Google Groups no longer supports new Usenet posts or subscriptions. Historical content remains viewable.

Dismiss

Abscisic acid & PPAR (gamma) Block Inflammation ----> IBD <----

21 views

Skip to first unread message

randall

unread,

Dec 10, 2010, 6:50:38 PM12/10/10

I'll open and post the pubmed links below the article

http://www.eurekalert.org/pub_releases/2010-12/vt-rdh120910.php
Researchers discover how natural drug fights inflammation

Researchers at the Virginia Bioinformatics Institute at Virginia Tech
have discovered how abscisic acid, a natural plant hormone with known
beneficial properties for the treatment of disease, helps fight
inflammation.

The results (http://www.ncbi.nlm.nih.gov/pubmed/210882970),
which are published in the November 2010 Journal of Biological
Chemistry, reveal important new drug targets for the development of
treatments for inflammatory and immune-mediated diseases.

The scientists had reported some of the key molecular events in the
immune system of mice that contribute to inflammation-related disease,
including the involvement of a specific molecule found on the surface
of immune cells involved in the body's fight against infection (http://
www.ncbi.nlm.nih.gov/pubmed/21068720).
They have now gone one step further and revealed the mechanism by
which the natural drug abscisic acid interacts with this protein,
known as peroxisome proliferator-activated receptor-gamma, to block
inflammation and the subsequent onset of disease.

"In previous work, our research group demonstrated that abscisic acid
has beneficial effects on several conditions and diseases including
obesity-related inflammation, diabetes, atherosclerosis, and
inflammatory bowel disease," said Josep Bassaganya-Riera, associate
professor of immunology at the Virginia Bioinformatics Institute,
leader of the Nutritional Immunology and Molecular Medicine Group in
the institute's CyberInfrastructure Division, and principal
investigator of the study. "One idea for how abscisic acid reduces
inflammation in these instances is that it binds to a special region
of peroxisome proliferator-activated receptor-gamma, a binding site
known as the ligand-binding domain where the drug would be expected to
latch on to and exert its effect. Our results show that this is not
the case and, for the first time, we have demonstrated that abscisic
acid works independently of this ligand-binding domain of the
receptor."

"This information is significant because it suggests the existence of
new therapeutic targets or alternative modes of action that account
for the effects of abscisic acid in the immune system," added
Bassaganya-Riera. "Drugs that bind to the ligand-binding domain of
peroxisome proliferator-activated receptor-gamma such as Avandia are
associated with severe cardiovascular side effects. In contrast, the
newly discovered alternative mechanism of peroxisome proliferator-
activated receptor-gamma activation by abscisic acid does not appear
to be linked to any known adverse side effects, thereby representing a
promising new therapeutic avenue."

"The outcomes of this research illustrate the synergism that can
result from combining computational and experimental approaches to
characterize therapeutic targets", said David Bevan, associate
professor of biochemistry at Virginia Tech. "By using molecular
modeling approaches we were able to identify a potential binding site
for abscisic acid on the lanthionine synthetase C-like 2 protein, a
protein required for the beneficial health effects of abscisic acid.
We were also able, again using docking studies, to reveal reasons for
the lack of direct association of abscisic acid with peroxisome
proliferator-activated receptor-gamma, which was experimentally
validated by ligand-binding assays."

"Lanthionine synthetase C-like 2 represents the first step in a
pathway leading to activation of peroxisome proliferator-activated
receptor-gamma in immune cells by abscisic acid," said Raquel
Hontecillas, assistant professor of immunology at the Virginia
Bioinformatics Institute and one of the lead investigators of the
study. "We have also shown that abscisic acid affects the expression
of several genes involved in inflammation, metabolism and cell
signaling, which provides further clues for possible intervention
points in the treatment of inflammatory and immune-mediated
diseases."

The researchers hope to more closely pinpoint some of the new drug
targets in the molecular network of the immune response as they
continue to dissect the way that the naturally occurring drug abscisic
acid reduces damage due to inflammation. In addition, the novel
understanding on how abscisic acid works will be used to develop new
classes of drugs that target the same alternative pathway of
peroxisome proliferator-activated receptor-gamma activation, a
potentially safer approach than the use of drugs that target direct
binding to the receptor.

