Is FAT really a Trigger? LPS ReDux -- IL-32
randall
This is for JR and Susan.
I started on it yesterday. So I won't take out what J already posted.
Is YOUR PSOR immune system ANGRY at YOU?
Sounds like a plausible theory considering the emotional high's and
low's of psor ville.
But we know your emotions and a dozen other things trigger psoriasis.
So
why doesn't everyone get flaky skin then?
This NEXT GUY is kicking some PSOR FAT and chewing it at the same
time.
http://endocrinology.ucsd.edu/Faculty/olefsky.html
Will Dr. Jerrold Olefsky chew the LPS right outa that FAT?
His most recent study of 430 studies, right here and right NOW.
WOW......
www.ncbi.nlm.nih.gov/pubmed/19883619
Hematopoietic Cell-Specific Deletion of Toll-like Receptor 4
Ameliorates Hepatic and Adipose Tissue Insulin Resistance in High-Fat-
Fed Mice.
Saberi M, Woods NB, de Luca C, Schenk S, Lu JC, Bandyopadhyay G, Verma
IM, Olefsky JM.
Department of Medicine, Division of Endocrinology and Metabolism,
University of California, San Diego, La Jolla, CA 92093, USA.
Chronic low-grade inflammation, particularly in adipose tissue, is an
important modulator of obesity-induced insulin resistance. The Toll-
like receptor 4 (Tlr4) is a key initiator of inflammatory responses in
macrophages. We performed bone marrow transplantation (BMT) of Tlr4lps-
del or control C57Bl/10J donor cells into irradiated wild-type C57Bl6
recipient mice to generate hematopoietic cell-specific Tlr4 deletion
mutant (BMT-Tlr4(-/-)) and control (BMT-WT) mice. After 16 weeks of a
high-fat diet (HFD), BMT-WT mice developed obesity, hyperinsulinemia,
glucose intolerance, and insulin resistance. In contrast, BMT-Tlr4
(-/-) mice became obese but did not develop fasting hyperinsulinemia
and had improved hepatic and adipose insulin sensitivity during
euglycemic clamp studies, compared to HFD BMT-WT controls. HFD BMT-Tlr4
(-/-) mice also showed markedly reduced adipose tissue inflammatory
markers and macrophage content. In summary, our results indicate that
Tlr4 signaling in hematopoietic-derived cells is important for the
development of hepatic and adipose tissue insulin resistance in obese
mice.
PMID: 19883619
http://en.wikipedia.org/wiki/Haematopoietic_stem_cell
http://en.wikipedia.org/wiki/Haematopoiesis
http://en.wikipedia.org/wiki/TLR4
http://en.wikipedia.org/wiki/Lipopolysaccharide
http://en.wikipedia.org/wiki/Endotoxin
http://en.wikipedia.org/wiki/Lymphocyte_antigen_96
Symbols LY96; MD-2
----
md-2 (look at the jpg in the LPS wiki link above)
http://www.ncbi.nlm.nih.gov/pubmed/10359581
MD-2, a molecule that confers lipopolysaccharide responsiveness on
Toll-like receptor 4.
Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M.
Department of Immunology, Saga Medical School, Saga, Japan.
Toll-like receptor 4 (TLR4) is a mammalian homologue of Drosophila
Toll, a leucine-rich repeat molecule that can trigger innate responses
against pathogens. The TLR4 gene has recently been shown to be mutated
in C3H/HeJ and C57BL/10ScCr mice, both of which are low responders to
lipopolysaccharide (LPS). TLR4 may be a long-sought receptor for LPS.
However, transfection of TLR4 does not confer LPS responsiveness on a
recipient cell line, suggesting a requirement for an additional
molecule. Here, we report that a novel molecule, MD-2, is requisite
for LPS signaling of TLR4. MD-2 is physically associated with TLR4 on
the cell surface and confers responsiveness to LPS. MD-2 is thus a
link between TLR4 and LPS signaling. Identification of this new
receptor complex has potential implications for understanding host
defense, as well as pathophysiologic, mechanisms.
PMID: 10359581 [PubMed - indexed for MEDLINE]
----
So the psor brew isn't complete without MD-2?
And drinking brew 102 will make your psor so much sorer. :(
I know. It's like reading the SFB abstract and putting the facts
together to come
to a contusion. LOL
And you know how my conclusions bruise your brain cells JR? <G>
----------
But,
OK, so will a TLR4 antagonist help psoriatics?
Off the top of my psor head, i'd say YES.
READ how Olefsky put two and two together to subtract TLR4's from LPS?
And what does LPS have to do with this immunity equation for folks on
AUTO?
EASY, by slowing TLR4, then LPS isn't going to cause the Th1 skew.
STILL, i'd rather slow it from gut translocation with sweet whey. :)
I'm so sweet. :) LOL
I'll even repost the article that J posted to go with the above
abstract ::
Isn't it odd how they hardly resemble each other? LOL
Maybe tomorrow i'll look at the hpa-axis and stress in relationship to
it?
nah...
http://www.eurekalert.org/pub_releases/2009-11/cp-hsf102809.php
How saturated fatty acids 'anger' the immune system (and how to stop
them)
Researchers have new evidence to explain how saturated fatty acids,
which soar in those who are obese, can lead the immune system to
respond in ways that add up to chronic, low-grade inflammation. The
new results could lead to treatments designed to curb that
inflammatory state, and the insulin resistance and type 2 diabetes
that come with it.
One key, according to the report in the November Cell Metabolism, a
Cell Press publication, is an immune receptor (called Toll-like
receptor 4 or Tlr4) at the surface of blood cells, including a
particularly "angry" class of macrophages known to pump out toxic
molecules and spur inflammation. It now appears that fatty acids may
in essence "hijack" those immune cells via Tlr4.
"Tlr4 is out there to sense bacterial products, but one of those looks
a lot like fatty acids," said the study's senior author Jerrold
Olefsky of the University of California, San Diego. "They don't know
it's not bacteria."
That bacterial product is something called lipopolysaccharide (LPS)
found in bacterial membranes. Olefsky notes, however, that they have
not yet fully demonstrated that fatty acids bind Tlr4 directly.
