Tie2 & SRF Links + More
randall
The Tie-2 gene abstract PoPed uP yesterday.
http://www.ncbi.nlm.nih.gov/pubmed/19342373?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Keratinocyte but not endothelial cell-specific overexpression of tie2
leads to the development of psoriasis.
Wolfram JA, Diaconu D, Hatala DA, Rastegar J, Knutsen DA, Lowther A,
Askew D, Gilliam AC, McCormick TS, Ward NL.
Case Western Reserve University, Departments of Dermatology and
Neuroscience, BRB519, 10900 Euclid Ave, Cleveland, OH 44106.
nicol...@case.edu.
Psoriasis is initiated and maintained through a multifaceted interplay
between keratinocytes, blood vessels, gene expression, and the immune
system. One previous psoriasis model demonstrated that overexpression
of the angiopoietin receptor Tie2 in endothelial cells and
keratinocytes led to the development of a psoriasiform phenotype;
however, the etiological significance of overexpression in each cell
type alone was unclear. We have now engineered two new mouse models
whereby Tie2 expression is confined to either endothelial cells or
keratinocytes. Both lines of mice have significant increases in dermal
vasculature but only the KC-Tie2-overexpressing mice developed a
cutaneous psoriasiform phenotype. These mice spontaneously developed
characteristic hallmarks of human psoriasis, including extensive
acanthosis, increases in dermal CD4(+) T cells, infiltrating epidermal
CD8(+) T cells, dermal dendritic cells and macrophages, and increased
expression of cytokines and chemokines associated with psoriasis,
including interferon-gamma, tumor necrosis factor-alpha, and
interleukins 1alpha, 6, 12, 22, 23, and 17. Host-defense molecules,
cathelicidin, beta-defensin, and S100A8/A9, were also up-regulated in
the hyperproliferative skin. All of the phenotypic traits were
completely reversed without any scarring following repression of the
transgene and were significantly improved following treatment with the
anti-psoriasis systemic therapeutic, cyclosporin A. Therefore,
confining Tie2 overexpression solely to keratinocytes results in a
mouse model that meets the clinical, histological, immunophenotypic,
biochemical, and pharmacological criteria required for an animal model
of human psoriasis.
PMID: 19342373
Tie2 has been all over this place in the last week or so.
==========================================
This abstract
http://www.ncbi.nlm.nih.gov/pubmed/19307725
was posted here 3/26/09. [see abstract below story]
And here's an article to go with it today.
http://www.ethlife.ethz.ch/archive_articles/090325_srf_psoriasis_per/index_EN
Molecular basis of psoriasis
When too little leads to too much
If skin cells lack a particular factor, skin complaints like psoriasis
can develop. This is what ETH Zurich biologists have demonstrated in a
mouse model, which can easily be applied to humans.
http://www.ethlife.ethz.ch/archive_articles/090325_srf_psoriasis_per/0903xx_srf_zellen_l.jpg?
The Serum Response Factor (SRF) protein is well known in cell and
development biology. As a so-called transcription factor, it regulates
the reading of genetic information by binding to the so-called
promoter region of genes.
SRF plays a key role in the development of different organs and
tissues. It is an important cog in the regulation of cell division and
differentiation, cell migration and cell death. Nevertheless, whether
the protein also plays a role in adults’ skin cells remained unknown
until recently.
Cell biologists from Sabine Werner’s team at ETH Zurich have taken a
big step forward in this respect and can now accredit the factor with
yet another crucial function. The study was just published in the
Journal of Clinical Investigation.
Without sufficient SRF, skin becomes diseased
In normal, healthy skin, the cells in the upper layer of skin
(epidermal keratinocytes) produce relatively large amounts of SRF.
This maintains the skin’s equilibrium. However, if there is an absence
of SRF for whatever reason (due to the deletion of the corresponding
gene locus “srf”, for example), lab mice develop symptoms reminiscent
of psoriasis in humans. Just like psoriasis patients, “srf” knockout
mice developed flaky, inflamed patches on their backs, paws and tails.
