
Indoleamine 2,3 Dioxygenase ◽  
Rate Limiting ◽  
Accumulation Of Lipids

AbstractCoronary heart disease and stroke, the two most common cardiovascular diseases worldwide, are triggered by complications of atherosclerosis. Atherosclerotic plaques are initiated by a maladaptive immune response triggered by accumulation of lipids in the artery wall. Hence, disease is influenced by several non-modifiable and modifiable risk factors, including dyslipidaemia, hypertension, smoking, and diabetes. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway of tryptophan (Trp) degradation, is modulated by inflammation and regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. A large body of evidence indicates that IDO-mediated Trp metabolism is involved directly or indirectly in atherogenesis. This review summarizes evidence from basic and clinical research showing that IDO is a major regulatory enzyme involved in the maintenance of immunohomeostasis in the vascular wall, as well as current knowledge about promising targets for the development of new anti-atherosclerotic drugs.

scholarly journals Indoleamine-2,3-Dioxygenase as a Perioperative Marker of the Immune System

2021 ◽  
Vol 12 ◽  
Author(s):  
Corina Bello ◽  
Paul Philipp Heinisch ◽  
Maks Mihalj ◽  
Thierry Carrel ◽  
Markus M. Luedi
Keyword(s):  
Current Knowledge ◽  
Predictive Biomarker ◽  
Surgical Trauma ◽  
Indoleamine 2,3 Dioxygenase ◽  
Induced Stress ◽  
Immune Mediated ◽  
Autoimmune Processes ◽  
Systemic Infections ◽  
Rate Limiting

Indoleamine-2,3-dioxygenase (IDO) is the “rate-limiting” enzyme in the kynurenine (Kyn) pathway of the tryptophan (Trp) catabolism. By its immune-modulatory effect, IDO initiates changes to the physiologically balanced immune state and plays a key role in the pathogenesis of various diseases, as well as in the perioperative setting during surgery. In autoimmune processes, highly malignant cancers such as glioblastoma or organ transplantation, IDO’s involvement has been studied extensively. However, in severe systemic infections, as present in sepsis, it is not yet completely understood. Hereafter, in this narrative review, we present the current knowledge of IDO’s implication on such complex immune-related processes. Moreover, we address the role of IDO as a predictive biomarker as well as a therapeutic target for immune-mediated diseases. Finally, we discuss IDO in the setting of surgical trauma-induced stress and highlight its promising use as a biomarker in the pre-operative setting for all disciplines involved in the decision-making process and treatment of patients undergoing surgery.

scholarly journals Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 909
Author(s):  
Krzysztof Kotowski ◽  
Jakub Rosik ◽  
Filip Machaj ◽  
Stanisław Supplitt ◽  
Daniel Wiczew ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Treatment Options ◽  
Protein Structures ◽  
New Drugs ◽  
Proliferating Cells ◽  
Cancer Tissues ◽  
The Impact ◽  
Rate Limiting ◽  
Synthesis And Degradation

Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.

scholarly journals GTP metabolic reprogramming by IMPDH2: unlocking cancer cells’ fuelling mechanism

2020 ◽  
Vol 168 (4) ◽  
pp. 319-328 ◽  
Author(s):  
Satoshi Kofuji ◽  
Atsuo T Sasaki
Keyword(s):  
De Novo ◽  
Current Knowledge ◽  
Metabolic Reprogramming ◽  
Inosine Monophosphate Dehydrogenase ◽  
Metabolic Demand ◽  
Adaptive Mechanisms ◽  
Key Aspects ◽  
Polymerase I ◽  
Rate Limiting

Abstract Growing cells increase multiple biosynthetic processes in response to the high metabolic demands needed to sustain proliferation. The even higher metabolic requirements in the setting of cancer provoke proportionately greater biosynthesis. Underappreciated key aspects of this increased metabolic demand are guanine nucleotides and adaptive mechanisms to regulate their concentration. Using the malignant brain tumour, glioblastoma, as a model, we have demonstrated that one of the rate-limiting enzymes for guanosine triphosphate (GTP) synthesis, inosine monophosphate dehydrogenase-2 (IMPDH2), is increased and IMPDH2 expression is necessary for the activation of de novo GTP biosynthesis. Moreover, increased IMPDH2 enhances RNA polymerase I and III transcription directly linking GTP metabolism to both anabolic capacity as well as nucleolar enlargement historically observed as associated with cancer. In this review, we will review in detail the basis of these new discoveries and, more generally, summarize the current knowledge on the role of GTP metabolism in cancer.

scholarly journals Indoleamine 2,3-Dioxygenase 2 Deficiency Exacerbates Imiquimod-Induced Psoriasis-Like Skin Inflammation