Scientists had suspected that Tlrs might be the "sensors" linking
obesity to inflammation. Indeed, earlier studies had supported that
notion. In the new study, the researchers show that this interaction
is particularly important in the bloodstream. Mice lacking Tlr4 only
in blood cells grew obese when they were fed a high-fat diet, but they
were largely spared the metabolic consequences of their obesity. The
mice were fat, but metabolically they continued to "look pretty
normal," Olefsky said.
The researchers showed in another Cell Metabolism report last year
that a "genetic trick" designed to kill off the offending macrophages,
which are distinguished by a CD11c marker, could reverse insulin
resistance in obese mice. The method used by the team wasn't one that
they could consider translating into the clinic, however (http://
www.eurekalert.org/pub_releases/2008-10/cp-ki093008.php).
The new findings suggest one that could. "A Tlr4 antagonist – now
that's a therapeutic," Olefsky said. "The jury is still out, but it
sure makes sense they could be a new class of insulin sensitizers."
They say that drugs aimed at Tlr4 have already been developed, and the
idea that those drugs may hold promise in fighting insulin resistance
and type 2 diabetes is one Olefsky's team is now exploring in detail
in the mice.
###
The researchers include Maziyar Saberi, University of California, San
Diego, La Jolla, CA; Niels-Bjarne Woods, The Salk Institute for
Biological Studies, La Jolla, CA; Carl de Luca, University of
California, San Diego, La Jolla, CA; Simon Schenk, University of
California, San Diego, La Jolla, CA; Juu Chin Lu, University of
California, San Diego, La Jolla, CA; Gautam Bandyopadhyay, University
of California, San Diego, La Jolla, CA; Inder M. Verma, The Salk
Institute for Biological Studies, La Jolla, CA; and Jerrold M.
Olefsky, University of California, San Diego, La Jolla, CA.
==================================
These anti TLR4 drugs could pay a FAT dividend for LARD Butts and psor
HEADs???? LOL
But why hasn't someone reported on it already?
Is this CRX-526 drug running around out there?
www.ncbi.nlm.nih.gov/pubmed/15879143
A synthetic TLR4 antagonist has anti-inflammatory effects in two
murine models of inflammatory bowel disease.
Fort MM, Mozaffarian A, Stöver AG, Correia Jda S, Johnson DA, Crane
RT, Ulevitch RJ, Persing DH, Bielefeldt-Ohmann H, Probst P, Jeffery E,
Fling SP, Hershberg RM.
Corixa Corporation, Seattle, WA 98101, USA.
Current evidence indicates that the chronic inflammation observed in
the intestines of patients with inflammatory bowel disease is due to
an aberrant immune response to enteric flora. We have developed a
lipid A-mimetic, CRX-526, which has antagonistic activity for TLR4 and
can block the interaction of LPS with the immune system. CRX-526 can
prevent the expression of proinflammatory genes stimulated by LPS in
vitro. This antagonist activity of CRX-526 is directly related to its
structure, particularly secondary fatty acyl chain length. In vivo,
CRX-526 treatment blocks the ability of LPS to induce TNF-alpha
release. Importantly, treatment with CRX-526 inhibits the development
of moderate-to-severe disease in two mouse models of colonic
inflammation: the dextran sodium sulfate model and multidrug
resistance gene 1a-deficient mice. By blocking the interaction between
enteric bacteria and the innate immune system, CRX-526 may be an
effective therapeutic molecule for inflammatory bowel disease.
PMID: 15879143
AT the very least, if this drug does nothing for psoriasis, we can
spend a lot more time looking at SFB (segmented filamentous bacterium)
for
PSOR cure clues.
Wouldn't SFB prove that Th17 is due to sFB and the Th1 skew isn't a
FACTOR?
Or ASS BIG a factor? <w>
I'd think so.
I'll run a trial and not let any of you know. LOL
Kiddding but will you get it anyway? <G>
Let's see what i can find for crx-526.
CRX-526 is a synthetic lipid A mimetic molecule, also known as an
aminoalkyl-glucosaminide-phosphate (AGP)
Wow... seems that there is a crx-527 and it's the agonist and not
atagonist.
www.ncbi.nlm.nih.gov/pubmed/18835160
The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class
of lipid A mimetics.
Bazin HG, Murray TJ, Bowen WS, Mozaffarian A, Fling SP, Bess LS,
Livesay MT, Arnold JS, Johnson CL, Ryter KT, Cluff CW, Evans JT,
Johnson DA.
GlaxoSmithKline Biologicals, 553 Old Corvallis Road, Hamilton, MT
59840, USA.
To overcome the chemical and metabolic instability of the secondary
fatty acyl residues in the AGP class of lipid A mimetics, the
secondary ether lipid analogs of the potent TLR4 agonist CRX-527 (2)
and TLR4 antagonist CRX-526 (3) were synthesized and evaluated along
with their ester counterparts for agonist/antagonist activity in both
in vitro and in vivo models. Like CRX-527, the secondary ether lipid 4
showed potent agonist activity in both murine and human models. Ether
lipid 5, on the other hand, showed potent TLR4 antagonist activity
similar to CRX-526 in human cell assays, but did not display any
antagonist activity in murine models and, in fact, was weakly
agonistic. Glycolipids 2, 4, and 5 were synthesized via a new highly
convergent method utilizing a common advanced intermediate strategy. A
new method for preparing (R)-3-alkyloxytetradecanoic acids, a key
component of ether lipids 4 and 5, is also described.
PMID: 18835160
But what haPPens if we BLOCK all the TLR4?
Your colon dies? Your screwed BIG TIME?
Yikes...
But, but, why, why? (in my best Nancy Kerigan voice)
Look at this one.
www.ncbi.nlm.nih.gov/pubmed/19710105
Regulation of Toll-like receptor 4-associated MD-2 in intestinal
epithelial cells: a comprehensive analysis.
Vamadevan AS, Fukata M, Arnold ET, Thomas LS, Hsu D, Abreu MT.
University of Miami Miller.
The intestinal epithelium maintains a state of controlled inflammation
despite continuous contact with Gram-negative commensal bacteria and
lipopolysaccharide (LPS) on its luminal surface. Recognition of LPS by
the Toll-like receptor (TLR) 4/MD-2 complex results in pro-
inflammatory gene expression and cytokine secretion in intestinal
epithelial cells (IECs). We have shown that IECs express low levels of
MD-2 and TLR4 and are poorly responsive to LPS. In this study, we did
a comprehensive analysis to understand the immune-mediated and
epigenetic mechanisms by which IECs down-regulate MD-2 expression.
