Hey Guys! Ever have a persistent FUN GAL? IDO -&- YOU
randall
OK, got your attention?
A quick John Updike (RiP) comment regarding psoriasis.
---------------
[...]
He lived with ___psoriasis___ and said his skin's "embarrassing
overproduction" was a large source of his prolific creativity.
<sniP>
============================
Back to FUNGAL's --- GET the STRAIGHT doPe here.
So? Do you have a persistent FUNGAL problem?
Maybe you do and don't know it?
Anyway here's a possible New Way to deal with it...
It may start flaky but ends in a FLURRY.
http://www.sciencedaily.com/releases/2009/01/090127131657.htm
DNA Component Can Stimulate And Suppress Immune Response
ScienceDaily (Feb. 2, 2009) — A component of DNA that can both
stimulate and suppress the immune system, depending on the dosage, may
hold hope for treating cancer and infection, Medical College of
Georgia researchers say.
Low levels of CpG increase inflammation, part of the body's way of
eliminating invaders. But high doses block inflammation by increasing
expression of the enzyme indoleamine 2,3 dioxygenase, or IDO, an
immunosuppressor, the researchers say.
[ http://en.wikipedia.org/wiki/CpG_site ]
http://en.wikipedia.org/wiki/CpG_island
"The same therapy can have two different effects," says Rusty Johnson,
a fifth-year M.D./Ph.D. student in the MCG Schools of Medicine and
Graduate Studies. "It was assumed that giving this treatment at higher
doses would cause more stimulation, but it has the opposite effect."
The researchers hope that manipulating the dosage can help them
optimize the role of inflammation in fighting invaders such as tumors
and harmful bacteria. Mr. Johnson presented the findings at the
Midwinter Conference of Immunologists this month in Asilomar, Calif.
He is working with Drs. Andrew Mellor and David Munn, co-directors of
the School of Medicine Immuno Discovery Institute, who discovered
IDO's immunosuppressive capabilities more than a decade ago.
With the help of Drs. Babak Baban and Phillip Chandler, scientists in
MCG's Immunotherapy Center, they've also learned IDO inhibits
inflammation by blocking production of interleukin 6, a secreted
factor that causes inflammation.
"This suggests that IDO is a counter-regulatory mechanism that serves
as a balance to prevent too much inflammation," Mr. Johnson says. "Too
much inflammation leads to destruction of normal body tissue, and this
shows IDO's importance in preventing this from occurring."
The researchers already knew that IDO protects tumors from the immune
system. While working with collaborators Drs. Alex Muller and George
Prendergast at the Lankenau Institute in Philadelphia, they learned
its role in tumor formation.
"Without it, a mouse becomes resistant to skin tumor formation, and
tumors that do form are smaller and less malignant," Mr. Johnson says.
They've also learned that the cells IDO uses to suppress the immune
system – IDO-competent dendritic cells – originate from B cells, which
produce antibodies to fight infection.
Mr. Johnson was in his second year of medical school when he heard Dr.
Munn lecture about his and Dr. Mellor's groundbreaking discovery of
IDO's role in protecting a fetus from the mother's immune system. It
was at that point that the Augusta native decided to pursue a career
in immunology. Mr. Johnson earned a bachelor's degree in chemistry
from the Georgia Institute of Technology and studied piano and voice
at Augusta State University prior to coming to MCG.
------------------
http://en.wikipedia.org/wiki/TLR_9
TLR 9 is a toll-like receptor.
It recognizes unmethylated CpG sites on DNA molecules. CpG sites are
relatively rare (~1%) on vertebrate genomes in comparison to bacterial
genomes or viral DNA. TLR9 is expressed by numerous cells of the
immune system such as dendritic cells, B lymphocytes and natural
killer (NK) cells. TLR9 is expressed intracellularly, within the
endosomal compartments and functions to alert the immune system of
viral and bacterial infections by binding to DNA rich in CpG motifs.
TLR9 signals leads to activation of the cells initiating pro-
inflammatory reactions that result in the production of cytokines such
as type-I inteferon and IL-12. There are new immunomodulatory
treatments undergoing testing which involve the administration of
artificial DNA oligonucleotides containing the CpG motif. CpG DNA has
applications in treating allergies such as asthma, immunostimulation
against cancer, immunostimulation against pathogens, and as adjuvants
in vaccines.
=============
TLR9 and P (11 hits on pubmed)
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=psoria*+AND+TLR9&log$=activity
And these eleven hits have the BIG ONE (ll37) from Lande and Gilliet:
So wouldn't this mean it's simply Ai?
Antimicrobial peptides and self-DNA in autoimmune skin inflammation.
Gilliet M, Lande R.
Department of Immunology, The University of Texas MD Anderson Cancer
Center, Houston, TX 77030, USA. mgil...@mdanderson.org
Toll-like receptor (TLR)-mediated detection of viral nucleic acids and
production of type I interferons (IFNs) by plasmacytoid dendritic
cells (pDCs) are key elements of antiviral defense. By contrast,
inappropriate recognition of self-nucleic acids with induction of IFN
responses in pDCs can lead to autoimmunity. In this review we describe
how pDC responses to self-DNA are normally avoided and focus on our
recent finding that in psoriasis, a common autoimmune disease of the
skin, these barriers can be breached by the cationic antimicrobial
peptide LL37. LL37 binds extracellular self-DNA fragments into
aggregated particles that enter pDCs and trigger robust IFN responses
by activating endosomal TLR9 as if they were viruses. We also describe
the mechanisms that normally control production and activity of LL37
in human skin and propose that the persistent overexpression of LL37
in psoriasis leads to uncontrolled IFN responses that drive autoimmune
skin inflammation.