In these areas, the skin cells had divided excessively and were no
longer able to develop normally.
The researchers were able to demonstrate that the skeleton of the skin
cells is disturbed and destroyed as a direct result of the SRF
deficiency. The cells lose contact with their neighbors and the matrix
that surrounds them. Consequently, the outer layer of skin loses its
compact layering. Fissures form, which enables water to evaporate more
easily and the skin dries out more quickly, thus making the
intermediate spaces more susceptible to foreign bodies and bacteria.
This in turn triggers an inflammatory reaction that induces the skin
cells to divide and impairs their differentiation.
Psoriasis patients lack SRF almost entirely
Interestingly, the ETH-Zurich researchers have now discovered that the
affected skin in psoriasis patients almost lacks the SRF protein
entirely. Together with the results of the mouse tests, this suggests
that the loss of SRF is involved in the development of the common skin
disease. Like the mice, psoriasis patients develop red, inflamed
patches that constantly shed squames – the necrotic skin cells. The
patients thus become partially disfigured and suffer from severe
itching. Ointments offer some relief, restoring the protective and
barrier function of the skin and, in more severe cases, anti-
inflammatory substances. The renowned spa treatment in the mineral-
rich water of the Dead Sea can also alleviate the effects of the
disease, but not cure it.
Trigger still unknown
The researchers still do not know which factor(s) cause(s) the down-
regulation of SRF. This is a key issue which Werner’s team is set to
address next. The suspects include other proteins, such as cytokines
or other transcription factors. Moreover, we still do not know whether
and which triggers from the environment contribute to to the down-
regulation of SRF.
For a long time, the school of thought was that abnormalities in the
immune system trigger psoriasis. Today, however, the research is also
looking for defects in the epidermis that could be genetic or even
environmental. “In the case of psoriasis, it is not always the immune
system that is the trigger, but often a defect in the keratinocytes,”
explains Sabine Werner.
========================
Loss of serum response factor (SRF) in keratinocytes results in
hyperproliferative skin disease in mice.
Koegel H, von Tobel L, Schäfer M, Alberti S, Kremmer E, Mauch C, Hohl
D, Wang XJ, Beer HD, Bloch W, Nordheim A, Werner S.
The transcription factor serum response factor (SRF) plays a crucial
role in the development of several organs. However, its role in the
skin has not been explored. Here, we show that keratinocytes in normal
human and mouse skin expressed high levels of SRF but that SRF
expression was strongly downregulated in the hyperproliferative
epidermis of wounded and psoriatic skin. Keratinocyte-specific
deletion within the mouse SRF locus during embryonic development
caused edema and skin blistering, and all animals died in utero.
Postnatal loss of mouse SRF in keratinocytes resulted in the
development of psoriasis-like skin lesions. These lesions were
characterized by inflammation, hyperproliferation, and abnormal
differentiation of keratinocytes as well as by disruption of the actin
cytoskeleton. Ultrastructural analysis revealed markedly reduced cell-
cell and cell-matrix contacts and loss of cell compaction in all
epidermal layers. siRNA-mediated knockdown of SRF in primary human
keratinocytes revealed that the cytoskeletal abnormalities and
adhesion defects were a direct consequence of the loss of SRF. In
contrast, the hyperproliferation observed in vivo was an indirect
effect that was most likely a consequence of the inflammation. These
results reveal that loss of SRF disrupts epidermal homeostasis and
strongly suggest its involvement in the pathogenesis of
hyperproliferative skin diseases, including psoriasis.
PMID: 19307725
===========================================
New Horny Layer Marker Proteins for Evaluating Skin Condition in
Atopic Dermatitis.Yamane Y, Moriyama K, Yasuda C, Miyata S, Aihara M,
Ikezawa Z, Miyazaki K.
Department of Environmental Immuno-Dermatology, Yokohama City
University Graduate School of Medicine, Yokohama, Japan.