Expression of MD-2 and TLR4 mRNA was examined in human inflammatory
bowel disease and intestinal epithelial cell lines (T84, HT-29,
Caco-2). Nuclear factor-kappaB transcriptional activation was used as
a measure of LPS responsiveness. Intestinal epithelial cells in
patients with inflammatory bowel disease exhibited increased
expression of MD-2 and TLR4 mRNA. Lipopolysaccharide responsiveness in
IECs was polarized to the basolateral membrane. Bisulfite sequencing
of the MD-2 promoter demonstrated methylation of CpG dinucleotides.
Inhibition of methylation by 5-azacytidine and histone de-actylation
by trichostatin A, two forms of epigenetic silencing, resulted in
increased mRNA expression of MD-2 in IECs. These results demonstrate
various molecular mechanisms by which IECs down-regulate MD-2 and,
thereby, protect against dysregulated inflammation to commensal
bacteria in the intestinal lumen.
PMID: 19710105
----------
So while the crx agonist may by good for cancer folks, crx
looks like a temporary fix for autoimmune folks.
And my sweet whey looks whey bETTER.
To me anywhey as it works and is easy.
================================
======================================
IL32 as a marker of psoriasis?
Really?
YES...
http://en.wikipedia.org/wiki/Interleukin_32
Alt. symbols , NK4, TAIF, TAIFb, TAIFd
Interleukin 32 (IL-32) is a cytokine that can induce cells of the
immune system (such as monocytes and macrophages) to secrete tumor
necrosis factor-alpha (TNF-α) in addition to chemokines such as IL-8
and MIP-2/CXCL2.[1]
IL-32 can also support osteoclast differentiation but not osteoclast
activation by regulating the MAPK/ERK pathway and the actin
cytoskeleton. [2]
<sniP>
From 2006 NOV:
www.ncbi.nlm.nih.gov/pubmed/17038476
IL-32, a novel cytokine with a possible role in disease.
Dinarello CA, Kim SH.
University of Colorado, Health Science Center, 4200 East Ninth Avenue,
80262 Denver, CO, USA. cdina...@aol.com.
IL-32 is the name given to the NK4 transcript first reported in IL-2
activated T lymphocytes and natural killer cells 13 years ago without
known function. The novel cytokine has six isoforms. In an study to
isolate a soluble form of the IL-32 receptor from human urine,
IL-32alpha bound proteinase-3 with high affinity and was not affected
by enzyme inhibition. IL-32alpha/IL-32gamma were expressed as
recombinant molecules. The cytokine exhibits properties characteristic
of proinflammatory cytokines and also induces the degradation of
inhibitory kappaB and phosphorylation of mitogen activated protein
p38. Monoclonal antibodies to IL-32 identify its presence in a variety
of human tissues from diseases states. Epithelial cells from healthy
subjects express low levels of the cytokine, but in disease conditions
such as chronic obstructive pulmonary disease, Crohn's disease and
psoriasis, the expression increases markedly. IL-32 is a major
transcript in gene array studies in epithelial cells stimulated with
IFNgamma in vitro. In rheumatoid arthritis, synovial tissues reveals
increased content of IL-32, which correlates with severity of disease.
A highly significant correlation has been observed between the number
of synovial and macrophagic cells positive for IL-32 and the level of
erythrocytes sedimentation, IL-1beta, tumour necrosis factor alpha,
and IL-18. Thus, IL-32 exhibits many properties of proinflammatory
cytokines and associations with disease severity.
PMID: 17038476 [PubMed - indexed for MEDLINE]
Does IL-32 come from SFB?
I don't know...
Here's the most recent IL-32 and psoria* hit.
Oct 30 2009
www.ncbi.nlm.nih.gov/pubmed/19880327
Suppressing IL-32 in monocytes impairs the induction of the
proinflammatory cytokines TNFalpha and IL-1beta.
Hong J, Bae S, Kang Y, Yoon D, Bai X, Chan ED, Azam T, Dinarello CA,
Lee S, Her E, Rho G, Kim S.
Laboratory of Cytokine Immunology, Medical Immunology Center,
Institute of Biomedical Science and Technology, Konkuk University 1
Hwayang dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
Targeting major proinflammatory cytokines such as IL-1beta and
TNFalpha is of great interest in patients with chronic inflammatory
diseases, including rheumatoid arthritis, colitis, and psoriasis. The
cytokine Interleukin (IL)-32 induces proinflammatory cytokines such as
TNFalpha, IL-1beta, IL-6, and chemokines. We previously used an IL-32
ligand-affinity column to purify proteinase 3, which is abundantly
expressed in neutrophil and monocytic leukocytes but not in other cell
types, and found that IL-32 is mainly produced by monocytic
leukocytes. This evidence suggested that silencing endogenous IL-32 by
short hairpin RNA (shRNA) in monocytic cells might reveal the precise
function of endogenous IL-32. Indeed, lipopolysaccharide (LPS)- or
phorbol myristate acetate (PMA)-induced proinflammatory cytokine
production was significantly inhibited in shRNA/IL-32 stable clones as
compared to control clones. Furthermore, macrophages in PMA-
differentiated shRNA/IL-32 stable clones displayed remarkably impaired
LPS- and IL-1beta-induced proinflammatory cytokine production. These
data suggest that IL-32 is not only involved in host defense against
pathogens, but also might play a role in chronic inflammatory
diseases. IL-32 production leads to major proinflammatory cytokine
production during the initial immune response.
PMID: 19880327
Where does IL-32 come from? Certainly if it's a crohn's or IFB
condition with autoimmune gut conditions we should KNOW about it.
But you can't KNOW till some scientist finds it and names it...
Makes sense. WE didn't know about sFB till a few weeks ago.
Now we know and some folks don't want to know.
I'm pretty sure big Pharma doesn't want to know about SFB's.
Sort of KILLs their biologicals programs.
Why use a TNF blocker when a cure is right around the corner?
www.ncbi.nlm.nih.gov/pubmed/19828090
IL-32: a newly-discovered proinflammatory cytokine.
Felaco P, Castellani ML, De Lutiis MA, Felaco M, Pandolfi F, Salini V,
De Amicis D, Vecchiet J, Tete S, Ciampoli C, Conti F, Cerulli G,
Caraffa A, Antinolfi P, Cuccurullo C, Perrella A, Theoharides TC,
Conti P, Toniato E, Kempuraj D, Shaik YB.
