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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 8, Number 3, April 2007
Contents
Clinical Relevance of Indoleamine 2,3-Dioxygenase
Guest Editor: Dietmar Fuchs
Editorial Pp. 195
The Human Indoleamine 2,3-Dioxygenase Gene and Related
Human Genes Pp. 197-200
M.F. Murray
[Abstract]
Substrate and Cofactor Requirements of Indoleamine
2,3 Dioxygenase in Interferon-Gamma-Treated Cells: Utilization
of Oxygen Rather Than Superoxide Pp. 201-203
E.R. Werner and G. Werner-Felmayer
[Abstract]
Indoleamine 2,3-Dioxygenase in Materno-Fetal Interaction
Pp. 205-208
P. Sedlmayr
[Abstract]
Tryptophan Catabolism in IDO+ Plasmacytoid
Dendritic Cells Pp. 209-216
F. Fallarino, S. Gizzi, P. Mosci, U. Grohmann and P. Puccetti
[Abstract]
How Does Indoleamine 2,3-Dioxygenase Contribute to
HIV Mediated Immune Dysregulation Pp. 217-223
A. Boasso and G.M. Shearer
[Abstract]
Indoleamine 2,3-Dioxygenase and Other Interferon-γ-Mediated
Pathways in Patients with Human Immunodeficiency Virus Infection
Pp. 225-236
K. Schroecksnadel, R. Zangerle, R. Bellmann-Weiler, K.
Garimorth and G. Weiss, D. Fuchs
[Abstract]
Role of Indoleamine 2,3-Dioxygenase in Antimicrobial
Defence and Immuno-Regulation: Tryptophan Depletion Versus
Production of Toxic Kynurenines Pp. 237-244
C.R. MacKenzie, K. Heseler, A. Müller and W. Däubener
[Abstract]
Pharmacological Targeting of IDO-Mediated Tolerance
for Treating Autoimmune Disease Pp. 245-266
W. Penberthy
[Abstract]
Indoleamine 2,3-Dioxygenase in Hematopoietic Stem
Cell Transplantation Pp. 267-272
U. Hainz, B. Jürgens, T. Wekerle, M.G. Seidel and
A. Heitger
[Abstract]
Implications of IFN-γ-Mediated
Tryptophan Catabolism on Solid Organ Transplantation
Pp. 273-282
G. Brandacher, R. Margreiter and D. Fuchs
[Abstract]
IDO and Clinical Conditions Associated with Depressive
Symptoms Pp. 283-287
C. Kohl and B. Sperner-Unterweger
[Abstract]
Chronic Immune Activation Underlies Morbid Obesity:
Is IDO A Key Player ? Pp. 289-295
G. Brandacher, E. Hoeller, D. Fuchs and H.G. Weiss
[Abstract]
Abstracts
[Back to top]
Editorial
Almost 30 years ago, indoleamine 2,3-dioxygenase (IDO) was
discovered as a tryptophan-degrading enzyme, which is inducible
by interferons. IDO converts tryptophan to N-formyl-kynurenine,
and this catabolism of the essential amino acid turned out
as an important anti-proliferative activity, which is directed
to halt reproduction of pathogens in infected cells and to
stop malignant growth. Consequently, induction of IDO was
considered as one out of several anti-proliferative pathways
which are induced by the Th1-type cytokine interferon-γ
and which are established during immune response.
For clinical studies, it was introduced to estimate the rate
of tryptophan degradation by calculating the quotient of kynurenine
to tryptophan concentrations (kyn/trp), although being aware
that kynurenine is further converted to several down-stream
products, the most important ones being quinolinic acid and
nicotinamide/adenine dinucleotides. In the later eighties,
the in vitro induction of tryptophan degradation
by cytokines was demonstrated in various cells and cell lines
of human and non-human origin. In patients enhanced tryptophan
degradation has been described in cytokine-treated patients
and in a variety of disorders such as infections including
HIV infection, in autoimmune syndromes, in malignant diseases,
in cardiovascular disorders and in neurodegeneration. These
disorders often go along with inflammation and immune activation,
and significant associations were observed between kyn/trp
and markers of Th1-type immune activation such as neopterin
or soluble cytokine receptors. Thus, accelerated tryptophan
degradation was referred to enhanced IDO activity which is
due to endogenous formation of its primary inducer, namely
interferon-γ.