PMID: 18611439
Or (LL-37) + LPS is MY GUESS and has been for the last few weeks.
So? Let's do it dawg.
http://www.ncbi.nlm.nih.gov/pubmed/19166322?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Structure-function relationship of the human antimicrobial peptide
LL-37 and LL-37 fragments in the modulation of TLR responses.
Molhoek EM, den Hertog AL, de Vries AM, Nazmi K, Veerman EC, Hartgers
FC, Yazdanbakhsh M, Bikker FJ, van der Kleij D.
1TNO Defense, Security and Safety, NL-2280AA Rijswijk, The
Netherlands, 2Department of Parasitology, Leiden University Medical
Center, Leiden, The Netherlands, 3Department of Oral Biochemistry,
Academic Center for Dentistry Amsterdam, Free University and
University of Amsterdam, Amsterdam, The Netherlands.
Abstract Cathelicidins are effector molecules of the innate host
defense system that establish an antimicrobial barrier at epithelial
interfaces. The human cathelicidin LL-37, in addition to its
antimicrobial activity, also exhibits immunomodulatory effects such as
inhibition of pro-inflammatory responses to bacterial LPS in human
monocytic cells. In this report we demonstrate that LL-37 almost
completely prevents the pro-inflammatory cytokine release by human
PBMCs following stimulation with TLR4 and TLR2/1 agonists while
leaving TLR2/6, TLR5, TLR7 and TLR8 responses unchanged. Modulation of
the TLR response by LL-37 occurred at least partly through the MAP
kinase pathway via inhibition of p38 phosphorylation. By using an
LL-37 library with overlapping sequences, we identified the mid-region
of LL-37, comprising amino acids 13-31, as the active domain for
modulation of TLR responses. The mechanism of immunomodulation of
LL-37 and LL-37 fragments is LPS binding. Correlations between the
capacity of LL-37 fragments to modulate TLR responses and their
physico-chemical properties revealed that cationicity and
hydrophobicity are essential for the modulation of LL-37-mediated TLR
responses.
PMID: 19166322
There WE GO, LL-37, LPS, with TLR9 and means TNF is downstream.
Is it any old fungal or simply endogenous endotoxin from a permeable
Gi tract?
No wonder their (pharma) looking at TLR9 blockers.
40 hits on the P NG for TLR9
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=tlr9&start=0&scoring=d&
Will IDO undo the autoimmune reaction?
And HOW much IDO is JUST RIGHT to slow Ai?
=============================
http://www.sciencedaily.com/images/2009/01/090127131657.jpg
DNA component can stimulate and suppress the immune response Amy
Connell - 2009 January 27 AUGUSTA, Ga. –
A component of DNA that can both stimulate and suppress the immune
system, depending on the dosage, may hold hope for treating cancer and
infection, Medical College of Georgia researchers say. Low levels of
CpG increase inflammation, part of the body's way of eliminating
invaders. But high doses block inflammation by increasing expression
of the enzyme indoleamine 2,3 dioxygenase, or IDO, an
immunosuppressor, the researchers say. "The same therapy can have two
different effects," says Rusty Johnson, a fifth-year M.D./Ph.D.
student in the MCG Schools of Medicine and Graduate Studies. "It was
assumed that giving this treatment at higher doses would cause more
stimulation, but it has the opposite effect." (Credit: Image courtesy
of Medical College of Georgia)
<sniP>
------------------------
The methylation pattern of p16INK4a gene promoter in psoriatic
epidermis and its clinical significance.
Chen M, Chen ZQ, Cui PG, Yao X, Li YM, Li AS, Gong JQ, Cao YH.
Department of Clinical Dermatology and Immunology, Institute of
Dermatology, Chinese Academy of Medical Sciences & Peking Union
Medical College, Nanjing, China. drch...@126.com
BACKGROUND: Alteration of the p16INK4a gene by epigenetic changes has
been described in some hyperproliferative skin diseases, but its
importance in psoriasis has not yet been established. OBJECTIVES: To
investigate the methylation status of the p16INK4a gene in psoriatic
epidermis, its clinical significance and the possible epigenetic
mechanisms of psoriasis. METHODS: DNA and RNA specimens were obtained
from the lesional epidermis of 56 patients with plaque psoriasis.
Methylation-specific polymerase chain reaction (PCR) and DNA
sequencing were used to detect the density and sites of methylation in
the p16INK4a promoter region. The reverse transcription-PCR technique
was applied to detect the mRNA expression of p16INK4a. RESULTS:
p16INK4a gene promoter methylation was shown in 17 of 56 (30%)
patients with psoriasis. Psoriasis Area and Severity Index scores in
patients showing methylation were higher than in those who did not
(P<0.05). The mRNA expression level of p16INK4a in the methylated
group was significantly lower than in the unmethylated group (t=2.515,
P=0.015). In the methylated group, about 50% of the CpG islands were
methylated in the promoter region. CONCLUSIONS: Overall, methylation
of the p16INK4a gene promoter is found in psoriatic epidermis, which
is associated with the mRNA level of p16INK4a expression and activity
of the disease. These data indicate that methylation of the p16INK4a
promoter may play a potential role in the pathogenesis of psoriasis.
PMID: 18373711
More CpG:
[The methylation locus and frequency pattern on p16 INK4a gene
promoter CpG in epidermis of patients with psoriasis]
[Article in Chinese]
Chen M, Cui PG, Yao X, Cao YH, Gong JQ, Li AS, Chen ZQ.
