Th22 (IL-22) -- APOE Gene & P -- Forskolin Inducts PXR
randall
A NEW T Helper Cell called Th22?
OK.
I guess if Th17 doesn't explain everything then we bring in another
one?
First we found out that autoimmune conditions like psoriasis (low
IL-10) was a Th1 skew
and that conditions like hiv/aids and cancer was a Th2 skew (high
IL-10).
So iL-10 is rather pivotal:
http://en.wikipedia.org/wiki/Interleukin_10
[...]
It down-regulates the expression of Th1 cytokines, MHC class II
antigens, and costimulatory molecules on macrophages.
<sniP>
So let's get familiar with Th22 now.
http://insciences.org/article.php?article_id=7596
Scientists discover cells that control inflammation in chronic
disease
Published on 17 November 2009, 02:50 Last Update: 34 minute(s) ago by
Insciences
Tags: Asthma Chronic diseases IL-22 Immunity Inflammation Inflammatory
diseases Psoriasis Skin Th22 cells
A new type of immune cell that can be out of control in certain
chronic inflammatory diseases, worsening the symptoms of conditions
like psoriasis and asthma, is described for the first time this week
in the Journal of Clinical Investigation.
The authors of the study, from Imperial College London, the Istituto
Dermopatico dell'Immacolata in Rome and the Center of Allergy and
Environment (ZAUM) in Munich, hope their discovery could lead to new
treatments for these diseases that would bring the cells under
control.
The new cell described in the study, called a Th22 cell, is a kind of
T-helper cell. These cells are white blood cells that help to activate
other immune cells when the body is infected by a pathogen, such as a
virus or bacterium. They also control inflammation in the body to help
fight off infection.
According to the new study, Th22 cells play a special role in
overseeing and coordinating immune cells that cause inflammation. In
chronic and allergic inflammatory diseases like psoriasis and allergic
eczema, Th22 cells appear to be malfunctioning, leading to excessive
inflammation, which can worsen symptoms.
The researchers hope that it may ultimately be possible to treat
chronic skin and possibly also airway diseases by targeting Th22 cells
with new drugs.
Dr Carsten Schmidt-Weber, one of the lead authors of the study from
the National Heart and Lung Institute at Imperial College London,
said: "We are seeing an increase in chronic diseases like skin and
airway disease because of changes in people's lifestyles. These
diseases can have a big impact on people's lives and patients can face
a constant battle to keep their symptoms at bay. We are very excited
about discovering this new subset of T-helper cells, as we believe it
could provide a new target for the treatment of chronic inflammatory
diseases in the future."
The researchers discovered Th22 cells by looking at skin samples from
people with psoriasis, atopic eczema and allergic contact dermatitis.
They analysed the samples and found a completely new type of cell. The
researchers examined the molecules the cells made and found that one
of them was a signalling molecule called interleukin-22 (IL-22). This
signalling molecule warns tissues that inflammation or infection is
going to occur, so the tissues can get ready to recognise and attack
pathogens or protect themselves against inflammation. The effect of
this can be either protective or detrimental - for example, IL-22
molecules and Th22 cells can cause skin cells to grow too quickly,
resulting in painful, flaking skin.
The authors of the new study hope that their new discovery will
provide scientists developing treatments for inflammatory disorders
with a new cellular drug target. The researchers are now investigating
the role of these cells in greater detail and exploring their role in
disease progression. In addition, Dr Schmidt-Weber and his colleagues
want to know how the cells are generated in the body and whether there
is any way to control these cells before they cause unwanted damage.
---------------
http://en.wikipedia.org/wiki/Interleukin_22
Interleukin-22 (IL-22) is protein that in humans is encoded by the
IL22 gene.[2][3]
IL-22 a member of a group of cytokines called the IL-10 family or
IL-10 superfamily (including IL-19, IL-20, IL-24, and IL-26),[4] a
class of potent mediators of cellular inflammatory responses. It
shares us of IL-10R2 in cell signaling with other members of this
family, IL-10, IL-26, IL-28, (?and IL-29?). IL-22 is produced by
activated DC and T cells and initiates innate immune responses against
bacterial pathogens especially in epithelial cells such as respiratory
and gut epithelial cells. IL-22 along with IL-17 is rapidly produced
by splenic LTi-like cells [5] and can be also produced by Th17 cells
and likely plays a role in the coordinated response of both adaptive
and innate immune systems.