In the above-mentioned clinical conditions, striking associations
exist between accelerated tryptophan degradation and the extent,
the activity and the course of the disease. Moreover, in case
of malignancy and HIV infection accelerated catabolism of
tryptophan and immune activation predicted shorter survival
and it concurred with the loss of immunocompetence, the development
of cachexia and anemia, and predicted shorter survival. Data
suggest a pathogenetic role of tryptophan deprivation also
in these symptoms typical of chronic inflammatory conditions.
Because tryptophan is also required for the biosynthesis of
neurotransmitter 5-hydroxytryptamine (5-HT, serotonin), accelerated
catabolism of tryptophan is likely to disturb also the serotonergic
system. Thus, reduced availability of tryptophan would affect
serotonin biosynthesis and thus could represent an important
aspect in the pathogenesis of cognitive impairment and depression.
Accordingly, the immune system-induced deprivation of tryptophan
seems to provide a direct link between the higher risk for
the development of depression in patients who suffer from
chronic inflammatory conditions such as autoimmune syndromes,
infections and myocardial infarction but also cancer. Indeed,
in patients under treatment with forward-regulatory cytokines
like interferon-α
a significant relationship is found between the decline of
tryptophan levels which is due to enhanced degradation and
the risk of mood disturbances and depression. In a similar
way, in patients with cancer enhanced degradation of tryptophan
is not only found to predict shorter survival but is also
associated with impaired quality of life. Thus, the enhanced
activity of IDO during states of immune activation suggests
an important link between the neuro-and immunoendocrine systems.
Accelerated tryptophan degradation together with immune activation
was demonstrated also in normal human pregnancy, and in 1998
enhanced IDO activity was demonstrated to be critical in the
induction of immunotolerance during pregnancy. Until that
time, only a very limited number of laboratories was interested
in basic research on IDO, but from now on interest in IDO
was rapidly spread into several labs throughout the world.
Numerous studies of basic regulation and consequences of IDO
broadly extended the knowledge and understanding about the
clinical relevance of IDO. In particular, studies were able
to demonstrate the central place of IDO activation in the
development of immunodeficiency and immunotolerance. IDO activation
was also claimed as an intrinsic tumoral immune resistance
mechanism based on tryptophan degradation. Indeed, tryptophan
degradation is going on in patients with malignant disease.
However, degradation of tryptophan in unstimulated tumor cells
is observed only rarely in vitro, and thus tryptophan
degradation is unlikely to represent a spontaneous activity
of tumor cells to escape host immune response. Rather IDO
activity in patients is induced by interferon-γ
released from surrounding immunocompetent cells as part of
their anti-tumoral immune defense strategy, which in the long
run becomes detrimental when tryptophan deprivation becomes
strong enough to also halt T-cell responsiveness.
All together, data on IDO provide a basis for the better understanding
of the complex interplay between immune activation cascades
and the development of immunotolerance, apoptosis and immunodeficiency,
or in other words, of the pro- and anti-inflammatory consequences
of Th1-type cytokine interferon-γ,
among which IDO is a central component. Thus, when enhanced
tryptophan degradation is demonstrated, e.g., in cancer patients,
it reflects part of the cytocidal activity which is achieved
by the activated immune system, which however is also an important
aspect in the failure of the immune system to eradicate the
malignant process. The same two-edged situation is true in
autoimmunity when accelerated tryptophan degradation is demonstrated
along with the disease course, however, the immunosuppressive
component of activated IDO is unable to counteract the destructive
autoimmune process.
Research on IDO has already deepened the insight into the
mechanisms which underlie the interplay between immune response
and immunoresponsiveness, and also between immune response
and the neuroendocrine system. Better knowledge about IDO
also provided a more complete picture about cytokine interferon-γ,
the forward-regulatory activity of which appears to be well
understood in the acute (and experimental) immune response,
whereas its 2nd negative-regulatory impact on immune
surveillance still has to be more acknowledged in the years
to come. Future research on IDO will provide an important
cornerstone in the full understating of this cytokine and
thus of immunoregulation, which is of utmost relevance for
chronic diseases. These are the challenges, which we are and
will be dealing with most in the clinics. It will also provide
a basis for the better understanding of neuropsychiatric abnormalities
in patients suffering from chronic inflammatory conditions.
This special issue of Current Drug Metabolism on the Clinical
Relevance of Indoleamine 2,3-dioxygenase provides a collection
of review articles on several basic and clinical aspects in
which IDO is of special relevance and it should initiate new
ideas and thus intensification of these and other research
directions.