Institute of Dermatology, Chinese Academy of Medical Sciences and
Peking Union Medical College, Nanjing, Jiangsu, 210042 PR China.
OBJECTIVE: To investigate the CpG methylation locus and frequency
pattern on p16 INK4a gene promoter in epidermis of p16 INK4a
methylated patients with psoriasis vulgaris. METHODS: The DNA
specimens were obtained from epidermal lesion of 50 plaque psoriatic
patients. Methylation specific PCR and DNA sequencing were used to
detect the frequency and locus of methylation in p16 INK4a gene
promoter region. RESULTS: Approximately 50% CpG was methylated in p16
INK4a methylated patients, methylation was found in specifical locus
of p16 INK4a gene promoter. CONCLUSION: The distinct methylation
pattern is showed on the p16 INK4a gene promoter region in patients
with psoriasis.
PMID: 18067081
47 hits for CpG in the P ng:
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=cpg&start=0&scoring=d&
67 hits for methylation on the p ng:
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=methylation&start=0&scoring=d&
=====================
BACK to IDO:
IDO 1085 hits on pubmed:
indoleamine 2,3-dioxygenase + cpg = 11 hits on pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=indoleamine+2,3-dioxygenase+cpg&log$=activity
------------------
http://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase
Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 1.13.11.52) is an
immunomodulatory enzyme secreted by some alternatively activated
macrophages and other immunoregulatory cells (also used as an immune
subversion strategy by many tumors).
Gamma-interferon (IFNG; MIM 147570) has an antiproliferative effect on
many tumor cells and inhibits intracellular pathogens such as
Toxoplasma and Chlamydia, at least partly because of the induction of
indoleamine 2,3-dioxygenase (INDO; EC 1.13.11.42). This enzyme
catalyzes the degradation of the essential amino acid L-tryptophan to
N-formylkynurenine.[supplied by OMIM][1]
IDO is the first and rate limiting enzyme of Tryptophan catabolism
through Kynurenine pathway, thus causing depletion of tryptophan which
can cause halted growth of microbes as well as T cells.
It catalyzes conversion of L-tryptophan to N-formylkynurenine.
-------------
http://en.wikipedia.org/wiki/Tryptophan
-----------------
http://en.wikipedia.org/wiki/Kynurenine
Kynurenine is a metabolite of the amino acid tryptophan used in the
production of niacin. It has been associated with tics.
Kynureninase catabolizes the conversion of kynurenine into anthranilic
acid while kynurenine—oxoglutarate transaminase (also known as
Kynurenine amino-transferase and glutamine transaminase K, GTK)
catabolizes its conversion into kynurenic acid and kynurenine 3-
hydroxylase - to 3-hydroxykynurenine.
-----------------
http://en.wikipedia.org/wiki/N%27-Formylkynurenine
N'-Formylkynurenine is an intermediate in the catabolism of
tryptophan.
========================
IDO in the P NG: 11 hits:
=======================
http://en.wikipedia.org/wiki/Eu-FEDS
The Eutherian Fetoembryonic Defense System (eu-FEDS) is a hypothetical
model describing a method by which immune systems are capable of
recognizing additional states of relatedness like "own species" such
as is observed in maternal tolerance of a related fetus. The model
includes descriptions of the proposed signaling mechanism and several
proposed examples of exploitation of this signaling in disease states.
Background
The concept of immunity refers to an organism's ability to respond to
various foreign intrusions (as occurs in infection). A basic
requirement in such a system is the ability to avoid self harm through
some mechanism of recognizing "self". In classic immunity several
types of molecules label the organism's own cells as "self". Cells
lableled in this manner are tolerated and not damaged by the various
defense mechanisms employed to protect against infection.
Dysregulation of this system is responsible for several types of
disease states known collectively as autoimmune disorders.
[...]
Hypothesis
The basic premise of the eu-FEDS hypothesis is that both soluble and
cell surface associated glycoproteins, present in the reproductive
system and expressed on gametes, suppress any potential immune
responses, and inhibit rejection of the fetus[1]. The eu-FEDS model
further suggests that specific carbohydrate sequences
(oligosaccharides) are covalently linked to these immunosuppressive
glycoproteins and act as “functional groups” that suppress the immune
response. The major uterine and fetal glycoproteins that are
associated with the eu-FEDS model in the human include alpha-
fetoprotein,CA125, and glycodelin-A (also known as placental protein
14 (PP14)).
Normally, a low level of these glycoproteins is detected in the
maternal serum during the early stages of pregnancy. It appears that
the effects of these eu-FEDS associated glycoproteins are manifested
only during implantation and the very early development of the embryo.
In humans, the expression of such glycoproteins greatly decreases
toward the end of the first trimester. Therefore, more highly targeted
mechanisms of immune suppression (such as the expression of the enzyme
_____ indoleamine dioxygenase (IDO))____ are likely employed by the
fetus during the subsequent stages of development. One potential
reason for early inactivation of the system is that the
immunosuppressive effect of these glycoproteins may be so complete
that their continued leakage into the circulatory system could lead to
a global suppression of the maternal immune response, compromising the
mother's ability to carry the fetus to term.
<sniP>
-------------
So?