Nephrology Division, Medical School, University of Chieti, Pescara,
Chieti, Italy.
IL-32, a newly-discovered proinflammatory cytokine that activates the
p38MAPK and NF-kappaB pathways, is an important player in innate and
adaptive immune response. IL-32, a cytokine produced mainly by T,
natural killer, and epithelial cells induces significant amounts of
TNFalpha and MIP-2 and increases the production of both cytokines in a
dose-dependent manner. IL-32 has been implicated in inflammatory
disorders, mycobacterium tuberculosis infections, inflammatory bowel
disease, and influenza A virus infection, as well as in some
autoimmune diseases, such as rheumatoid arthritis, ulcerative colitis
and Crohn?s disease and in human stomach cancer, human lung cancer and
breast cancer tissues. Moreover, it has been reported that IL-32 has
pro-inflammatory effects on myeloid cells and causes the
differentiation of osteoclast precursors into multinucleated cells
expressing specific osteoclast markers. We recently found that human
IL-32 has the capacity to provoke histamine release in human-derived
cord blood mast cells (HDCBMC), but not in LAD 2 cells nor in rat
peritoneal mast cells (RPMC), showing that IL-32 may be specie
specific and act more in mature human mast cells (HDCBMC) than in
transformed mast cells (LAD 2 cells). Certainly, IL-32 is another
potent proinflammatory cytokine, however, the specific role of this
newly-discovered protein in the network of cytokine biology remains to
be determined.
PMID: 19828090
And the next one has IL-10 implications.
www.ncbi.nlm.nih.gov/pubmed/19740314
A proinflammatory cytokine interleukin-32beta promotes the production
of an anti-inflammatory cytokine interleukin-10.
Kang JW, Choi SC, Cho MC, Kim HJ, Kim JH, Lim JS, Kim SH, Han JY, Yoon
DY.
Department of Bioscience and Biotechnology, Konkuk University, Seoul,
Korea.
A new proinflammatory cytokine interleukin-32 (IL-32) has six
isoforms. Although IL-32 can be detected in sera from patients
suffering from Crohn's disease and rheumatoid arthritis, it is unclear
which isoforms are involved. To this end, we investigated the
functions of the most abundant IL-32beta by generating K562-IL-32beta
stable cell lines. This report confirms, using IL-32 small interfering
RNA, that IL-32beta induces an anti-inflammatory cytokine IL-10 in
K562-IL-32beta cells and U937 promonocytic cells, which express
endogenous IL-32beta upon phorbol 12-myristate 13-acetate (PMA)
treatment, and monocyte-derived dendritic cells (DC) upon
lipopolysaccharide (LPS) treatment. Interleukin-32beta was induced in
monocyte-derived macrophages by LPS and in monocyte-derived DC by LPS,
poly(I:C), or anti-CD40 antibody, but was not induced by PMA. We
showed that IL-32beta expression was increased in a time-dependent
manner in monocyte-derived DC upon LPS treatment and peaked at 24 hr.
Production of IL-10 was exactly coincident with IL-32beta expression,
but IL-1beta and tumour necrosis factor-alpha production peaked at 6
hr after LPS treatment, then steeply declined. Interleukin-12 p40 was
induced at 9 hr and gradually increased until 48 hr, at which time
IL-32beta and IL-10 were no longer increased. Knock-down of IL-32beta
by IL-32 small interfering RNA led to the decrease of IL-10, but the
increase of IL-12 in monocyte-derived DC, which means that IL-32beta
promotes IL-10 production, but limits IL-12 production. We also showed
that IL-10 neutralization increases IL-12, IL-1beta and tumour
necrosis factor-alpha production, which implies that IL-10 suppresses
such proinflammatory cytokines. Taken together, our results suggest
that IL-32beta upregulates the production of an anti-inflammatory
cytokine IL-10, and then IL-10 suppresses proinflammatory cytokines.
PMID: 19740314 [PubMed - in process]
www.ncbi.nlm.nih.gov/pubmed/19364659
Molecular characterization of IL-32 in human endothelial cells.
Kobayashi H, Lin PC.
Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center,
Vanderbilt University Medical Center, 712 PRB, 2220 Pierce Ave.,
Nashville, TN 37232, USA.
IL-32 is a newly discovered protein found in human and certain
primates, but absent in rodent. Various reports suggest its role as a
proinflammatory mediator. Since vascular endothelium is critical in
inflammation, we investigate IL-32 in endothelial cells. We found that
the gene is expressed in human endothelial cells and Akt strongly
induces its expression. Sequence analysis indicates IL-32 beta as the
major isoform in endothelial cells. Surprisingly, we did not detect
any secretion of IL-32 beta in human endothelial cells; instead we
observed co-localization of IL-32 beta with endoplasmic reticulum,
suggesting IL-32 beta is an intracellular protein in these cells.
Promoter analysis identified a minimum required region for IL-32
transcription at -0.1 to +0.5 kb around the initially identified
transcription start site. We also defined a transcriptional suppressor-
binding site at -2.0 to -1.5 kb. Importantly, RNA ligase mediated
rapid amplification of cDNA ends in endothelial cells determined the
transcription start site at the 328 bp downstream from the original
identified site. Finally, we found a positive correlation of IL-32
levels with human breast cancer and glioblastoma multiforme (GBM).
These findings improve our understanding of IL-32 in vascular
endothelium. IL-32 expression might be valuable as a biomarker for
cancer.
PMID: 19364659
IL17 with RA and IL32
www.ncbi.nlm.nih.gov/pubmed/19234208
www.ncbi.nlm.nih.gov/pubmed/18291623
INcreased IL-32 with Phospholipase A(2) (PLA(2))-activating protein
(PLAA) & prostaglandins (PGE(2)) and tumor necrosis factor (TNF)-alpha
Tlr's with NOD1 and NOD2 -- IL-32
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1283464/
This IL32 may be bigger then TLR4, but i have the feeling their
interconnected
and we haven't seen the last of LPS or SFB's.
Wow the DATA is coming... I salute the science community.
Keep it up. And in another ten years we could have a cure. LOL
randall... is haPPy now & NEARLY CLEAR--- whey to GO...