###

The research was funded by award number 5R01AT004308 from the National
Center for Complementary and Alternative Medicine at the National
Institutes of Health, European Commission grant number 224836, the
Ramon y Cajal Program, National Institute of Allergy and Infectious
Diseases Contract No. HHSN272200900040C, National Institute of Allergy
and Infectious Diseases Contract No. HHSN272201000056C, and funds from
the Nutritional Immunology and Molecular Medicine Laboratory.

About the Nutritional Immunology and Molecular Medicine Group

The Nutritional Immunology and Molecular Medicine Group conducts
translational research aimed at developing novel therapeutic and
prophylactic approaches for modulating immune and inflammatory
responses. The group combines computational modeling, bioinformatics
approaches, pre-clinical experimentation and human clinical studies to
better understand the mechanisms of immune regulation at mucosal
surfaces and ultimately accelerate the development of novel treatments
for infectious and immune-mediated diseases. Learn more at: www.vbi.vt.edu/nimm

Learn more about Josep Bassaganya-Riera at
https://www.vbi.vt.edu/vbi_faculty/vbi_persons/dev_vbi_faculty?personId=177

Kofi

unread,

Dec 10, 2010, 11:51:38 PM12/10/10

Stimulating PPARgamma can be a problem viz. adiposity and heart
function. It's unclear if abscisic acid dodges this. Celiacs might
want to be careful fooling around with PPARgamma since this might stir
up transglutaminase.

From my previous postings here, you should know the IDO/niacin pathway
well by now. PGD2, synthesized by niacin, predicts better recovery from
IBD. 15d-PGJ2 is a PPARgamma agonist.

AA -> COX2 -> PGD2 -> 15d-PGJ2 -> PPARgamma, macrophages, mu opioid, NGF
-> NO/cGMP/PKG/KATP+ (see hyperbaric O2, eNOS/SIRT1/NGF info)

PGD2 -> 15d-PGJ2 -> PPARgamma, macrophages -> NO/cGMP/PKG/KATP+
!
! AKR1C3 (Aldo-keto reductase (AKR) 1C3)
v
9alpha11beta-PGF(2alpha) / PGF2alpha

The fact that low-dose naltrexone helps to upregulate the mu opioid
receptor might indicate that mu opioid receptor levels are naturally
deficient in certain diseases like Crohn's, M.S. and cancer. Loss of
15d-PGJ2 or some other PPARgamma deficiency could plausibly explain why
LDN is beneficial in these diseases.

Human peripheral CD4(+)CD25(-) T cells can be induced to express Foxp3
when activated in vitro by TCR stimulation with TGF-beta and IL-2.
However, these TGF-beta-induced Foxp3(+) regulatory T cells (iTregs)
lack a regulatory phenotype. From libraries of nuclear receptor ligands
and bioactive lipids, we screened three peroxisome
proliferator-activated receptor (PPAR)alpha (bezafibrate, GW7647, and
5,8,11,14-eicosatetraynoic acid) and two PPARgamma agonists (ciglitazone
and 15-deoxy--(12,14)-PG J(2)) as molecules that increased Foxp3
expression in human iTregs significantly compared with that in
DMSO-treated iTregs (control). These PPARalpha and PPARgamma
agonist-treated iTregs maintained a high level of Foxp3 expression and
had suppressive properties. There were no significant differences in the
suppressive properties of iTregs treated with the three PPARalpha and
two PPARgamma agonists, and all of the treated iTregs increased
demethylation levels of the Foxp3 promoter and intronic conserved
noncoding sequence 3 regions. Furthermore, PPARalpha and PPARgamma
agonists, together with TGF-beta, more strongly inhibited the expression
of all three DNA methyltransferases (DNMTs) (DNMT1, DNMT3a, and DNMT3b)
in activated CD4(+) T cells; PPARalpha and PPARgamma agonists together
with TGF-beta elicit Foxp3 DNA demethylation through potent
downregulation of DNMTs and induce potent and stable Foxp3 expression,
resulting in the generation of functional iTregs. Moreover, trichostatin
A and retinoic acid enhanced the generation of iTregs synergistically
with PPARalpha and PPARgamma agonists [PMID 21057085], ³Peroxisome
Proliferator-Activated Receptor {alpha} and {gamma} Agonists Together
with TGF-{beta} Convert Human CD4+CD25- T Cells into Functional Foxp3+
Regulatory T Cells²