Dietmar Fuchs
Division of Biological Chemistry
Biocenter, Innsbruck Medical University
Innsbruck, Austria
E-mail: dietmar.fuchs@i-med.ac.at
[Back to top]
The Human Indoleamine 2,3-Dioxygenase Gene and Related
Human Genes
M.F. Murray
Tryptophan oxidation occurs via both extra-hepatic
and hepatic pathways. Although these pathways share many enzymes,
the first and rate-limiting step in each pathway is carried
out by two different enzymes: Indoleamine-Pyrrole 2,3 Dioxygenase
(INDO) and Tryptophan 2,3-Dioxygenase (TDO2). Over the course
of the last forty years extensive and detailed research by
many groups have led to an understanding of some of the important
biologic functions of these pathways and their metabolic products.
One of the tasks that now lie ahead is linking variations
in these genes with variable human responses in different
disease states. This short review will focus on known aspects
of the INDO and TDO2 gene structure and variability. In addition
to INDO and TDO2 a third related gene, the Indoleamine-Pyrrole
2,3 Dioxygenase-like 1 (INDOL1) gene will be discussed. INDOL1
is a gene of unknown function that lies adjacent to INDO on
chromosome 8.
[Back to top]
Substrate and Cofactor Requirements of Indoleamine
2,3 Dioxygenase in Interferon-Gamma-Treated Cells: Utilization
of Oxygen Rather Than Superoxide
E.R. Werner and G. Werner-Felmayer
Much attention has been paid in initial biochemical studies
on the ability of indoleamine 2,3-dioxygenase to use superoxide
as substrate to cleave tryptophan to N-formyl kynurenine.
This ability, however, is limited to the ferric form of the
enzyme only, whereas the ferrous form requires oxygen rather
than superoxide as substrate. As long as the enzyme is held
in the ferrous form, high yield formation of product proceeds
from the ferrous oxygen tryptophan ternary complex without
the participation of superoxide. Enzyme assays in homogenates
are carried out in presence of Methylene Blue, ascorbate and
catalase. Ascorbate can be replaced by other reductants like
e.g. tetrahydrobiopterin. Experiments with alteration of intracellular
tetrahydrobiopterin concentrations in intact interferon-gamma
treated cells clearly showed that tetrahydrobiopterin is not
required for the indoleamine 2,3-dioxygenase reaction. In
homogenates of interferon-gamma treated T-24 cells, substrates
of xanthine oxidase did not stimulate the indoleamine 2,3-dioxygenase
reaction, nor did allopurinol inhibit the reaction, nor did
superoxide dismutase alter indoleamine 2,3-dioxygenase activity
irrespective of the reductant used. From these experiments
we concluded that molecular oxygen rather than superoxide
is used in cell homogenates by indoleamine 2,3-dioxygenase
to cleave L-tryptophan. A detailed analysis of available reports
on oxygen and superoxide utilization by indoleamine 2,3-dioxygenase
gives a comprehensive picture that the enzyme uses oxygen
bound to the ferrous enzyme for cleavage of tryptophan, that
the enzyme needs to be held by reductants in the ferrous state
in enzyme incubations, and that superoxide is one of the reductants
capable performing this reduction.
[Back to top]
Indoleamine 2,3-Dioxygenase in Materno-Fetal Interaction
P. Sedlmayr
The mechanism of maternal immunotolerance of the semiallogeneic
fetus has been a matter of intense investigation. The tryptophan-degrading
enzyme indoleamine 2,3-dioxygenase (IDO) is reported to be
critically implicated. This article discusses findings pertaining
to the role of IDO in pregnancy, its location at the feto-maternal
interface, systemic induction of IDO in pregnancy and the
association of IDO to spontaneous abortion and preeclampsia.
Whereas there is a large body of evidence supporting the relevance
of IDO as a key immunoregulatory factor in feto-maternal tolerance,
open questions remain concerning as to its role.
[Back to top]
Tryptophan Catabolism in IDO+ Plasmacytoid
Dendritic Cells
F. Fallarino, S. Gizzi, P. Mosci, U. Grohmann and P. Puccetti
Plasmacytoid dendritic cells (pDCs) represent a specialized
cell population that produces large amounts of type I interferons,
the so-called natural interferon-producing cells. Recently,
murine and human pDCs have been credited with a unique ability
to express indoleamine 2,3-dioxygenase (IDO) and to mediate
immunosuppression in specific settings. This suggests an important
role for IDO-expressing pDCs in controlling the balance of
inflammation and tolerance. Here we review recent advances
in our understanding of how these cells may be critical at
the interface of inflammation and tolerance and discuss the
potential for therapeutic IDO modulation as an immunoregulatory
maneuver targeting pDC function.