IL-22 biological activity is initiated by binding to a cell-surface
complex composed of IL-22R1 and IL-10R2 receptor chains and further
regulated by interactions with a soluble binding protein, IL-22BP,
which shares sequence similarity with an extracellular region of
IL-22R1 (sIL-22R1). IL-22 and IL-10 receptor chains play a role in
cellular targeting and signal transduction to selectively initiate and
regulate immune responses.[1] IL-22 can contribute to immune disease
through the stimulation of inflammatory responses, S100s and
defensins. IL-22 also promotes hepatocyte survival in the liver and
epithelial cells in the lung and gut similar to IL-10.[6]
Signaling
IL-22, signals through the interferon receptor-related proteins CRF2-4
and IL-22R.[3] It forms cell surface complexes with IL-22R1 and
IL-10R2 chains resulting in signal transduction through receptor,
IL-10R2. The IL-22/IL-22R1/IL-10R2 complex activates intracellular
kinases (JAK1, Tyk2, and MAP kinases) and transcription factors,
especially STAT3. It can induce IL-20 and IL-24 signaling when IL-22R1
pairs with IL-20R2.
<sniP>
The pubmed abstract isn't available yet.
So we'll use this instead till a pmid # can be added.
http://www.jci.org/articles/view/40202
Th22 cells represent a distinct human T cell subset involved in
epidermal immunity and remodeling
Stefanie Eyerich1, Kilian Eyerich2, Davide Pennino2, Teresa Carbone2,
Francesca Nasorri2, Sabatino Pallotta3, Francesca Cianfarani4, Teresa
Odorisio4, Claudia Traidl-Hoffmann5, Heidrun Behrendt5, Stephen R.
Durham6, Carsten B. Schmidt-Weber1 and Andrea Cavani2
Th subsets are defined according to their production of lineage-
indicating cytokines and functions. In this study, we have identified
a subset of human Th cells that infiltrates the epidermis in
individuals with inflammatory skin disorders and is characterized by
the secretion of IL-22 and TNF-α, but not IFN-γ, IL-4, or IL-17. In
analogy to the Th17 subset, cells with this cytokine profile have been
named the Th22 subset. Th22 clones derived from patients with
psoriasis were stable in culture and exhibited a transcriptome profile
clearly separate from those of Th1, Th2, and Th17 cells; it included
genes encoding proteins involved in tissue remodeling, such as FGFs,
and chemokines involved in angiogenesis and fibrosis. Primary human
keratinocytes exposed to Th22 supernatants expressed a transcriptome
response profile that included genes involved in innate immune
pathways and the induction and modulation of adaptive immunity. These
proinflammatory Th22 responses were synergistically dependent on IL-22
and TNF-α. Furthermore, Th22 supernatants enhanced wound healing in an
in vitro injury model, which was exclusively dependent on IL-22. In
conclusion, the human Th22 subset may represent a separate T cell
subset with a distinct identity with respect to gene expression and
function, present within the epidermal layer in inflammatory skin
diseases. Future strategies directed against the Th22 subset may be of
value in chronic inflammatory skin disorders.
<sniP>
-----
50 hits for : IL-22 + psoria*
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=psoria*+AND+IL-22&log$=activity
========================
Ok, let's move on. We've got around 20 new abstracts the last few
days.
But only one that interested me. :)
www.ncbi.nlm.nih.gov/pubmed/19911187
Apolipoprotein epsilon4 allele is associated with psoriasis severity.
Coto-Segura P, Coto E, Alvarez V, Morales B, Soto-Sánchez J, Corao AI,
Santos-Juanes J.
Dermatology II Department, Hospital Universitario Central de Asturias
(HUCA), Celestino Villamil s/n, 33006, Oviedo, Spain.
Many reports provided strong evidence of the influence of genetic
factors in the pathogenesis of psoriasis (Ps). A higher prevalence of
lipid disorders in psoriatic patients has been reported. Because
apolipoprotein E (apoE) is involved in lipid metabolism, APOE gene
variants could be candidates to influence Ps-risk. However, data about
the potential influence of the APOE genotypes in Ps are inconclusive.