Background: Atopic dermatitis (AD) has a complicated pathogenesis and
its clinical features vary greatly among patients. Although many
clinical parameters have been reported, it remains difficult to
evaluate AD skin conditions adequately. Objective: To support better
evaluation of AD patients, we attempted to develop a new, objective
and noninvasive method that assesses skin condition in AD using
biochemical markers in the skin's horny layer (HL). Methods: Thirty-
six patients with AD, 8 with psoriasis and 16 healthy volunteers were
recruited. HL samples were obtained by tape stripping from involved
and uninvolved skin of the forearms. Expression levels of 6 proteins
in the HL [fatty acid-binding protein-5 (FABP-5), squamous cell
carcinoma antigens 2 (SCCA2), alpha-enolase, annexin II,
apolipoprotein A-I and albumin] were analyzed by immunoblotting and
compared with clinical data. Results: The 6 proteins were detected at
a high level in AD skin lesions, but scarcely in the normal controls.
FABP-5 showed correlation with the local severity of the involved
skin. Annexin II, apoprotein A-I and albumin showed correlation with
the severity of specific eruptions. SCCA2 correlated significantly
with total serum IgE level. Albumin levels in the uninvolved skin of
AD patients showed significant correlation with the local severity in
the involved skin of the same patient and with the trans-epidermal
water loss. Albumin levels in psoriatic skin were very low, even with
scratch marks, compared to those in AD skin. Conclusion: FABP-5,
albumin and some other proteins in HL seem to be useful as biomarkers
to evaluate inflammation and skin barrier conditions in AD patients.
Copyright © 2009 S. Karger AG, Basel.
PMID: 19339807
---------------
Hypoxia links for Manfred
http://www.ncbi.nlm.nih.gov/pubmed/19342680?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
IL-20 is regulated by hypoxia-inducible factor and up-regulated after
experimental ischemic stroke.
Chen WY, Chang MS.
Institute of Basic Medical Sciences, College of Medicine, National
Cheng Kung University, Tainan, Taiwan.
IL-20, an IL-10 family member, is involved in various inflammatory
diseases, such as psoriasis, rheumatoid arthritis, and
atherosclerosis. We investigated whether hypoxia in vitro and an in
vivo model of ischemic stroke would up-regulate IL-20 expression. In
vitro, IL-20 expression increased in hypoxic HaCaT, HEK293 cells,
chondrocytes, monocytes, and glioblastoma cells. Inhibition of hypoxia-
inducible factor 1alpha inhibited CoCl(2)-induced IL-20 expression. We
identified two putative hypoxia response elements in the human il20
gene promoter. Promoter activity assays showed that CoCl(2) mimicked
hypoxia-activated luciferase reporter gene expression. In vivo,
experimental ischemic stroke up-regulated IL-20 in the sera and brain
tissue of rats. IL-20 stained positively in glia-like cells in peri-
infarcted lesions, but not in contralateral tissue. Administration of
IL-20 mAb ameliorated ischemia-induced brain infarction of rats after
experimental ischemic stroke. In vitro, RT-PCR analysis showed that
glioblastoma cells, GBM8901, expressed IL-20 and its receptor subunits
IL-20R1, IL-20R2, and IL-22R1. IL-20 induced cell proliferation in
GBM8901 cells by activating the JAK2/STAT3 and ERK1/2 pathways. IL-20
also induced production of IL-1beta, IL-8, and MCP-1 in GBM8901 cells.
We conclude that IL-20 was responsive to hypoxia in vitro and in the
ischemic stroke model and that up-regulation of IL-20 in the ischemic
brain may contribute to brain injury.
PMID: 19342680
===================
Increased expression of CD208 (DC-LAMP) in epidermal keratinocytes of
psoriatic lesions.
Higaki M, Higaki Y, Kawashima M.
Research Center for Medical Sciences, The Jikei University School of
Medicine, Tokyo, Japan.