[Back to top]
How Does Indoleamine 2,3-Dioxygenase Contribute to
HIV Mediated Immune Dysregulation
A. Boasso and G.M. Shearer
Infection with the human immunodeficiency virus type 1 (HIV)
results in a chronic infection that progressively cripples
the host immune defenses. HIV infection is associated with
increased tryptophan (trp) catabolism by the cytokine-inducible
enzyme indoleamine 2,3-dioxygenase (IDO). IDO has powerful
immune suppressive activity, which could contribute to the
immune dysfunction observed in HIV-infected patients. In this
review we discuss the immune mechanisms that could mediate
the HIV-induced increase of IDO activity (such as IFN-γ,
IFN-α,
CTLA-4/B7 and direct viral exposure). We then consider the
current knowledge of IDO-mediated immune suppressive mechanisms
with regard to different cell types (CD4+ T cells,
CD8+ T cells, natural killer cells, B cells and
regulatory T cells), from the perspective of their potential
consequences for the HIV-infected host. HIV-induced, IDO-mediated
trp catabolism may contribute to the perpetuation of HIV infection
into its chronic phase by dampening efficient immune anti-viral
responses. Therapeutic approaches aimed at manipulating this
powerful immune suppressive mechanism might be considered
in the setting of HIV infection.
[Back to top]
Indoleamine 2,3-Dioxygenase and Other Interferon-γ-Mediated
Pathways in Patients with Human Immunodeficiency Virus Infection
K. Schroecksnadel, R. Zangerle, R. Bellmann-Weiler, K.
Garimorth and G. Weiss, D. Fuchs
Human immunodeficiency virus type 1 (HIV) infection is characterized
by progressive immunodeficiency despite of an overwhelming
cellular immune activation. Patients show highly elevated
serum/plasma concentrations of the proinflammatory cytokine
interferon-γ
(IFN-γ),
which induces human monocytes to form neopterin, to produce
reactive oxygen species (ROS) and in parallel, to degrade
tryptophan. Enhanced tryptophan degradation by the enzyme
indoleamine-2, 3-dioxygenase (IDO) contributes importantly
to disease progression and “complications” of
HIV infection: By a subsequent impairment of protein metabolism
and serotonin formation, the development of neuropsychiatric
disorders and weight loss in HIV infected patients can be
enforced. Furthermore, increased IDO-activation efficiently
suppresses the growth and proliferation of pathogens as well
as host T-cells. IDO and other IFN-γ-mediated
pathways are strongly induced in patients with HIV infection
and are also linked with disease progression: Neopterin formation
by GTP-cyclohydrolase I sensitively reflects the stage of
the disease, and determination of the pteridine in body fluids
is useful to monitor the efficacy of antiretroviral therapy.
Neopterin is an independent prognostic factor for the outcome
of disease, and well suited to estimate the degree of immune
activation in vivo and the responsiveness of immunocompetent
cells to stimulation in vitro. ROS formation may
contribute to the development of oxidative stress in HIV infection,
resulting in depletion of antioxidants. The cause-effective
role of an overwhelming Th1-type immune response together
with the activation of IDO and other IFN-γ-mediated
biochemical pathways for the course of HIV infection, the
development of immunodeficiency, anemia and weight loss in
HIV patients is discussed.
[Back to top]
Role of Indoleamine 2,3-Dioxygenase in Antimicrobial
Defence and Immuno-Regulation: Tryptophan Depletion Versus
Production of Toxic Kynurenines
C.R. MacKenzie, K. Heseler, A. Müller and W. Däubener
Tryptophan metabolism occurs via the protohemoprotein enzymes
tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase
(IDO), the latter action of which has a number of effects
in the body including both antimicrobial defence and immune
regulation. Whilst the antimicrobial action of IDO is largely
due to depletion of the essential amino acid tryptophan, the
immune regulatory function of IDO is still unclear and controversial.
The list of pathogens that are “sensitive” to
IDO-mediated tryptophan degradation covers intra-cellular
parasites such as toxoplasma and possibly plasmodia, viruses
(herpes viruses) to intra-cellular bacteria (chlamydia and
rickettsia) and extra-cellular bacteria such as streptococci,
enterococci and staphylococci. Immune regulation may be a
consequence of tryptophan depletion, the accumulation of immune-active
or toxic metabolites or due to other signalling events. This
review covers the latest data and controversy pertaining to
the antimicrobial and immune regulatory effects of tryptophan
metabolism.