=======================
IDO- jpg:
http://www.nature.com/nri/journal/v4/n10/images/nri1457-f4.jpg
a | Potential mechanisms for the 'bystander' effects of indoleamine
2,3-dioxygenase (IDO)-expressing cells. In vitro and in vivo studies
indicate that even small numbers of IDO+ dendritic cells (DCs) can
have widespread suppressive effects on T cells that recognize antigen
presented by IDO- DCs. The figure depicts hypothetical mechanisms by
which suppression of adjacent T cells might occur. There could be
bystander suppression mediated by the IDO-expressing DC itself — for
example, through toxic metabolites, widespread local tryptophan
depletion or IDO-induced regulatory cytokines. Neighbouring cells (for
example, macrophages, regulatory T or B cells) might similarly be
induced by IDO-responsive signalling pathways to secrete regulatory
cytokines. Naive T cells (CD4+ or CD8+) might be biased by IDO+ DCs to
adopt a regulatory phenotype. Any of these effects could then suppress
nearby T cells responding to IDO- antigen-presenting cells (APCs). The
effect of IDO would therefore be to convert the local tissue
microenvironment into a tolerizing milieu, even for antigens presented
by other, normally immunogenic APCs. b | Model of a self-amplifying
regulatory network involving interactions between IDO-competent DCs
and regulatory T cells. The generation of regulatory T cells by IDO-
expressing DCs could be a potent mechanism, as these regulatory T
cells might in turn create other tolerogenic DCs through the induction
of IDO expression by cytotoxic T lymphocyte antigen 4 (CTLA4)
interactions. This could provide one possible molecular mechanism for
epitope spreading and 'infectious' tolerance, as described in other
systems132.
<sniP>
From:
http://www.nature.com/nri/journal/v4/n10/fig_tab/nri1457_F4.html
http://www.nature.com/nri/journal/v7/n8/fig_tab/nri2132_F3.html
http://www.nature.com/nri/journal/v7/n8/fig_tab/nri2132_F2.html
http://www.nature.com/nri/journal/v7/n8/fig_tab/nri2132_F1.html
-----------
Similar jpg: IDO & renal failure
http://www.jpp.krakow.pl/journal/archive/0603/gfx/rys0401.gif
from:
http://www.jpp.krakow.pl/journal/archive/0603/articles/04_article.html
=======================
Are we full of fungi? Does IDO come in to play for Ai then?
And what about psoriasis?
------------------
http://www.ncbi.nlm.nih.gov/pubmed/19180748?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Cell mediated immunity to fungi: a reassessment.
Romani L.
Microbiology Section, Department of Experimental Medicine and
Biochemical Sciences, University of Perugia, Italy. lro...@unipg.it
Protective immunity against fungal pathogens is achieved by the
integration of two distinct arms of the immune system, the innate and
adaptive responses. Innate and adaptive immune responses are
intimately linked and controlled by sets of molecules and receptors
that act to generate the most effective form of immunity for
protection against fungal pathogens. The decision of how to respond
will still be primarily determined by interactions between pathogens
and cells of the innate immune system, but the actions of T cells will
feed back into this dynamic equilibrium to regulate the balance
between tolerogenic and inflammatory responses. In the last two
decades, the immunopathogenesis of fungal infections and fungal
diseases was explained primarily in terms of Th1/Th2 balance. Although
Th1 responses driven by the IL-12/IFN-gamma axis are central to
protection against fungi, other cytokines and T cell-dependent
pathways have come of age. The newly described Th17 developmental
pathway may play an inflammatory role previously attributed to
uncontrolled Th1 responses and serves to accommodate the seemingly
paradoxical association of chronic inflammatory responses with fungal
persistence in the face of an ongoing inflammation. Regulatory T cells
in their capacity to inhibit aspects of innate and adaptive antifungal
immunity have become an integral component of immune resistance to
fungi, and provide the host with immune defense mechanisms adequate
for protection, without necessarily eliminating fungal pathogens which
would impair immune memory--or causing an unacceptable level of tissue
damage. The enzyme indoleamine 2,3-dioxygenase and tryptophan
metabolites contribute to immune homeostasis by inducing Tregs and
taming overzealous or heightened inflammatory responses.
PMID: 19180748
---------------
http://en.wikipedia.org/wiki/Systemic_inflammation
[...]
Lack of Control by Tolerogenic Dendritic Cells and T-regulatory Cells
While SI may be induced by multiple external factors, research
suggests that a lack of control by tolerogenic dendritic cells and T-
regulatory cells (Treg) is possibly the primary risk factor for the
development of SI. In functioning immune responses, T-helper and T-
cytotoxic cells are activated by presentation of antigens by antigen-
presenting cells (APCs). Chief among these are dendritic cells (DCs).
When a DC presents an antigen to a Treg cell, a signal is then sent to
the nucleus of the DC, resulting in the production of Indoleamine 2,3-
Dioxygenase (IDO). IDO inhibits T cell responses by depleting
tryptophan and producing kynurenine, which is toxic to the cell.
Individuals susceptible to developing chronic systemic inflammation
appear to lack proper functioning of Treg cells and TDCs. In these
individuals, a lack of control of inflammatory processes results in
multiple chemical and food intolerances, autoimmune diseases and many
other symptoms and diseases.
=======================
Tryptophan degradation in irritable bowel syndrome: evidence of
indoleamine 2,3-dioxygenase activation in a male cohort
Irritable bowel syndrome (IBS) is a common disorder that affects
10-15% of the population. Although characterised by a lack of reliable
biological markers, the disease state is increasingly viewed as a
disorder of the brain-gut axis.
In particular, accumulating evidence points to the involvement of both
the central and peripheral serotonergic systems in disease
symptomatology. Furthermore, altered tryptophan metabolism and
indoleamine 2,3-dioxygenase (IDO) activity are hallmarks of many
stress-related disorders.