Inhibitors of DNA methyltransferase (Dnmt) and histone deacetylases
(HDAC) synergistically activate the methylated metallothionein I gene
(MT-I) promoter in mouse lymphosarcoma cells. The cooperative effect of
these two classes of inhibitors on MT-I promoter activity was robust
following demethylation of only a few CpG dinucleotides by brief
exposure to 5-azacytidine (5-AzaC) but persisted even after prolonged
treatment with the nucleoside analog. HDAC inhibitors (trichostatin A
[TSA] and depsipeptide) either alone or in combination with 5-AzaC did
not facilitate demethylation of the MT-I promoter. Treatment of cells
with HDAC inhibitors increased accumulation of multiply acetylated forms
of H3 and H4 histones that remained unaffected after treatment with
5-AzaC. Chromatin immunoprecipitation (ChIP) assay showed increased
association of acetylated histone H4 and lysine 9 (K9)-acetyl H3 with
the MT-I promoter after treatment with TSA, which was not affected
following treatment with 5-AzaC. In contrast, the association of
K9-methyl histone H3 with the MT-I promoter decreased significantly
after treatment with 5-AzaC and TSA. ChIP assay with antibodies specific
for methyl-CpG binding proteins (MBDs) demonstrated that only methyl-CpG
binding protein 2 (MeCP2) was associated with the MT-I promoter, which
was significantly enhanced after TSA treatment. Association of histone
deacetylase 1 (HDAC1) with the promoter decreased after treatment with
TSA or 5-AzaC and was abolished after treatment with both inhibitors.
Among the DNA methyltransferases, both Dnmt1 and Dnmt3a were associated
with the MT-I promoter in the lymphosarcoma cells, and association of
Dnmt1 decreased with time after treatment with 5-AzaC. Treatment of
these cells with HDAC inhibitors also increased expression of the MTF-1
(metal transcription factor-1) gene as well as its DNA binding activity.
In vivo genomic footprinting studies demonstrated increased occupancy of
MTF-1 to metal response elements of the MT-I promoter after treatment
with both inhibitors. Analysis of the promoter by mapping with
restriction enzymes in vivo showed that the MT-I promoter attained a
more open chromatin structure after combined treatment with 5-AzaC and
TSA as opposed to treatment with either agent alone. These results
implicate involvement of multifarious factors including modified
histones, MBDs, and Dnmts in silencing the methylated MT-I promoter in
lymphosarcoma cells. The synergistic activation of this promoter by
these two types of inhibitors is due to demethylation of the promoter
and altered association of different factors that leads to
reorganization of the chromatin and the resultant increase in
accessibility of the promoter to the activated transcription factor
MTF-1 [PMID 12417732]

low doses of insulin-sensitizing drugs (PPARgamma agonists) might be
useful as vaccine adjuvants, particularly for people with weakened
immune systems who cannot produce a proper antibody response. This would
include some infants, the elderly, and patients with chronic health
problems that lower immunity; Currently the only widely approved vaccine
adjuvant in the United States is alum. A vaccine adjuvant is a substance
added to a vaccine to improve the body's immune response. Various forms
of aluminum salts have been used for 70 years. (Adjuvants are added to
some vaccines but not all. For example, live viral vaccines given during
childhood and seasonal flu vaccines do not contain adjuvants.); a
protein called PPAR gamma and its ligands, which are present inside B
cells and are involved in inflammation and in regulating the properties
of immune cells and cancer cells. The way B cells evolve, or
differentiate, is central to the body's immune response; A closer
examination of the role of PPAR gamma in relation to B cell function
showed that PPAR levels increase upon B cell activation, according to a
study published in 2009 by Phipps' laboratory in the Journal of
Immunology; any molecule that binds to and activates PPAR gamma would,
in turn, improve B cell secretion of antibodies. Researchers tested both
natural and synthetic PPAR gamma ligands and discovered that the
synthetic molecules used to create anti-diabetic drugs such as Actos and
Avandia stimulated human and mouse B cells to better produce antibodies;
the drawback, Phipps said, is the possibility that too much stimulation
would cause the immune system to overreact, triggering autoimmune
diseases such as rheumatoid arthritis or lupus. Additional research is
needed to better understand this process
<http://www.sciencedaily.com/releases/2010/08/100804161632.htm>, [T. M.
Garcia-Bates, C. J. Baglole, M. P. Bernard, T. I. Murant, P. J.
Simpson-Haidaris, R. P. Phipps. Peroxisome Proliferator-Activated
Receptor Gamma Ligands Enhance Human B Cell Antibody Production and
Differentiation. The Journal of Immunology, 2009; 183 (11): 6903 DOI:
10.4049/jimmunol.0900324]