JRStern
>As it happens, anxiety and hyperemotionalism are results, not causes, of
>HPA axis excitability
That's silly, just measure your reactions when reading these messages!
J.
JRStern
wrote:
>This IL32 may be bigger then TLR4, but i have the feeling their
>interconnected
>and we haven't seen the last of LPS or SFB's.
I'm holding out for IL33.33333
J.
randall
> x-no-archive: yes
>
> randall wrote:
> > But we know your emotions and a dozen other things trigger psoriasis.
>
OK, so i'm quoting Big pharma? Or those hungry derms that support
PHARMA?
Guilty.
>
> OTOH, I do know that high epidermal growth factor is a marker for HPA
> axis hyperexcitability, and that it's also associated with the most
> aggressive pituitary adenomas. That leads us back to CRH, the root of
> HPA axis hyperexcitability, and a substance that biopsied psoriatic skin
> is loaded with, along with the pituitary hormone ACTH.
>
> As it happens, anxiety and hyperemotionalism are results, not causes, of
> HPA axis excitability and the newest anti anxiety drugs and the old anti
> depressants address this feedback loop either directly or indirectly.
> Note that Astressin and Antalarmin both target CRH reduction.
>
> Susan
Ok, and i'm working on my angles now. :)
When it intersects hPa and it always does i'll keep
you on your toes.
What is the end all and BE ALL of psoriasis and most autoimmune
conditions ruled by Th17?
It's in YOUR GUT. So susan, is your gut uPstream of HPA and cortisol?
Why not?
I've said this for HOW many YEARS now?
Only 8 in this group. :(
But i've lived it for how many in the real world?
More then I like to think.
I've fought my way from 70% pasi at times down to nearly zero.
And even now i worry that heart disease still looms.
I want to CURE me.
And you by default. LOL
Sure I love you.
But, not as much as I LOVE ME. <g>
So you ask what is this gut trip?
EASY... do what i say and eat sweet whey. :)
Duh..
http://www.wellnessresources.com/health/articles/how_fiber_friendly_flora_reduce_inflammation/
How Fiber & Friendly Flora Reduce Inflammation
Wednesday, November 04, 2009 - Byron Richards, CCN
Scientists have made a major breakthrough in understanding why dietary
fiber and friendly GI tract flora (acidophilus) provide significant
benefit to such inflammatory problems as colitis, asthma, and
arthritis.
Dietary fiber is fermented in the lower colon by friendly flora,
resulting in the production of short chain fatty acids (SCFAs). The
new discovery is that SCFAs bind on to a receptor on immune cells
called G-protein-coupled receptor 43 (GPR43).
The scientist showed that when GPR43 is activated by the SCFAs then
inflammation is controlled. And conversely, their experiments showed
that when GPR43 is not activated then inflammation persists. This is
an extremely important discovery.
It means that if you have adequate dietary fiber and friendly flora
then you have an intestinal “rain forest” that is producing enough of
the short chain fatty acids to help regulate immune cells to not
produce excessive inflammatory signals.
On the other hand, diets high in sugar and other forms of junk will
create an imbalance in the gut, as will repeated use of antibiotics.
True enough, this situation promotes an overgrowth of hostile bacteria
(like H. Pylori) or Candida albicans. However, there is more to it.
The lack of production of SCFAs due to the imbalanced condition is an
additional source of inflammation. The inflammation then weakens the
digestive lining, making it easier for the hostile inhabitants to gain
a foothold and wreak further harm.
It is now correct to view both dietary fiber and friendly flora as
anti-inflammatory nutrition, not just for the digestive tract but as a
possible factor in any problem of ongoing inflammation (including knee
joints). I have repeatedly fixed serious inflammatory problems in
infants and children by fixing their digestive tracts – now I
understand a key aspect explaining why this works.
==============
OK so much for Houdini randallisms that no body seems to accept for
yin/yang reasons aPParently. LOL
What do i care?
I'm out to CURE me first anyway.
Duh, don't be a dumbell here.
Let's start with something esoteric yet germane.
FoxP3 perhaPs?
Exactly...
www.ncbi.nlm.nih.gov/pubmed/19880293
Polymorphisms in the FOXP3 gene in Han Chinese psoriasis patients.
Gao L, Li K, Li F, Li H, Liu L, Wang L, Zhang Z, Gao T, Liu Y.
Department of Dermatology of Xijing Hospital, Fourth Military Medical
University, Xi'an 710032, Shaanxi, China.
BACKGROUND: Psoriasis is a common dermatological disorder, in which
autoimmunity plays an important role. CD4(+)CD25(+) regulatory T cells
(T-regs) have been suggested to be involved in the pathogenesis of
some autoimmune diseases. T-regs express the fork head/winged helix
transcription factor, FOXP3, which appears to be of key importance in
the development and function of T-regs. Studies have found that single-
nucleotide polymorphisms (SNPs) in the FOXP3 gene contribute to
susceptibility to some autoimmune disorders. However, information
about FOXP3 gene in psoriasis is limited. OBJECTIVE: This study
evaluated the association between FOXP3 gene SNPs and susceptibility
to psoriasis in a Han Chinese population. METHODS: In a hospital-based
case-control study, 524 patients with psoriasis and 549 psoriasis-free
controls were recruited according to age and gender. We investigated
four SNPs in the FOXP3 gene (-6054, deletion/ATT; -3279, A/C; -924, A/
G; IVS9+459, A/G) in psoriatic patients, and assessed allele and
genotype frequencies in psoriatic patients (237 females, 287 males)
and normal controls (272 females, 277 males). The polymorphisms were
genotyped using the PCR sequence-specific primer (PCR-SSP) technique
and PCR-restriction fragment length polymorphism (RFLP) analysis.