2020 ◽  
Vol 21 (15) ◽  
pp. 5515
Author(s):  
Kento Fujii ◽  
Yasuko Yamamoto ◽  
Yoko Mizutani ◽  
Kuniaki Saito ◽  
Mariko Seishima
Keyword(s):  
Immune Responses ◽  
Immune Cells ◽  
Skin Inflammation ◽  
Kynurenine Pathway ◽  
Immune Functions ◽  
Wild Type ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tnf Α ◽  
In The Wild

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme known to suppress immune responses, and several reports have showed that it is associated with psoriasis. IDO2 is an isoform of IDO1, recently identified as a catalytic enzyme in the tryptophan-kynurenine pathway, which is expressed in dendritic cells and monocytes. The expression of IDO2 in immune cells suggests that IDO2 may contribute to immune functions. However, the role of IDO2 in the pathogenesis of psoriasis remains unclear. In this study, to elucidate the role of IDO2 in psoriasis, we assessed imiquimod (IMQ)-induced psoriasis-like dermatitis in IDO2 knockout (KO) mice. Skin inflammation, evaluated by scoring erythema, scaling, and ear thickness, was significantly worse in the IDO2 KO mice than in the wild-type (WT) mice. The mRNA expression levels of TNF-α, IL-23p19, and IL-17A, key cytokines involved in the development of psoriasis, were also increased in the IDO2 KO mice. Furthermore, immunohistochemistry revealed that the number of Ki67-positive cells in the epidermis and CD4-, CD8-, and IL-17-positive lymphocytes infiltrating the dermis were significantly increased in the IDO2 KO mice. These results suggest that IDO2 might decrease IL-17 expression, thereby resulting in the suppression of skin inflammation in IMQ-induced psoriasis-like dermatitis.

Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase

2009 ◽  
Vol 37 (2) ◽  
pp. 408-412 ◽  
Author(s):  
Sara A. Rafice ◽  
Nishma Chauhan ◽  
Igor Efimov ◽  
Jaswir Basran ◽  
Emma Lloyd Raven
Keyword(s):  
Structural Information ◽  
Recombinant Expression ◽  
Kynurenine Pathway ◽  
Expression Systems ◽  
Indoleamine 2,3 Dioxygenase ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
The Family ◽  
And Function ◽  
Rate Limiting

The family of haem dioxygenases catalyse the initial oxidative cleavage of L-tryptophan to N-formylkynurenine, which is the first, rate-limiting, step in the L-kynurenine pathway. In the present paper, we discuss and compare structure and function across the family of haem dioxygenases by focusing on TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase), including a review of recent structural information for both enzymes. The present paper describes how the recent development of recombinant expression systems has informed our more detailed understanding of the substrate binding, catalytic activity and mechanistic properties of these haem dioxygenases.

scholarly journals Kynurenine pathway: the link between depressive disorders and inflammation

2020 ◽  
Vol 74 ◽  
pp. 331-339
Author(s):  
Justyna Kubacka ◽  
Anna Stefańska ◽  
Grażyna Sypniewska
Keyword(s):  
Genetic Basis ◽  
Depressive Disorders ◽  
Genetic Factors ◽  
Current Knowledge ◽  
Kynurenine Pathway ◽  
Major Depression Disorder ◽  
Pathway Activation ◽  
Neuropsychiatric Diseases ◽  
Depression Disorder

Depression is highly prevalent worldwide and the leading cause of disability. It is believed that currently more than 300 million people of all ages suffer from depression. However, the unambiguous cause of the depression remains unknown. It is suggested that the occurrence of this disease is primarily affected by genetic factors, psychological factors and atypical brain structure or function. Recently, an increasingly important role is attributed to the inflammatory response, which is considered to be the main cause of depression. Activation of the kynurenine pathway (KP) is one of the described mechanisms by which inflammation can induce depression. Kynurenine pathway activation is associated with several neuropsychiatric diseases, including major depression disorder (MDD). The imbalance between the neuroprotective and neurotoxic metabolites in the kynurenine pathway and the associated serotonin and melatonin deficiency, may contribute to the manifestation of depressive symptoms. In this review we discuss the role of the major enzymes of the tryptophan KP: tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) and the role of selected kynurenic metabolites in the depressive disorders. Particular attention was also paid to the genetic basis of depressive disorders and to the summary of current knowledge on the effectiveness of treatment and supplementation with tryptophan and 5-hydroxytryptophan in depression.

scholarly journals Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington’s disease

2019 ◽  
Author(s):  
David W. Donley ◽  
Marley Realing ◽  
Jason P. Gigley ◽  
Jonathan H. Fox
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Microglial Activation ◽  
Iron Supplementation ◽  
Kynurenine Pathway ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tryptophan Degradation ◽  
Microglial Morphology