PPARgamma critically regulates adipogenesis and lipogenesis. Obesity is
closely associated with increased oxidative stress, and pharmacological
activation of PPARgamma by its ligands significantly suppresses
oxidative stress in cultured adipocytes. On the other hand, a
PPARgamma2(Pro12Ala) polymorphism, which decreases receptor
transcription activity, is associated with lower body mass index and
increased insulin sensitivity in humans. This mutation is also found to
be positively associated with increased human lifespan. Here we show
that adipose tissue-specific PPARgamma heterozygous mice, which exhibit
significant improvement in insulin sensitivity in skeletal muscle, show
increased resistance to paraquat-induced oxidative stress. The enhanced
oxidative stress tolerance is associated with significant upregulation
of antioxidant genes in white adipose tissue and skeletal muscle whereas
prooxidant genes are not changed. This is also associated with a
significant increase in adipose tissue of Foxo3a, a transcription factor
that is known to regulate clearance of reactive oxygen species.
Consistently, Foxo3a dependent genes are significantly upregulated in
adipose tissue. These data implicate adipose tissue PPARgamma in the
regulation of oxidative stress, which may underlie extended lifespan in
humans bearing PPARgamma2(Pro12Ala) mutation [PMID 18083318]

PPARalpha activates SIRT1 during fasting and PPARalpha is a proxy for
NADH/NAD+, lactate/pyruvate ratio;; Calorie restriction (CR) extends
lifespans in a wide variety of species. CR induces an increase in the
NAD(+)/NADH ratio in cells and results in activation of SIRT1, an
NAD(+)-dependent protein deacetylase that is thought to be a metabolic
master switch linked to the modulation of lifespans. CR also affects the
expression of peroxisome proliferator-activated receptors (PPARs). The
three subtypes, PPARalpha, PPARgamma, and PPARbeta/delta, are expressed
in multiple organs. They regulate different physiological functions such
as energy metabolism, insulin action and inflammation, and apparently
act as important regulators of longevity and aging. SIRT1 has been
reported to repress the PPARgamma by docking with its co-factors and to
promote fat mobilization. However, the correlation between SIRT1 and
other PPARs is not fully understood. CR initially induces a fasting-like
response. In this study, we investigated how SIRT1 and PPARalpha
correlate in the fasting-induced anti-aging pathways. A 24-h fasting in
mice increased mRNA and protein expression of both SIRT1 and PPARalpha
in the livers, where the NAD(+) levels increased with increasing
nicotinamide phosphoribosyltransferase (NAMPT) activity in the NAD(+)
salvage pathway. Treatment of Hepa1-6 cells in a low glucose medium
conditions with NAD(+) or NADH showed that the mRNA expression of both
SIRT1 and PPARalpha can be enhanced by addition of NAD(+), and decreased
by increasing NADH levels. The cell experiments using SIRT1 antagonists
and a PPARalpha agonist suggested that PPARalpha is a key molecule
located upstream from SIRT1, and has a role in regulating SIRT1 gene
expression in fasting-induced anti-aging pathways [PMID 20148352]