Psoriasis is a chronic inflammatory skin disease characterized by
epidermal hyperproliferation and infiltration of inflammatory
leukocytes. The aim of this study was to clarify the role of innate
immunity involving dendritic cells (DC) and keratinocytes in
psoriasis. We immunohistochemically examined the expression of DC
markers such as CD1a, CD83, CD207 (Langerin), CD208 (DC-LAMP) and
CD209 (DC-SIGN) in psoriatic skin and gamma-interferon (IFN-gamma)/12-
O-tetradecanoylphorbol-13-acetate (TPA)-stimulated keratinocytes in
vitro. CD208 was strongly expressed in basal and suprabasal layer
keratinocytes in addition to DC in the perivascular lesions of the
psoriatic dermis. Furthermore, the enhanced expression of CD208 in the
perinuclear lesions of IFN-gamma-/TPA-stimulated keratinocytes was
observed in vitro. Because a defect of the granular layer in psoriatic
lesions has been recognized, increased expression of lysosome-related
CD208 in the basal and suprabasal keratinocytes of psoriatic lesions
might represent aberrant epidermal differentiation. Additionally,
these CD208-positive keratinocytes possessing putative antigen-
processing activity might play a key role as20antigen-presenting cells
in psoriatic skin.
PMID: 19335688
http://www.ncbi.nlm.nih.gov/pubmed/19335423
Lipoprotein (a) in patients with psoriasis: associations with lipid
profiles and disease severity.
Pietrzak A, Kadzielewski J, Janowski K, Roliński J, Krasowska D,
Chodorowska G, Paszkowski T, Kapeć E, Jastrzebska I, Tabarkiewicz J,
Lotti T.
Departments of Dermatology, Venereology and Pediatric Dermatology,
Clinical Immunology, Gynecology, and Internal Nursing, Medical
University of Lublin, Lublin, Poland.
Background Lipoprotein (a) [Lp(a)] is a genetically determined
molecule whose role has been implied in cardiovascular pathology, and
whose levels have been reported to be elevated in patients with
psoriasis. Aim To assess the serum levels of Lp(a) in patients with
psoriasis, and to investigate the associations of Lp(a) with other
lipids and with psoriasis severity. Methods Thirty-four patients with
psoriasis and 26 healthy control subjects took part in the study.
Serum levels of Lp(a) and total, high density lipoprotein (HDL), low
density lipoprotein (LDL), and very low density lipoprotein (VLDL)
cholesterol fractions were measured in all participants. The levels of
triglycerides and total cholesterol were measured using enzymatic
colorimetric tests; HDL and LDL cholesterol concentrations were
determined by precipitation methods; the VLDL concentration was
calculated according to the formula: VLDL cholesterol = triglycerides/
5. Results Patients with psoriasis showed signifi cantly higher serum
levels of Lp(a) relative to controls. Even when controlling for
normolipidemic vs. hyperlipidemic status, abnormal levels of Lp(a) (>
30 mg/dL) were observed significantly more often in patients than in
controls. In both patients and controls, Lp(a) levels correlated
positively with total and HDL cholesterol levels. In patients, Lp(a)
levels correlated positively with psoriasis severity. Conclusions Lp
(a) may be a factor contributing to an increased cardiovascular risk
in patients with psoriasis. A pathogenetic link may exist between this
lipoprotein and psoriatic pathophysiology.
PMID: 19335423
http://www.ncbi.nlm.nih.gov/pubmed/19334540
[The comparative analysis of psoriasis and Crohn disease molecular-
genetical processes under pathological conditions][Article in Russian]
[No authors listed]
The comparative bioinformatic analysis of psoriasis and Crohn disease
pathological processes was carried out using the results of microarray
experiments deposited in GEO DataSets database. Several common for
both pathologies genes and molecular-genetical processes were found.
It is suggested that some transcriptional factors including AP-1
system of transcriptional factors are involved in pathological
processes both under psoriasis and Crohn disease.