The kynurenine pathway of tryptophan degradation may serve to link
these findings to the low level immune activation recently described
in IBS. In this study, we investigated tryptophan degradation in a
male IBS cohort (n=10) and control subjects (n=26).
Methods: Plasma samples were obtained from patients and healthy
controls. Tryptophan and its metabolites were measured by high
performance liquid chromatography (HPLC) and neopterin, a sensitive
marker of immune activation, was measured using a commercially
available ELISA assay.
Results: Both kynurenine levels and the kynurenine:tryptophan ratio
were significantly increased in the IBS cohort compared with healthy
controls. Neopterin was also increased in the IBS subjects and the
concentration of the neuroprotective metabolite kynurenic acid was
decreased, as was the kynurenic acid:kynurenine ratio.
Conclusions: These findings suggest that the activity of IDO, the
immunoresponsive enzyme which is responsible for the degradation of
tryptophan along this pathway, is enhanced in IBS patients relative to
controls. This study provides novel evidence for an immune-mediated
degradation of tryptophan in a male IBS population and identifies the
kynurenine pathway as a potential source of biomarkers in this
debilitating condition.
Author: Gerard Clarke, Peter Fitzgerald, John F Cryan, Eugene M
Cassidy, Eamonn M Quigley and Timothy G Dinan
Credits/Source: BMC Gastroenterology 2009, 9:6
===================
http://www.innovations-report.de/html/berichte/biowissenschaften_chemie/missing_piece_a_work_125646.html
Missing piece gets a work over
nächste Meldung
19.01.2009
Researchers working in Japan have developed a new theory that may
explain the activity of two unusual, but vitally important, enzymes
that were discovered over 40 years ago.
Anzeige
New pathways for the biological activity of two little-understood
enzymes emerge from a theoretical investigation
The enzymes, indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-
dioxygenase (TDO), known as dioxygenases, are responsible for the
cleavage of the essential amino acid, L-tryptophan. Both enzymes
contain heme—a metal-containing organic ring structure—to which
molecular oxygen is bound before being transferred to L-tryptophan.
This important oxidation reaction releases energy into the body in all
cells in mammals, but its mechanism is little understood.
Now, Hiroshi Sugimoto and colleagues at the RIKEN SPring-8 Center,
Harima, in collaboration with Keiji Morokuma, Lung Wa Chung and
colleagues at Kyoto University, have studied the structures of these
enzymes and modeled some potential reaction pathways to better
understand how they work1.
Recently, crystal structures of IDO (Fig. 1) 2 and TDO with tryptophan
or similar compounds were obtained. Surprisingly, these structures
showed different active sites for these enzymes compared to other heme
systems. Consequently, the researchers concluded that different
mechanistic pathways must also be operating for the dioxygenase
reaction.
The researchers used a detailed modeling method, called Density
Functional Theory, to calculate and evaluate the energy of the
starting compounds, products, possible reaction intermediates and
transition states. They then used comparisons to provide insight into
which reaction pathways are the most energetically favorable and,
therefore, which mechanism is most likely to take place in the body.
They found that one proposed mechanism involved a highly distorted
transition state, which would lead to a very high energy barrier,
making this route doubtful. Instead, they suggest that a new and
energetically favorable mechanistic pathway explains the unusual
dioxygen activation and oxidation reactions for the enzymes. This
proposed mechanism is sharply distinct from other mechanisms for heme-
containing oxygenases.
The enzyme-bound oxygen was found to react directly with the electron-
rich indole carbon on the tryptophan via either a 2-electron
(electrophilic) or 1-electron (radical) transfer pathway. Either of
these reactions would lead to the formation of a low-energy
intermediate making it a much more realistic possibility. Sugimoto and
colleagues are now investigating exactly how oxygen binds to the heme
and evaluating the contribution of the enzyme to the mechanism.
“[The research] might also be informative for rational drug design
because IDO is emerging as an important new therapeutic target for the
treatment of cancer, chronic viral infections, and other diseases
characterized by pathological immune suppression,” says Sugimoto.
Reference
1. Chung, L.W., Li, X., Sugimoto, H., Shiro, Y. & Morokuma, K. Density
Functional Theory Study on a Missing Piece in Understanding of Heme
Chemistry: The Reaction Mechanism for Indoleamine 2,3-Dioxygenase and
Tryptophan. Journal of the American Chemical Society 130, 12299–12309
(2008).
2. Sugimoto, H., Oda, S., Otsuki, T., Hino, T., Yoshida, T. & Shiro,
Y. Crystal structure of human indoleamine 2,3-dioxygenase: catalytic
mechanism of O2 incorporation by a heme-containing dioxygenase.
Proceedings of the National Academy of Sciences USA 103, 2611–2616
(2006).
The corresponding author for this highlight is based at the RIKEN
Biometal Science Laboratory
=====================
DEC/2007
http://www.ncbi.nlm.nih.gov/pubmed/18055547?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Indoleamine 2,3-dioxygenase (IDO): the antagonist of type I interferon-
driven skin inflammation?
Scheler M, Wenzel J, Tüting T, Takikawa O, Bieber T, von Bubnoff D.