AbstractHuntington’s disease (HD) is a neurodegenerative disorder caused by a dominant CAG-repeat expansion in the huntingtin gene. Morphologic activation of microglia is a key marker of neuroinflammation that is present before clinical onset in HD patients. The kynurenine pathway of tryptophan degradation is restricted in part to microglia and is activated in HD, where it contributes to disease progression. Indoleamine-2,3-dioxygenase (IDO) is a microglial enzyme that catalyzes the first step in this pathway. HD brain microglial cells also accumulate iron; however, the role of iron in promoting microglial activation and the kynurenine pathway is unclear. Based on analyses of morphological characteristics of microglia, we showed that HD mice demonstrate an activated microglial morphology compared with controls. Neonatal iron supplementation resulted in additional microglial morphology changes compared with HD controls. Increased microglial activation in iron-supplemented HD mice was indicated by increased soma volume and decreased process length. In our assessment of whether iron can affect the kynurenine pathway, iron directly enhanced the activity of human recombinant IDO1 with an EC50 of 1.24 nM. We also detected elevated microglial cytoplasmic labile iron in N171-82Q HD mice, an increase that is consistent with the cellular location of IDO. We further demonstrated that neonatal iron supplementation, a model for studying the role of iron in neurodegeneration, activates IDO directly in the mouse brain and promotes neurodegeneration in HD mice. Kynurenine pathway metabolites were also modified in HD and by iron supplementation in wild-type mice. These findings indicate that iron dysregulation contributes to the activation of microglia and the kynurenine pathway in a mouse model of HD.

scholarly journals Tryptophan 2,3-Dioxygenase Expression Identified in Murine Decidual Stromal Cells Is Not Essential for Feto-Maternal Tolerance

2020 ◽  
Vol 11 ◽  
Author(s):  
Delia Hoffmann ◽  
Tereza Dvorakova ◽  
Florence Schramme ◽  
Vincent Stroobant ◽  
Benoit J. Van den Eynde
Keyword(s):  
Stromal Cells ◽  
Kynurenine Pathway ◽  
Immune Rejection ◽  
Cell Type ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Tryptophan Catabolism ◽  
Maternal Tolerance ◽  
Rate Limiting

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) catalyze the rate-limiting step of tryptophan catabolism along the kynurenine pathway, which has important immuno suppressive properties, particularly in tumor cells and dendritic cells. The prominent expression of IDO1 in the placenta also suggested a role in preventing immune rejection of fetal tissues, and pharmacological inhibition of IDO1 induced abortion of allogeneic fetuses in mice. However, this was later challenged by the lack of rejection of allogeneic fetuses in IDO1-KO mice, suggesting that other mechanisms may compensate for IDO1 deficiency. Here we investigated whether TDO could contribute to feto-maternal tolerance and compensate for IDO1 deficiency in IDO1-KO mice. Expression of TDO mRNA was previously detected in placental tissues. We developed a new chimeric rabbit anti-TDO antibody to confirm TDO expression at the protein level and identify the positive cell type by immunohistochemistry in murine placenta. We observed massive TDO expression in decidual stromal cells, starting at day E3.5, peaking at day E6.5 then declining rapidly while remaining detectable until gestation end. IDO1 was also induced in decidual stromal cells, but only at a later stage of gestation when TDO expression declined. To determine whether TDO contributed to feto-maternal tolerance, we mated TDO-KO and double IDO1-TDO-KO females with allogeneic males. However, we did not observe reduced fertility. These results suggest that, despite its expression in decidual stromal cells, TDO is not a dominant mechanism of feto-maternal tolerance able to compensate for the absence of IDO1. Redundant additional mechanisms of immunosuppression likely take over in these KO mice. The massive expression of TDO during decidualization might suggest a role of TDO in angiogenesis or vessel tonicity, as previously described for IDO1.

scholarly journals Helicobacter Pylori Infection And Gastric Cancer: Is It Our National Problem?

2018 ◽  
Vol 36 (2) ◽  
pp. 70-76 ◽  
Author(s):  
M Mizanur Rahman ◽  
Shahjadul Alam ◽  
Abu Mohammad Khaled Iqbal ◽  
Md Monoar Hossain ◽  
Abu Mohammad Kawser Sarker ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Current Knowledge ◽  
Large Body ◽  
High Prevalence ◽  
The World ◽  
Leading Position ◽  
The Common ◽  
H Pylori

Gastric cancer is a leading cause of cancer death worldwide. In Bangladesh it ranks a leading position among the cancers patients. A large body of evidence supports a causal role of Helicobacter pylori in the majority of gastric malignancies. Scientists throughout the world explored and reached to the understanding about the pathogenesis of their relationship, but much remains to be learned. Moreover, because of the high prevalence of infection, the lack of definitive trials, and the challenges of H. pylori treatment, there remains a debate regarding the consensus on the role of routine screening and treatment of this infection to prevent cancer. This article reviews the current knowledge on H. pylori and its role for gastric cancer, present status of Bangladesh and a recommendation for reduction of the infectivity among the common population.J Bangladesh Coll Phys Surg 2018; 36(2): 70-76

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