PMID: 19334540
http://www.ncbi.nlm.nih.gov/pubmed/19334527
[Association of NAT2 polymorphism with risks to develop psoriasis and
various dermatological dise ases in Moscow population][Article in
Russian]
[No authors listed]
Ruacetyltransferase 2 (NAT2) is one of key enzymes of the second phase
of biotransformation that metabolize genotoxic compounds such as
carcinogens and mutagens in different types of cells. There is a
correlation between the decreasing activity of NAT2 gene product and
the sensitivity to harmful environmental factors that increase the
risk of occurrence of different multifactorial diseases, including
dermatological ones like psoriasis. We developed the NAT2-biochip for
17 SNPs. The biochip was been tested on 279 clinical DNA samples from
180 patients with psoriasis and 99 healthy individuals, residents of
Moscow. We found only six SNPs that were significant for European
populations (282C > T, 341T > C, 481C > T, 590G > A, 803A > G and 857G
> A). The analysis in psoriasis group did not show any genotype
association. The increase in frequency of a slow acetylation phenotype
in group of patients with type II psoriasis and in group of patients
with normosthenic constitution, in comparison with control group (OR =
1.76,p = 0.177 and OR = 2.07,p = 0.050, respectively) has been
revealed. The results for patients smoking one or more pack of
cigarettes per day, and daily alcohol drinking in comparison with the
control showed an increase in frequency for the genotype 341C/C, 481T/
T, 803G/G (OR = 7.42, p = 0.008 and OR = 106.11, p = 0.003,
respectively). We also found an increase of frequency of genotype 341T/
T, 481C /C, 590A/-, 803A/A in patients with side reactions to medical
products comparing with group of healthy donors (OR = 2.05, p =
0.099). Thus, the present data show that the certain NAT2 genotypes
and some styles of life can be considered as risk factors of psoriasis
development in this muscovite population.
PMID: 19334527
31 hits for nat2 + bowel
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=nat2+bowel&log$=activity
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum
1: NAT2 N-acetyltransferase 2 (arylamine N-acetyltransferase) [ Homo
sapiens ]
[...]
Also known as AAC2; PNAT; NAT2
<sniP>
------------
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=81539&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum
solute carrier family 38, member 1
[...]
AKA -- ATA1; NAT2; SAT1; SNAT1; SLC38A1
Summary Amino acid trans porters play essential roles in the uptake of
nutrients, production of energy, chemical metabolism, detoxification,
and neurotransmitter cycling. SLC38A1 is an important transporter of
glutamine, an intermediate in the detoxification of ammonia and the
production of urea. Glutamine serves as a precursor for the synaptic
transmitter, glutamate (Gu et al., 2001 [PubMed 11325958]).
Summary This gene encodes an enzyme that functions to both activate
and deactivate arylamine and hydrazine drugs and carcinogens.
Polymorphisms in this gene are responsible for the N-acetylation
polymorphism in which human populations segregate into rapid,
intermediate, and slow acetylator phenotypes. Polymorphisms in this
gene are also associated with higher incidences of cancer and drug
toxicity. A second arylamine N-acetyltransferase gene (NAT1) is
located near this gene (NAT2).
===================================
Golimumab, a new human tumor necrosis factor alpha antibody,
administered every four weeks as a subcutaneous injection in psoriatic
arthritis: Twenty-four-week efficacy and safety results of a
randomized, placebo-controlled study.
Kavanaugh A, McInnes I, Mease P, Krueger GG, Gladman D, Gomez-Reino J,
Papp K, Zrubek J, Mudivarthy S, Mack M, Visvanathan S, Beutler A.
University of California, San Diego, La Jolla.