Department of Dermatology, Friedrich-Wilhelms University, Sigmund
Freud-Strasse 25, 53105 Bonn, Germany. marina....@ukb.uni-bonn.de
Recent studies have provided evidence that a type I interferon (IFN)-
driven immune response might play an important role in the
pathogenesis of lichen planus (LP), an inflammatory disorder of the
skin of unclear etiology. Plasmacytoid dendritic cells in affected
skin from LP have been proposed to produce IFN-alpha/beta locally,
which leads to the expression of IFN-inducible chemokines such as IP10/
CXCL10 in the epidermis. This chemokine recruits chemokine receptor
CXCR3-expressing T-lymphocytes into the skin via CXCR3/IP10
interactions. Indoleamine 2,3-dioxygenase (IDO), which degrades
tryptophan and suppresses T-cell proliferation, is induced by IFNs and
other inflammatory cytokines. We show that type I IFN-mediated skin
disorders, such as LP, strongly express IDO in lesional skin. This
expression closely correlates to the expression of the highly specific
type I IFN marker MxA. We further demonstrate that the IDO+ cells in
LP are large myeloid CD11c+S100+CD68(-) dendritic cells. Accordingly,
CD11c+ antigen-presenting cells significantly up-regulate IDO gene
expression and intracellular IDO protein expression after stimulation
with IFN-alpha in vitro. These findings reveal that both
proinflammatory and counterregulatory mechanisms are operative in
cutaneous lesions of LP. We propose that the balance of these
mechanisms may be involved in the pathogenesis of this disorder.
PMID: 18055547
From 2004
http://www.ncbi.nlm.nih.gov/pubmed/15541637?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Gene expression of enzymes for tryptophan degradation pathway is
upregulated in the skin lesions of patients with atopic dermatitis or
psoriasis.
Ito M, Ogawa K, Takeuchi K, Nakada A, Heishi M, Suto H, Mitsuishi K,
Sugita Y, Ogawa H, Ra C.
Genox Research Inc., Ibaraki, Japan.
BACKGROUND: Atopic dermatitis (AD) and psoriasis are common
inflammatory skin diseases. Although many reports implicate Th2
cytokines in the pathophysiology of AD and Th1 cytokines in psoriasis,
the precise etiology of these diseases remains elusive. OBJECTIVE: We
investigated novel AD- or psoriasis-related genes to further
understand the pathogenesis of these diseases. METHODS: We performed a
comprehensive analysis of mRNA expression in skin biopsies from AD or
psoriasis patients using DNA microarrays. Quantitative PCR was then
used to monitor the expression of novel disease-related genes in human
keratinocytes or pinnae from NC/Nga mice. RESULTS: Levels of mRNA for
IDO (indoleamine 2,3-dioxygenase) and kynureninase, enzymes
constituting the tryptophan degradation pathway, were found to be
upregulated in the skin lesions as compared to the uninvolved skin of
patients with AD or psoriasis. Expression of these two genes was
induced in human epidermal keratinocytes stimulated with IFN-gamma in
vitro. Moreover, in NC/Nga mice, the expression of kynureninase mRNA
in the ear skin was induced following development of AD-like skin
lesions. CONCLUSION: The tryptophan degradation pathway may play an
important role in the pathophysiology of AD and psoriasis.
PMID: 15541637
Tryptophan catabolism in synovial fluid of various arthropathies and
its relationship with inflammatory cytokines.
Bertazzo A, Punzi L, Bertazzolo N, Pianon M, Pozzuoli A, Costa CV,
Allegri G.
Department of Pharmaceutical Sciences, University of Padova, Italy.
Bert...@dsfarm.unipd.it
Synovial fluids (SF) from patients with rheumatoid arthritis (RA),
psoriatic arthritis (PsA), gout, and osteoarthritis (OA) were
investigated for the levels of interleukin (IL)-1 beta, IL-6 and IL-8,
tryptophan (Trp) and indoleamine 2,3-dioxygenase (IDO) activity.
Significant differences exist in the levels of IL-1 beta between
inflammatory arthritides RA, PsA and gout and non inflammatory
arthritis, such as OA. The highest concentration of IL-1 beta was
found in RA, that showed high levels also of IL-6 and IL-8. In the
same disease we also found the highest IDO activity and the lowest Trp
concentration. In addition, IDO activity seems to be related with the
decrease in Trp, as demonstrated by the inverse correlation found
between these two substances in the SF of all patients.
PMID: 10721101
-------------
I read an article in Sciam last year this time. Feb/2008 Called Your
cells ARE MY Cells
by J. Lee Nelson:
http://myprofile.cos.com/nelsonab36
244 hits for Nelson on pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Nelson%20JL%22[Author]&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus
Yet, NO hits for "Nelson JL"[Author] + ido
Oh well could be a hole in her research?
Or my head? LOL
Lets see: try keywords: CTLA4Ig + microchimerism
----------
CTLA4Ig is critically required for the induction of chimerism and
tolerance in a murine model of nonmyeloablative BMT, IDO activity is
not. No significant differences were detectable in the kynurenine to
tryptophan ratios (indicative of IDO activity) in sera of BMT
recipients treated with CTLA4Ig (tolerant group) versus BMT recipients
treated without CTLA4Ig (nontolerant group) versus naïve controls. In
vivo inhibition of IDO immediately after BMT with CTLA4Ig or several
months thereafter did not block achievement of chimerism and
tolerance. Thus, IDO does not play a critical role in the induction or
maintenance of chimerism and tolerance in a CTLA4Ig-based BMT model.
PMID: 17353791
---------
CTLA4Ig: a novel inhibitor of costimulation.
Dall'Era M, Davis J.
Division of Rheumatology, University of California San Francisco, San
Francisco, USA.