Our objective was to investigate the relationship between the common
APOE-epsilon2/epsilon3/epsilon4 variation and Ps in a Caucasian
population. Our study involved 331 unrelated Ps-patients and 400
healthy controls. Patients and controls were genotyped for the APOE-
epsilon2/epsilon3/epsilon4 polymorphism, and allele and genotype
frequencies were statistically compared between the two groups and
between patients according to disease severity. Mean lipid values were
also compared between the APOE genotypes. Allele and genotype
frequencies did not differ between patients and controls. APOE-
epsilon4 carriers were significantly more frequent in patients with
severe Ps compared to controls (P = 0.003) and to non-severe Ps (P =
0.017). No significant difference in mean lipid values was found
between the APOE genotypes. The APOE-epsilon4 allele could be a risk
factor for developing a severe form of psoriasis.
PMID: 19911187
---
APOE and Psor:
http://en.wikipedia.org/wiki/Apolipoprotein_E
[...]
[edit] Function
APOE[2] is essential for the normal catabolism of triglyceride-rich
lipoprotein constituents. APOE was initially recognized for its
importance in lipoprotein metabolism and cardiovascular disease. More
recently, it has been studied for its role in several biological
processes not directly related to lipoprotein transport, including
Alzheimer's disease (AD), immunoregulation, and cognition.
[...]
http://en.wikipedia.org/wiki/Apolipoprotein_E#Alzheimer.27s_Disease
From medscape:
APOE Gene on Chromosome 19q13.2
The APOE gene is a genetic locus for inherited susceptibility to late-
onset AD (>65 years) that was confirmed in multiple studies.[12] It
encodes a lipoprotein involved in cholesterol metabolism and has three
common alleles: epsilon 4 (AD-associated), epsilon 3 (neutral), and
epsilon 2 (AD-protective). The frequency of the epsilon 2 allele is
reduced in AD subjects (~2% versus ~10% in the general population),
whereas the frequency of the epsilon 4 allele is significantly
increased in individuals with AD (up to 40%). In addition, the epsilon
4 allele is associated with a decreased age at onset: from 90 years
for the non-epsilon 4 carriers to ~70 years in patients homozygous for
the epsilon 4 allele.[12]
Nevertheless, genetic testing based on the APOE epsilon 4 allele is
ambiguous when used as the sole criterion to diagnose AD since not all
epsilon 4 carriers will develop disease and epsilon 4 association is
not entirely specific to AD.[13] However, in the future, APOE
genotypes could be useful in combination with other clinical measures
or genetic variations. Indeed, in at least half of AD cases there is
no known cause of the disease, suggesting the existence of additional
environmental and genetic factors responsible for late-onset AD.
<sniP>
----
Let's go deePer as I know OLD psoriatics with AD.
http://www.sciencedaily.com/releases/2009/11/091106112119.htm
New Mechanism Increases Atherosclerosis In Mice
ScienceDaily (Nov. 9, 2009) — A shot of espresso may rev you up in the
morning, but the downside is that it may also ramp up levels of bad
cholesterol due to its effects on a unique liver protein called PXR.
New research from Rockefeller University now shows that when
chronically activated, the protein rejiggers how cholesterol is broken
down in and cleared from the liver, a disturbance that can lead to
high levels of the waxy substance or worse, full-blown
atherosclerosis.
"It's the first time that PXR has been shown to have a direct impact
on balancing cholesterol levels in the body," says first author
Changcheng Zhou, a research associate in Jan L. Breslow's Laboratory
of Biochemical Genetics and Metabolism at Rockefeller.
Unlike other receptor proteins, which can recognize only one or a few
chemicals, PXR -- short for pregnane x receptor -- can recognize more
than a hundred, including cafestrol, present in unfiltered brewed
coffee, and many prescription medications. The research, led by
Breslow, may have direct clinical consequences for patients taking
drugs such as the antibiotic rifampicin for tuberculosis treatment,
the antiretroviral drug ritonavir for HIV treatment and the
antiepileptic drugs carbamazipine and phenobarbital, all of which
activate PXR.
"At the time these drugs were being developed -- the antivirals, the
antibiotics, anti-cancers and even herbal supplements like St. John's
Wort -- their interactions with PXR weren't known," explains Zhou.
"Now patients under long-term treatment with PXR-activating drugs can
be more informed about these drugs' effects."