RESULTS: We found that increased risk of psoriasis was associated with
the FOXP3 -3279 AC genotype (adjusted OR, 1.32; 95% CI, 1.01-1.74) and
the combined AC+AA genotype (adjusted OR, 1.38; 95% CI, 1.07-1.78),
compared with the -3279 CC genotype. We also found that an increased
risk of psoriasis was associated with the FOXP3 IVS9+459 GG genotype
(adjusted OR, 2.24; 95% CI, 1.41-3.58). However, the combined GA+GG
genotype showed no such tendency (adjusted OR=1.28; 95% CI,
1.00-1.64), compared with the IVS9+459 AA genotype. There was no
evidence of an increased risk associated with the FOXP3-6054 deletion/
ATT or FOXP3-924 A/G genotype. In combined genotype analyses, the
FOXP3-3279 AC+AA genotype was more obviously associated in males
(adjusted OR=1.60, 95% CI=1.11-2.31) and severe psoriasis patients
(PASI score >20; adjusted OR=1.97, 95% CI=1.41-2.75). Meanwhile, the
FOXP3 IVS9+459 GA+GG genotype was also associated with severe
psoriasis patients (adjusted OR=1.69, 95% CI=1.21-2.36). CONCLUSIONS:
FOXP3 polymorphisms appear to contribute to the risk of psoriasis in a
Han Chinese population. Larger studies are needed to confirm these
findings.
PMID: 19880293
FOXp3 again?
YeP and with Treg's (T-reg's) in the next article.
HOW important are tREG'?
WEll that is one of the autoimmune conundrums.
Not enough TREG's or to much Th17?
Which i believe Th17 leves are due to SFB.
So let's nail this Psor PuPPy down which ever it is.
www.newscientist.com/article/dn18096-injected-cells-stop-body-from-attacking-self.html
Injected cells stop body from attacking self
18:24 03 November 2009 by Jessica Hamzelou
A virtually unlimited supply of rare cells can now be produced in the
laboratory to fight diseases such as rheumatoid arthritis in mice.
Crucially, these cells, which dampen down the body's immune response,
have been engineered so that they target damaged tissue yet don't
leave the rest of the body open to infection.
Vaccines have long harnessed the body's natural ability to fight
disease. Therapies that boost our natural immune response to cancer
are also in the works (see Autoimmune disease cells harnessed to fight
cancer).
SEE: http://www.newscientist.com/article/dn18075-autoimmune-disease-cells-harnessed-to-fight-cancer.html
[or see the last article in this thread]
But in autoimmune disease – in which the immune system mistakenly
attacks the body's own tissue – the opposite is needed. So
immunologists have long eyed up the cells that dampen down the immune
response, known as regulatory T-cells or T-regs, for their potential
to treat autoimmune disorders such as rheumatoid arthritis, diabetes
and multiple sclerosis.
There have been two challenges: how to obtain large supplies of the
rare T-regs, which make up less than 1 per cent of all immune cells,
and how to neutralise dangerous immune cells without weakening the
entire immune system, leaving people open to infection. Now Hans
Stauss and his colleagues at University College London have made a
stab at solving both.
Straight to the joint
The team starts by extracting ordinary T-cells – immune cells that are
common in the blood – from mice and using a virus to insert two genes
into these cells. One gene, FOXP3, transforms the ordinary T-cells
into T-regs. The second gene codes for a receptor for a substance
called ovalbumin.
Next the researchers injected ovalbumin into mice with rheumatoid
arthritis, which is caused by normal T-cells attacking cartilage. Each
mouse had two arthritic joints, but the researchers injected the
ovalbumin into one only. Then they injected the lab-produced T-reg
cells into the same mice.
The idea was that the ovalbumin would attract the cells, which would
dampen down the arthritic inflammation that was attacking the joint's
cartilage. The rest of the immune system, however, would remain
intact.
Sure enough, the injected cells homed in on the ovalbumin-injected
arthritic joints and reduced inflammation, while the other joints
remained inflamed.
More targets
Stauss says that a similar T-reg therapy could be developed to target
autoimmune diseases that strike other parts of the body, by adding
genes for receptors specific to molecules found there.
Alexandre Corthay of the University of Oslo in Norway warns of the
unpredictable nature of T-regs, which regularly turn back into normal
T-cells in the body. Stauss admits that this is a risk but reckons
that artificially produced T-reg cells are more stable than naturally
occurring ones.
He also points out that because the T-regs are specific to a
particular part of the body, even if they did revert, the damage they
could do would be limited.
Journal reference: Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.0907396106
===============
How can cancer succumb to Th17 and what psoriatics create every day in
their bodies.
http://www.newscientist.com/article/dn18075-autoimmune-disease-cells-harnessed-to-fight-cancer.html
Autoimmune disease cells harnessed to fight cancer
18:14 29 October 2009 by Linda Geddes
Autoimmune disease has devastating consequences for healthy tissue.
Now, in mice, the same cells that can drive the body to destroy its
own tissue have been used to fight cancer.
The cells are a recently discovered type of immune cell called Th17.
These cells play a key role in autoimmune disease – in which the
immune system mistakenly identifies the body's own tissues as foreign
and attack them.
We already know that some people's immune systems have a natural
ability to fight some types of cancer. But how exactly this works –
and why it doesn't always do so – isn't known.
Discovered in 2005, Th17 cells are thought to have a part in
triggering the inflammation and tissue injury associated with
autoimmune diseases. But they also have a helpful role in fighting
bacterial infections.
Guilt assumed
In addition, Natalia Martin-Orozco at the MD Anderson Cancer Center in
Houston, Texas, and her colleagues noticed Th17 cells infiltrating
cancerous tumours. But as inflammation is known to promote the growth
of cancer, they assumed that the cells were helping the tumours to
grow.
To investigate further, the team engineered mice that were deficient
in Th17 cells and then injected them with a strain of melanoma that
affects the lungs.
To their surprise, they found that these Th17-deficient mice
experienced far more aggressive cancer growth than normal mice – with
the cancer completely smothering the lungs within 16 days. "It was the
opposite of what we expected," says Martin-Orozco. "If anything, [the
Th17 cells] were promoting an anti-tumour response."
Next, they incubated Th17 cells with proteins specific to the lung
melanoma. This process was designed to enable the cells to recognise
such a tumour if they encountered it. The researchers then injected
these tumour-specific cells into mice at the same time as injecting
melanoma cells.
After 16 days, mice injected with the tumour-specific Th17 cells had
barely detectable tumours, compared with mice injected with tumour
cells alone. What's more, injecting the cells into mice with
established tumours reduced the tumours' mass by 75 per cent.
Set the T cells on them
__Martin-Orozco__ believes that Th17 cells recognise tumours and, in
response, release chemicals that attract immune cells called dendritic
cells to the tumour. These seize tumour proteins and take them to
lymph nodes, where the dendritic cells prime killer T cells to
recognise and attack the tumour.