T cell costimulatory pathways are believed to play important roles in
the pathogenesis of various autoimmune diseases including systemic
lupus erythematosus (SLE). Animal models of SLE support the role of T
cell costimulation in B cell activation and the production of
autoantibodies. CTLA4Ig is a novel fusion protein that interferes with
T cell costimulation by inhibiting the CD28-B7 interaction. A pivotal
study demonstrated the ability of CTLA4Ig to suppress the production
of anti-dsDNA antibodies and decrease nephritis in lupus prone mice.
In an additional study, the combination of CTLA4Ig and
cyclophosphamide significantly reduced proteinuria and prolonged
survival in mice with advanced nephritis. In small human studies of
psoriasis and rheumatoid arthritis, CTLA4Ig improved clinical outcomes
and was well tolerated. These promising experiences with CTLA4Ig have
paved the way for future studies in human SLE.
PMID: 15230295
Six hits: CTLA4Ig psoria*
The one above pmid: 15230295 is one of the six.
========================
How about a negative feed back loop or enzymes gone missing?
2007 Mar
CTLA4Ig promotes the induction of hematopoietic chimerism and
tolerance independently of Indoleamine-2,3-dioxygenase.
Pree I, Bigenzahn S, Fuchs D, Koporc Z, Nierlich P, Winkler C,
Brandacher G, Sykes M, Muehlbacher F, Langer F, Wekerle T.
Division of Transplantation, Department of Surgery, Vienna General
Hospital, Medical University of Vienna, Vienna, Austria.
Bone marrow transplantation (BMT) under costimulation blockade induces
mixed chimerism and tolerance in rodent models. Recent data,
predominantly from in vitro studies, suggest that in addition to
blocking the CD28 costimulation pathway CTLA4Ig also acts through
upregulating the tryptophan-catabolizing enzyme indoleamine-2,3-
dioxygenase (IDO). Here we demonstrate that even though CTLA4Ig is
critically required for the induction of chimerism and tolerance in a
murine model of nonmyeloablative BMT, IDO activity is not. No
significant differences were detectable in the kynurenine to
tryptophan ratios (indicative of IDO activity) in sera of BMT
recipients treated with CTLA4Ig (tolerant group) versus BMT recipients
treated without CTLA4Ig (nontolerant group) versus naïve controls. In
vivo inhibition of IDO immediately after BMT with CTLA4Ig or several
months thereafter did not block achievement of chimerism and
tolerance. Thus, IDO does not play a critical role in the induction or
maintenance of chimerism and tolerance in a CTLA4Ig-based BMT model.
PMID: 17353791
---------------
http://en.wikipedia.org/wiki/Chimera_(genetics)
http://en.wikipedia.org/wiki/Microchimerism
-----------
CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to
promote tolerance.
Kurtz J, Raval F, Vallot C, Der J, Sykes M.
Bone Marrow Transplantation Section, Transplantation Biology Research
Center, Massachusetts General Hospital/Harvard Medical School, Boston,
MA, United States.
While the inhibitory receptor CTLA-4 (CD152) has been implicated in
peripheral CD4 T cell tolerance, its mechanism of action remains
poorly defined. We analyzed mechanisms of CD4 cell tolerance in a
model of tolerance induction involving establishment of mixed
hematopoietic chimerism in recipients of fully MHC-mismatched
allogeneic bone marrow cells with anti-CD154 mAb. Animals lacking CD80
and CD86 failed to achieve chimerism. We detected no T cell-intrinsic
requirement for CD28 for chimerism induction. However, a CD4 T cell-
intrinsic signal through CTLA-4 was shown to be essential within the
first 48 hours of exposure to alloantigen for the establishment of
tolerance and mixed chimerism. This signal must be provided by a
recipient CD80/86(+) non-T cell population. Donor CD80/86 expression
was insufficient to achieve tolerance. Together, our findings
demonstrate a surprising role for interactions of CTLA-4 expressed by
alloreactive peripheral CD4 T cells with CD80/86 on recipient APC in
the induction of early tolerance, suggesting a 3-cell tolerance model
involving directly alloreactive CD4 cells, donor antigen-expressing
bone marrow cells and recipient antigen-presenting cells. This
tolerance is independent of regulatory T cells and culminates in the
deletion of directly alloreactive CD4 T cells.
PMID: 19179471
===============
IDO and lPS with inflammation
Peripheral lipopolysaccharide (LPS) challenge promotes microglial
hyperactivity in aged mice that is associated with exaggerated
induction of both pro-inflammatory IL-1beta and anti-inflammatory
IL-10 cytokines.
Henry CJ, Huang Y, Wynne AM, Godbout JP.
Department of Molecular Virology, Immunology and Medical Genetics, The
Ohio State University, Room 2166B Graves Hall, 333 W. 10th Avenue,
Columbus, OH 43210, USA.