OBJECTIVE: To assess the efficacy and safety of golimumab in patients
with active psoriatic arthritis (PsA). METHODS: Adult patients with
PsA who had at least 3 swollen and 3 tender joints and active
psoriasis were randomly assigned to receive subcutaneous injections of
placebo (n = 113), golimumab 50 mg (n = 146), or golimumab 100 mg (n =
146) every 4 weeks through week 20. Efficacy assessments through week
24 included the American College of Rheumatology 20% improvement
criteria (ACR20), the Psoriasis Area and Severity Index (PASI) in
patients in whom at least 3% of the body surface area was affected by
psoriasis at baseline, the Short Form 36 Health Survey (SF-36), the
disability index of the Health Assessment Questionnaire (HAQ), the
Nail Psoriasis Severity Index (NAPSI), the physician's global
assessment of psoriatic nail disease, and enthesitis (using the PsA-
modified Maastricht Ankylosing Spondylitis Enthesitis Score [MASES]
index). RESULTS: At week 14, 48% of all patients receiving golimumab,
51% of patients receiving golimumab 50 mg, and 45% of patients
receiving golimumab 100 mg achieved an ACR20 response (the primary end
point), compared with 9% of patients receiving placebo (P < 0.001 for
all comparisons). Among the 74% of patients in whom at least 3% of the
body surface area was affected by psoriasis at baseline, 40% of those
in the golimumab 50 mg group and 58% of those in the golimumab 100 mg
group had at least 75% improvement in the PASI at week 14 (major
secondary end point), compared with 3% of placebo-treated patients (P
< 0.001 for both doses). Significant improvement was observed for
other major secondary end points (the HAQ and the SF-36), the20NAPSI,
the physician's global assessment of psoriatric nail disease, and the
PsA-modified MASES index in each golimumab group compared with
placebo. This efficacy was maintained through week 24. Golimumab was
generally well tolerated. CONCLUSION: Treatment with golimumab at
doses of 50 mg and 100 mg significantly improved active PsA and
associated skin and nail psoriasis through week 24.
PMID: 19333944
-----------
Not enough large psor heads for a syndrome X study in Turkey?
---
Serum lipid profile paraoxonase and arylesterase activities in
psoriasis.
Toker A, Kadı M, Yıldırım AK, Aksoy H, Akçay F.
Department of Biochemistry, Yoncali Hydrotherapy and Physical
Treatment Hospital, Kutahya, Turkey.
Psoriasis is a common chronic and recurrent inflammatory skin disease
with unknown etiology that has been associated with abnormal plasma
lipid metabolism and oxidative stress. There are controversial results
in the previous studies investigating oxidant/antioxidant systems in
psoriasis.The aim of this work was to evaluate dyslipidemia, oxidative
stress, total antioxidant capacity and serum paraoxonase (PON1) and
arylesterase (ARE) activities in psoriasis, and to look for a
correlation between these parameters and lesion percentage in
psoriasis.Thirty psoriatic patients and twenty three sex- and
agematched healthy volunteers were included in the study. From blood
samples, lipid profile, malondialdehyde (MDA) levels, total
antioxidant capacity (TAO), serum PON1 and ARE activities were
determined.No significant differences between the patients and
controls were found in terms of total cholesterol, triacylglycerol
(TAG), HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, MDA and TAO
levels. Serum PON1 and sodium-stimulated PON1 activities (p < 0.05)
and ARE activity (p < 0.01) were found significantly higher in the
patients than in the controls. There was not any significant
correlation between lesion percentage and the parameters studied.
Copyright (c) 2009 John Wiley & Sons, Ltd.
PMID: 19330810
http://en.wikipedia.org/wiki/Arylesterase
In enzymology, an arylesterase (EC 3.1.1.2) is an enzyme that
catalyzes the chemical reaction
a phenyl acetate + H2O a phenol + acetate
Thus, the two substrates of this enzyme are phenyl acetate and H2O,
whereas its two products are phenol and acetate.
This enzyme belongs to the family of hydrolases, specifically those
acting on carboxylic ester bonds. The systematic name of this enzyme
class is aryl-ester hydrolase. Other names in common use include A-
esterase, paraoxonase, and aromatic esterase. This enzyme participates
in bisphenol a degradation.
<sniP>
http://en.wikipedia.org/wiki/Paraoxonase
http://en.wikipedia.org/wiki/PON1
----
Pon1 found in only one hit in the p ng:
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/msg/e68fa17c04787adb
======================================
randall