The next step is to see if Th17 cells from humans also have an anti-
tumour effect. "While there is much work to be done, these findings
imply the possibility of taking a patient's Th17 cells, expanding them
in the lab and then reinfusing them as a treatment," adds Chen Dong,
also of MD Anderson, who supervised the work.
Similar approaches using killer T cells are already being investigated
as a cancer treatment, with some promising results.
The researchers also plan to explore whether the production of extra
Th17 cells could be stimulated through vaccination.
To avoid the risk of injected cells destroying healthy tissue, Th17
cells that are reactive to tumours but not to normal tissues would
have to be identified, Dong cautions.
The team also needs to figure out which types of cancer Th17 cells
respond to, and at which stage of the disease.
Caetano Reis e Sousa, head of the immunobiology lab at Cancer Research
UK's London Research Institute, sounds says the work is "exciting" but
cautions that it is at an early stage.
"The results need to be validated and extended before scientists know
if a treatment based on this approach could one day be used to help
cancer patients."
Journal reference: Immunity, DOI: 10.1016/j.immuni.2009.09.014
----------
www.ncbi.nlm.nih.gov/pubmed/19879162
T Helper 17 Cells Promote Cytotoxic T Cell Activation in Tumor
Immunity.
___Martin-Orozco__ N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S,
Hwu P, Restifo NP, Overwijk WW, Dong C.
Department of Immunology, MD Anderson Cancer Center, Houston, TX
77030, USA.
Although T helper 17 (Th17) cells have been found in tumor tissues,
their function in cancer immunity is unclear. We found that
interleukin-17A (IL-17A)-deficient mice were more susceptible to
developing lung melanoma. Conversely, adoptive T cell therapy with
tumor-specific Th17 cells prevented tumor development. Importantly,
the Th17 cells retained their cytokine signature and exhibited
stronger therapeutic efficacy than Th1 cells. Unexpectedly, therapy
using Th17 cells elicited a remarkable activation of tumor-specific CD8
(+) T cells, which were necessary for the antitumor effect. Th17 cells
promoted dendritic cell recruitment into the tumor tissues and in
draining lymph nodes increased CD8alpha(+) dendritic cells containing
tumor material. Moreover, Th17 cells promoted CCL20 chemokine
production by tumor tissues, and tumor-bearing CCR6-deficient mice did
not respond to Th17 cell therapy. Thus, Th17 cells elicited a
protective inflammation that promotes the activation of tumor-specific
CD8(+) T cells. These findings have important implications in
antitumor immunotherapies.
PMID: 19879162
-----------
Isn't it satisfying to find this out?
That Th1--> Th17(IL-17) will kill cancer and we should be able
to use that, as psoriatics or autoimmune folks, to prevent cancer?
HECK YES...
I'm so stoked i'm gonna post another one just like the above one.
http://news.biocompare.com/News/NewsStory/296724/NewsStory.html
Th17 Cells Summon an Immune System Strike Against Cancer
HOUSTON - A specific type of T helper cell awakens the immune system
to the stealthy threat of cancer and triggers an attack of killer T
cells custom-made to destroy the tumors, scientists from The
University of Texas M. D. Anderson Cancer Center report in the early
online edition of the journal Immunity.
The role of Th17, one of only four known types of T helper cell, opens
a possible avenue for overcoming cancer's ability to suppress or hide
from the body's immune system, said senior author Chen Dong, Ph.D.,
professor in M. D. Anderson's Department of Immunology. Dong and
colleagues found that Th17 stifled development of metastatic melanoma
tumors in the lungs of mice.
"While there is much work to be done, these preclinical findings imply
the possibility of taking a patient's Th17 cells, expanding them in
the lab, and then re-infusing them as treatment," Dong said.
Development of a vaccine to stimulate Th17 cells would be another
possible application.
Dong earlier discovered the existence of Th17 cells and established
that they secrete the inflammatory protein interleukin-17 (IL-17). His
lab showed that overexpression of IL-17 contributes to both autoimmune
and inflammatory diseases.
"Th17 cells also are found in a variety of solid tumors and we wanted
to know whether these cells promote cancer or play a preventive or
protective role," Dong said.
Their research showed that mice made deficient in Th17 cells and then
injected with a strain of melanoma that gathers in the lungs
experienced aggressive cancer growth compared to mice with normal
levels of Th17. At 16 days, tumors in the knockout mice had fused
together and coated the lung so extensively that they were no longer
countable.
Next, they tested Th17 for preventive effect, injecting Th17 cells
primed with tumor-specific antigens and the melanoma cells at the same
time. At 16 days, mice with Th17 had low or barely detectable levels
of cancer while control mice had a heavy tumor burden in their lungs.
A third set of experiments tested a treatment effect, showing that
mice injected with Th17 after they already had melanoma in their lungs
had a 75 percent reduction in tumor burden compared with normal mice.
In all experiments, mice with Th17 also had higher levels of several
categories of immune system cell than did those with normal or
suppressed Th17.
T cells are lymphocytes, a type of white blood cell produced by the
thymus equipped with receptors that recognize and bind to antigens,
pieces of invading organisms presented to the T cells by dendritic
cells. The bound antigen converts the T cell to T helper cells that
secrete signaling molecules called cytokines to launch an appropriate
immune response. Helper cells, in effect, guide the adaptive immune
response.
In the Immunity paper, additional experiments outlined the specific
pathway by which Th17 suppresses tumors:
•Tumor invasion of the lung attracts Th17 cells that secrete IL-17A.
•IL-17A in turn promotes the secretion of two chemokines, CCL2 and
CCL20, which recruit leukocytes to the tumor site.
•The leukocytes include dendritic cells, which seize tumor antigens
and migrate to the lymph nodes.
•There, the antigens are used to prime CD8+ killer cells, which then
migrate to the lung and kill established tumors.
###
The research was funded by grants from the National Institutes of
Health, M. D. Anderson's Center for Targeted Therapy, a Leukemia and
Lymphoma Society Scholar Award to Dong, and a Trust Fellowship of M.
D. Anderson.
==========================
So?
What are they doing about these Treg's that can KILL cancer?
Shouldn't we already have a few drugs to spur on the immune system
similar to what
happens with the average psoriatic day in and day out?