In the elderly, systemic infection is associated with an increased
frequency of behavioral and cognitive complications. We have reported
that peripheral stimulation of the innate immune system with
lipopolysaccharide (LPS) causes an exaggerated neuroinflammatory
response and prolonged sickness/depressive-like behaviors in aged BALB/
c mice. Therefore, the purpose of this study was to determine the
degree to which LPS-induced neuroinflammation was associated with
microglia-specific induction of neuroinflammatory mediators. Here, we
show that peripheral LPS challenge caused a hyperactive microglial
response in the aged brain associated with higher induction of
inflammatory IL-1beta and anti-inflammatory IL-10. LPS injection
caused a marked induction of mRNA expression of both IL-1beta and
IL-10 in the cortex of aged mice compared to adults. In the next set
of studies, microglia (CD11b(+)/CD45(low)) were isolated from the
brain of adult and aged mice following experimental treatments. An age-
dependent increase in major histocompatibility complex (MHC) class II
mRNA and protein expression was detected in microglia. Moreover,
peripheral LPS injection caused a more pronounced increase in
IL-1beta, IL-10, Toll-like receptor (TLR)-2, and indoleamine 2,3-
dioxygenase (IDO) mRNA levels in microglia isolated from aged mice
than adults. Intracellular cytokine protein detection confirmed that
peripheral LPS caused the highest increase in IL-1beta and IL-10
levels in microglia of aged mice. Finally, the most prominent
induction of IL-1beta was detected in MHC II(+) microglia from aged
mice. Taken together, these findings provide novel evidence that age-
associated priming of microglia plays a central role in exaggerated
neuroinflammation induced by activation of the peripheral innate
immune system.
PMID: 18814846
---------------
Dendritic cells modulated by innate immunity improve collagen-induced
arthritis and induce regulatory T cells in vivo.
Jaen O, Rullé S, Bessis N, Zago A, Boissier MC, Falgarone G.
INSERM ERI18, Paris 13 University, AP-HP Rheumatology Department,
Avicenne Hospital, Bobigny, France.
Dendritic cells (DCs) mediate interactions between innate and specific
immunity and may induce regulatory mechanisms. We investigated the
effects of modulated DCs in mice with collagen-induced arthritis (CIA)
and tested the responses of cells to induced naturally occurring
regulatory T cells. DCs were stimulated or not with DNA or
lipopolysaccharide (LPS) for 24 hr. DC maturation was assayed, and
then modulated DCs were intraperitoneally injected on day 14 into DBA/
1 mice to treat CIA. In addition to arthritis scores and type 2
collagen (CII) response, the induction of CD4(+) CD25(+) T cells was
analysed by flow cytometry in peripheral blood and the expression of
Foxp3, transforming growth factor (TGF)-beta, interleukin (IL)-10 and
cytotoxic T-lymphocyte antigen (CTLA)-4 was quantified. Finally, the
expression of indoleamine-2,3-dioxygenase (IDO) was assayed in DCs. In
comparison with LPS-stimulated DCs, plasmid-stimulated DCs expressed
lower levels of major histocompatibility complex (MHC) class II, CD40,
CD80 and CD86 molecules and secreted less IL-12p70, interferon (IFN)-
gamma, IL-10 and TNF-alpha, displaying a semi-mature phenotype.
Compared with non-stimulated DCs, stimulated DCs improved arthritis
scores when injected after immunization, without modifying the T
helper type 1 (Th1)/Th2 balance of the immune response against
collagen. Stimulated DCs induced markers for regulatory T cells
(Foxp3, TGF-beta1 and CTLA-4) in vivo. Only LPS-stimulated DCs
expressed IDO, which may explain their better therapeutic efficacy.
Regulatory mechanisms were induced using DCs modulated by innate
immunity stimulators. Innate immunity mechanisms do not require the
presence of the disease-causing antigen, even in T- and B-cell
specific diseases. Our results have implications for the treatment of
rheumatoid arthritis, an autoimmune disease whose triggering antigen
has not been identified, and substantially clarify the role of
regulatory T cells in CIA.
PMID: 18754812
------------
IFN a major P pathway & IDO:
Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase
in rat brain following a systemic inflammatory challenge: a role for
IFN-gamma?
Connor TJ, Starr N, O'Sullivan JB, Harkin A.
Neuroimmunology Research Group, Department of Physiology, School of
Medicine & Trinity College Institute of Neuroscience, Trinity College,
Dublin 2, Ireland. con...@tcd.ie <con...@tcd.ie>
Inflammation-mediated dysregulation of the kynurenine pathway has been
implicated as a contributor to a number of major brain disorders.
Consequently, we examined the impact of a systemic inflammatory
challenge on kynurenine pathway enzyme expression in rat brain.
Indoleamine 2,3-dioxygenase (IDO) expression was induced in cortex and
hippocampus following systemic lipopolysaccharide (LPS)
administration. Whilst IDO expression was paralleled by increased
circulating interferon (IFN)-gamma concentrations, IFN-gamma
expression in the brain was only modestly altered following LPS
administration. In contrast, induction of IDO was associated with
increased central tumour necrosis factor (TNF)-alpha and interleukin
(IL)-6 expression. Similarly, in cultured glial cells LPS-induced IDO
expression was accompanied by increased TNF-alpha and IL-6 expression,
whereas IFN-gamma was not detectable. These findings indicate that IFN-
gamma is not required for LPS-induced IDO expression in brain. A
robust increase in kynurenine-3-monooxygenase (KMO) expression was
observed in rat brain 24h post LPS, without any change in kynurenine
aminotransferase II (KAT II) expression. In addition, we report that
constitutive expression of KAT II is approximately 8-fold higher than
KMO in cortex and 20-fold higher in hippocampus. Similarly, in glial
cells constitutive expression of KAT II was approximately 16-fold
higher than KMO, and expression of KMO but not KAT II was induced by
LPS. These data are the first to demonstrate that a systemic
inflammatory challenge stimulates KMO expression in brain; a situation
that is likely to favour kynurenine metabolism in a neurotoxic
direction. However, our observation that expression of KAT II is much
higher than KMO in rat brain is likely to counteract potential
neurotoxicity that could arise from KMO induction following an acute
inflammation.
PMID: 18584961
=================================
randall... how come these things... never mind.