[Back to top]
Pharmacological Targeting of IDO-Mediated Tolerance
for Treating Autoimmune Disease
W. Penberthy
Cells at the maternal-fetal interface express indoleamine
2,3 dioxygenase (IDO) to consume all local tryptophan for
the express purpose of starving adjacent maternal T cells
of this most limiting and essential amino acid. This stops
local T cell proliferation to ultimately result in the most
dramatic example of immune tolerance, acceptance of the fetus.
By contrast, inhibition of IDO using 1-methyl-tryptophan causes
a sudden catastrophic rejection of the mammalian fetus. Immunomodulatory
factors including IFNγ,
TNFα,
IL-1, and LPS use IDO induction in responsive antigen presenting
cells (APCs) also to transmit tolerogenic signals to T cells.
Thus it makes sense to consider IDO induction towards tolerance
for autoimmune diseases in general. Approaches to cell specific
therapeutic IDO induction with NAD precursor supplementation
to prevent the collateral non-T cell pathogenesis due to chronic
TNFα-IDO
activated tryptophan depletion in autoimmune diseases are
reviewed. Tryptophan is an essential amino acid most immediately
because it is the only precursor for the endogenous biosynthesis
of nicotinamide adenine dinucleotide (NAD). Both autoimmune
disease and the NAD deficiency disease pellagra occur in women
at greater than twice the frequency of occurrence in men.
The importance of IDO dysregulation manifest as autoimmune
pellagric dementia is genetically illustrated for Nasu-Hakola
Disease (or PLOSL), which is caused by a mutation in the IDO
antagonizing genes TYROBP/DAP12 or TREM2.
Loss of function leads to psychotic symptoms rapidly progressing
to presenile dementia likely due to unchecked increases in
microglial IDO expression, which depletes neurons of tryptophan
causing neurodegeneration. Administration of NAD precursors
rescued entire mental hospitals of dementia patients literally
overnight in the 1930's and NAD precursors should help Nasu-Hakola
patients as well. NAD depletion mediated by peroxynitrate
PARP1 activation is one of the few established mechanisms
of necrosis. Chronic elevation of TNFα
leading to necrotic events by NAD depletion in autoimmune
disease likely occurs via combination of persistent
IDO activation and iNOS-peroxynitrate activation of PARP1
both of which deplete NAD. Pharmacological doses of NAD precursors
repeatedly provide dramatic therapeutic benefit for rheumatoid
arthritis, type 1 diabetes, multiple sclerosis, colitis, other
autoimmune diseases, and schizophrenia in either the clinic
or animal models. Collectively these observations support
the idea that autoimmune disease may in part be considered
as localized pellagra manifesting symptoms particular to the
inflamed target tissues. Thus pharmacological doses of NAD
precursors (nicotinic acid/niacin, nicotinamide/niacinamide,
or nicotinamide riboside) should be considered as potentially
essential to the therapeutic success of any IDO-inducing regimen
for treating autoimmune diseases. Distinct among the NAD precursors,
nicotinic acid specifically activates the g-protein coupled
receptor (GPCR) GPR109a to produce the IDO-inducing tolerogenic
prostaglandins PGE2 and PGD2. Next,
PGD2 is converted to the anti-inflammatory prostaglandin,
15d-PGJ2. These prostaglandins exert potent anti-inflammatory
activities through endogenous signaling mechanisms involving
the GPCRs EP2, EP4, and DP1 along with PPARγ
respectively. Nicotinamide prevents type 1 diabetes and ameliorates
multiple sclerosis in animal models, while nothing is known
about the therapeutic potential of nicotinamide riboside.
Alternatively the direct targeting of the non-redox NAD-dependent
proteins using resveratrol to activate SIRT1 or PJ34 in order
to inhibit PARP1 and prevent autoimmune pathogenesis are also
given consideration.
[Back to top]
Indoleamine 2,3-Dioxygenase in Hematopoietic Stem
Cell Transplantation
U. Hainz, B. Jürgens, T. Wekerle, M.G. Seidel and
A. Heitger
Hematopoietic stem cell transplantation (HSCT) is complicated
by unwelcome side-effects that arise on the basis of an altered
immune system. Infectious complications and alloreactive T-cell
responses trigger a process of ongoing immune activation and
inflammation. Negative-feedback mechanisms to counteract inflammation
involve the induction of the immunoregulatory enzyme indoleamine
2,3-dioxygenase (IDO), which mediates anti-inflammatory activities
and T-cell inhibition via tryptophan catabolism.