Yep.
http://www.reuters.com/article/pressRelease/idUS215024+20-Oct-2009+PRN20091020
Karmanos Cancer Institute Immunology Researcher Obtains Nearly $1
Million
National Institutes of Health Grant
DETROIT, Oct. 20 /PRNewswire-USNewswire/ -- Venuprasad K. Poojary,
Ph.D.,
assistant professor at the Barbara Ann Karmanos Cancer Institute and
Wayne
State University School of Medicine, has secured a two-year federal
grant for
almost $1 million to further his research into creating more effective
immunotherapy strategies for cancer treatment. Dr. Poojary's grant
brings the
total number of federal stimulus grant dollars received by Karmanos
researchers to approximately $8 million this year.
(Logo: http://www.newscom.com/cgi-bin/prnh/20071106/KARMANOSLOGO )
Among the more than 20,000 applications the National Institutes of
Health
received for the NIH Challenge Grants, Dr. Poojary's application
ranked within
the top 1 percent. He received a grant for $999,094. The NIH has
allocated
$200 million for the challenge grants for fiscal years 2009 and 2010.
They are
part of the American Recovery and Reinvestment Act of 2009 passed in
February
of this year.
Dr. Poojary's research is titled, "Role of ___TIEG1 in Foxp3+Treg___
development and
tumor progression," and explores tumor pathways that cause effector T
cells,
those that help maintain a healthy immune system, to be converted to
regulator
T cells, which allow the growth of cancerous tumor cells.
Researchers have already created vaccines that are effective in
controlling
regulator T cells in the lab environment, but so far immunotherapy
vaccines
have not been successful when used on humans.
"Immunotherapy for cancer has not been successful because tumors
exploit the
immune system," Dr. Poojary said. "We must now build on
immunotherapy's great
cancer treatment potential by learning how we can make it more
effective."
Dr. Poojary's research strives to understand on a molecular level how
immune
suppressor cells can be controlled so that tumor cells do not
proliferate. He
believes this research will provide him and his colleagues significant
new
insight to overcome the limitations of current immunotherapy
strategies.
"We want to develop inhibitors for regulator T cells to use along with
tumor
vaccines, and our goal is to block the development of tumor-promoting
regulator T cells in the tumor microenvironment," he said. "People
have tried
to deplete regulator T cells from the body using antibodies, but such
an
approach is associated with the risk of triggering autoimmunity in
patients."
The nearly $1 million NIH grant will allow Dr. Poojary and his staff
to invest
the grant monies in what they need to conduct work more quickly and
efficiently. As part of the grant, Dr. Poojary will hire four people
to assist
him. Without the grant, he says this research would have been very
difficult.
"If we can understand the pathway of T cells, we will be very close to
determining the inhibitors for what converts good cells into tumor-
promoting
bad cells," he said. "This is the hard step, but I am very confident
that I'll
achieve my goals with the project."
Dr. Poojary says it will be significant when doctors can control the
conversion of normal T cells into abnormal cells that allow tumors to
grow.
"With this knowledge, we would be very close to having the
immunological tools
to more effectively treat aggressive cancers, such as locally-advanced
and
metastatic breast cancer, prostate cancer and brain cancer," according
to Dr.
Poojary. He said he is fascinated by the intricacies of the immune
system and
how systems differ from patient to patient.
"I'm interested in knowing how the immune system works," he said.
"Immunotherapy is the future for cancer treatment and it can be
developed for
any disease. Immunotherapy is much safer, but we have to improve the
efficiency of tumor vaccines so that you get more specific and longer-
lasting
effects."
Dr. Poojary has been studying immunology since 1998 when he began his
doctorate studies at the National Center for Cell Science in Pune,
India.
After receiving his Ph.D., he served as a postdoctoral fellow and
later a
research scientist in the Division of Cell Biology at LaJolla
Institute for
Allergy and Immunology in San Diego, Calif. He has been with the
Karmanos
Cancer Institute since March 2009.
Co-authors with Dong and first author Natalia Martin-Orozco, Ph.D.,
are Yeonseok Chung, Ph.D., Xuexian O. Yang, Ph.D., and Tomohide
Yamazaki, all of the Department of Immunology; Pawel Muranski, M.D.,
and Nicholas Restifo, M.D., both of the National Cancer Institute of
the National Institutes of Health; Sijie Lu, Ph.D., of M. D.
Anderson's Department of Stem Cell Transplantation and Cell Therapy;
and Patrick Hwu, M.D., and William Overwijk, Ph.D., both of M. D.
Anderson's Department of Melanoma Medical Oncology.
======================
http://7thspace.com/headlines/323323/cd44_expression_positively_correlates_with_foxp3_expression_and_suppressive_function_of_cd4_treg_cells.html
CD44 expression positively correlates with Foxp3 expression and
suppressive function of CD4+ Treg cells
CD4+CD25+ regulatory T (Treg) cells develop in the thymus and can
suppress T cell proliferation, modulated by Foxp3 and cytokines;
however, the relevance of CD44 in Treg cell development is less clear.
To address this issue, we analyzed Foxp3 expression in CD44+ Treg
cells by using multiple parameters, measured the levels of the
immunoregulatory cytokine interleukin (IL)-10 in various thymocyte
subsets, and determined the suppressor activity in different splenic
Treg cell populations.
Results: Within mouse thymocytes, we detected Treg cells with two
novel phenotypes, namely the CD4+CD8-CD25+CD44+ and CD4+CD8-CD25+CD44-
staining features.
Additional multi-parameter analyses at the single-cell and molecular
levels suggested to us that CD44 expression positively correlated with
Foxp3 expression in thymocytes, the production of IL-10, and Treg
activity in splenic CD4+CD25+ T cells. This suppressive effect of Treg
cells on T cell proliferation could be blocked by using anti-IL-10
neutralizing antibodies.
In addition, CD4+CD25+CD44+ Treg cells expressed higher levels of
IL-10 and were more potent in suppressing effector T cell
proliferation than were CD4+CD25+CD44- cells.
Conclusions: This study indicates the presence of two novel phenotypes
of Treg cells in the thymus, the functional relevance of CD44 in
defining Treg cell subsets, and the role of both IL-10 and Foxp3 in
modulating the function of Treg cells.
Author: Tie LiuLynn SoongGang LiuRolf KonigAshok Chopra
Credits/Source: Biology Direct 2009, 4:40
====================
randall... Nice... like pie or sweet whey... :)