When activated, PXR, which resides in the nucleus of liver cells in
all animals, including humans, latches on to strips of DNA and turns
on genes that regulate how chemicals or drugs are metabolized and
cleared from the liver. Many drugs that can activate PXR have been
shown to increase cholesterol levels in patients, and too much of the
stuff in the bloodstream is a well-established risk factor for
cardiovascular disease, the nation's biggest killer. However, it was
not clear whether PXR could jumpstart this process.
In their work, Zhou and Breslow introduced a mouse-specific PXR
activator called PCN into the diets of normal mice for two weeks and
found that while their levels of good cholesterol, or HDL, were not
affected, their levels of bad cholesterol skyrocketed six-fold.
Another group of mice that were fed PCN for eight weeks and were
genetically engineered to lack the protein ApoE experienced the
flipside: Their good cholesterol plummeted and they also went on to
develop full-blown atherosclerosis.
Several gene targets of PXR were the same for both normal mice and
those lacking the ApoE protein, including a cholesterol metabolism
enzyme called CYP39A1 and a transportation protein called Apo-IV. A
gene called CD36 was another target specifically associated with the
uptake of modified bad cholesterol by certain cells, which contribute
to the accumulation of artery-clogging fat.
To Zhou, this research is only the beginning. "Many chemicals exposed
in the air are also PXR activators," says Zhou. "So what we have in
our hands now may not only be a heart health issue but also a public
health one."
<sniP>
------
Only four hits in our grouP for : pregnane X receptor
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=+pregnane+x+receptor&qt_g=Search+this+group
If you do a PXR search you'll get a few more i'd bet.
---------------
http://en.wikipedia.org/wiki/Pregnane_X_receptor
In the field of molecular biology, the pregnane X receptor (PXR), also
known as NR1I2 (nuclear receptor subfamily 1, group I, member 2), is a
nuclear receptor whose primary function is to sense the presence of
foreign toxic substances and in response up regulate the expression of
proteins involved in the detoxification and clearance of these
substance from the body.[1]
PXR is encoded by the NR1I2 gene.[2][3][4][5] The product of this gene
belongs to the nuclear receptor superfamily, members of which are
transcription factors characterized by a ligand-binding domain and a
DNA-binding domain. The encoded protein is a transcriptional regulator
of the cytochrome P450 gene CYP3A4, binding to the response element of
the CYP3A4 promoter as a heterodimer with the 9-cis retinoic acid
receptor RXR. It is activated by a range of compounds that induce
CYP3A4, including dexamethasone and rifampicin. Several alternatively
spliced transcripts encoding different isoforms, some of which use non-
AUG (CUG) translation initiation codon, have been described for this
gene. Additional transcript variants exist, however, they have not
been fully characterized.[6][5]
[...]
Function
Like other type II nuclear receptors, when activated, it forms a
heterodimer with the retinoid X receptor, and binds to hormone
response elements on DNA which elicits expression of gene products.[1]
One of the primary targets of PXR activation is the induction of
CYP3A4, an important phase I oxidative enzyme that is responsible for
the metabolism of many drugs.[4][5] In addition, PXR up regulates the
expression of phase II conjugating enzymes such as glutathione S-
transferase[7] and phase III transport uptake and efflux proteins such
as OATP2 (SLCO2A1)[8] and MDR1 (ABCB1).[9][10]
<sniP>
-----------
We come back to glutathione again and again. LOL
http://en.wikipedia.org/wiki/Glutathione_S-transferase
--------
When you have chronic inflammation you run short of glutathione.
Thereby you need more NAC to make extra.
http://en.wikipedia.org/wiki/Acetylcysteine
Believe me. I can clear a nice percentage with NAC as a stand
alone. :)
Another herbal supplement i've used is Forskolin which also
worked well.
Here's a pdf:
Induction of Drug Metabolism by Forskolin
http://jpet.aspetjournals.org/content/312/2/849.full.pdf
Further forskolin research:
http://www.google.com/search?hl=en&q=pregnane+receptor+PXR+forskolin&aq=f&oq=&aqi=
68 psoriasis group hits for Forskolin:
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=forskolin
62 for my trials with it:
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=forskolin+randall
http://groups.google.com/groups/search?hl=en&ie=UTF-8&q=psoriasis+forskolin+randall&sitesearch=
====================
randall...