However, persistent immune activation and generalized release
of pro-inflammatory cytokines deviate immune regulation towards
chronic suppression incapable to abrogate the inflammatory
response. This review focuses on the unique role of tryptophan
catabolism in modulating inflammatory processes and T-cell
responses after HSCT.
[Back to top]
Implications of IFN-γ-Mediated
Tryptophan Catabolism on Solid Organ Transplantation
G. Brandacher, R. Margreiter and D. Fuchs
The Th1-type cytokine interferon-γ
(IFN-γ)
is known as one of the most versatile players of the immune
system. In transplantation immunology IFN-γ
has been shown to have contradictory effects on allograft
survival via effects on both, the immune system and
on the graft itself. The immunomodulatory enzyme indoleamine
2,3-dioxygenase (IDO), widely distributed in mammals, is induced
pref-erentially by IFN-γ.
IDO degrades the essential amino acid tryptophan to form N-formyl
kynurenine which is subsequently converted to niacin. Recently,
it has been proposed that IFN-γ-mediated
activation of IDO is critically involved in the regulation
of immune responses, to establish immune-tolerance in pregnant
mice upon their fetuses, or to induce T-cell unresponsiveness.
Proliferation of alloreactive T-cells is thereby arrested
via local tryptophan deprivation and the accumulation
of toxic tryptophan catabolites. Despite growing recognition
of the molecular T-cell regulatory mechanisms, the physiologic
role of IDO in solid organ transplantation, however, remains
unclear. Available experimental data indicate that IDO is
involved in the mechanism of spontaneous donor-specific tolerance
of liver grafts, and that genetic manipulation by introduction
of the IDO gene into allografts is associated with prolonged
survival. Furthermore, antigenpresenting cells, such as dendritic
cells, can increase their expression of IDO, thus regulating
immune responses. Based on these findings, the concept that
cells expressing IDO can inhibit T-cell responses and hence
induce tolerance has emerged as a new paradigm in immunology.
Here we review the current literature on IDO in the context
of transplantation and outline its potential implication as
a target for tolerance induction.
[Back to top]
IDO and Clinical Conditions Associated with Depressive
Symptoms
C. Kohl and B. Sperner-Unterweger
In the pathogenesis of depressive symptoms the neurotransmitter
serotonin plays an important role – although the underlining
mechanisms are still not clear. The synthesis of serotonin
is dependent on the availability of tryptophan – an
amino acid that is linked to the immune system by its catabolism
via the enzyme indoleamine-2,3-dioxygenase (IDO).
Based on this connection research approaches addressing different
clinical conditions with depressive symptoms and immunological
involvement have been considered. This review provides an
overview on the latest research in the field.
[Back to top]
Chronic Immune Activation Underlies Morbid Obesity:
Is IDO A Key Player ?
G. Brandacher, E. Hoeller, D. Fuchs and H.G. Weiss
Morbid obesity is associated with low-grade systemic
inflammation and immune activation. Thereby various pro-inflammatory
cytokines like TNF-α,
IL-1, IL-6, IFN-γ
and hormones, such as leptin are synthesized and released
in human adipose tissue. The immunomodulatory enzyme indoleamine
2,3-dioxygenase (IDO) is widely distributed in mammals and
is inducible preferentially by IFN-γ.
IDO degrades the essential amino acid tryptophan to form N-formyl
kynurenine which, depending on cell type and enzymatic repertoires,
is subsequently converted to finally form niacin. More recently,
it has been proposed that activation of IDO is also critically
involved in the regulation of immune responses. In obesity
plasma tryptophan concentrations have been shown to be decreased
and to be independent of weight reduction or dietary intake.
In addition, we previously demonstrated that IDO mediated
tryptophan catabolism due to chronic immune activation is
the cause for such reduced tryptophan plasma levels in morbidly
obese patients compared to lean individuals. Furthermore,
these tryptophan metabolic changes may subsequently reduce
serotonin production and cause mood disturbances, depression,
and impaired satiety ultimately leading to increased caloric
uptake and obesity. IDO-mediated tryptophan degradation due
to chronic immune activation can therefore be considered as
the driving force for food intake. We here review the potential
pathogenic links between chronic immune activation and decreased
IDO mediated tryptophan and serotonin levels in morbid obesity.
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