PPAR transcription factors are pharmaceutical drug targets for treating
diabetes, atherosclerosis, and inflammatory degenerative diseases. The
possible mechanism of interaction between the three PPAR isotypes
(alpha, beta/delta, and gamma) is not yet clear. However, this is
important both for understanding transcription factor regulation and for
the development of new drugs. The present study was designed to compare
the effects of combinations of synthetic agonists of PPARalpha
[2-[4-[2-[4-cyclohexylbutyl (cyclohexylcarbamoyl)amino]ethyl]phenyl]
sulfanyl-2-methylpropanoic acid (GW7647)], PPARbeta/delta
[4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid,
(L-165041)], and PPARgamma (rosiglitazone, ciglitazone) on inflammatory
gene regulation in rat primary astrocytes. We measured COX-2 expression
and prostaglandin E(2) synthesis in LPS-stimulated cells. PPARalpha,
PPARbeta/delta, and PPARgamma knockdown models served to delineate the
contribution of each PPAR isotype. Thiazolidinediones enhanced the
LPS-induced COX-2 expression via PPARgamma-dependent pathway, whereas
L-165041 and GW7647 had no influence. However, the addition of L-165041
potentiated the effect of PPARgamma activation through
PPARbeta/delta-dependent mechanism. On the contrary, PPARalpha
activation (GW7647) suppressed the effect of the combined
L-165041/rosiglitazone application. The mechanism of the interplay
arising from combined applications of PPAR agonists involves changes in
PPAR expression levels. A PPARbeta/delta overexpression model confirmed
that PPARbeta/delta expression level is the point at which PPARgamma and
PPARalpha pathways converge in control of COX-2 gene expression. Thus,
we discovered that in primary astrocytes, PPARgamma has a positive
influence and PPARalpha has a negative influence on PPARbeta/delta
expression and activity. A positive/negative-feedback loop is formed by
PPARbeta/delta-dependent increase in PPARalpha expression level. These
findings elucidate a novel principle of regulation in the signaling by
synthetic PPAR agonists that involves modulating the interaction between
PPARalpha,-beta/delta, and -gamma isoforms on the level of their
expression [PMID 19483106]

statins upregulate PPARalpha/PPARgamma on macrophages via 15d-PGJ2 [PMID
17463321]

gamma tocopherol activates PPARgamma (a TGF-B antagonist) in skin
keratinocytes and transglutaminase-1, a PPARgamma target gene involved
in terminal keratinocyte differentiation [PMID 16530159]

Despite the magnitude of the obesity epidemic, the mechanisms that
contribute to increases in fat mass and to differences in fat depots are
still poorly understood. Prostanoids have been proposed as potent
adipogenic hormones, e.g. metabolites of prostaglandin J2 (PGJ2) bind
and activate PPARgamma. We hypothesize that an altered expression of
enzymes in PGJ2 synthesis may represent a novel pathogenic mechanism in
human obesity. We characterized adipose depot-specific expression of
enzymes in PGJ2 synthesis, prostaglandin transporter and PPARgamma
isoforms. Paired omental and subcutaneous adipose tissue samples were
obtained from 26 women undergoing elective abdominal surgery; All
enzymes involved in prostaglandin synthesis were expressed in both
adipose tissues. Expression of prostaglandin synthase-1 (PGHS1),
prostaglandin D synthase (PTGDS), human prostaglandin transporter (hPGT)
and PPARgamma2 was higher in OM adipose tissue compared to SC, whereas
17beta-hydroxysteroid dehydrogenase 5 (AKR1C3) showed predominance in SC
adipose tissue. In SC adipose tissue, PGHS1 mRNA expression increased
with BMI. The differential, depot-specific expression of key enzymes
involved in transport, synthesis and metabolism of prostaglandins may
have an important impact upon fat cell biology and may help to explain
some of the observed depot-specific differences. In addition, the
positive correlation between PGHS1 and BMI offers the novel hypothesis
that the regulation of PG synthesis may have a role in determining fat
distribution in human obesity [PMID 16842938]; overexpression of AKR1C3
in breast cancer reduces the antiproliferative qualities of PGD2/PGJ2
(PPARgamma?) and encourages estrogen receptor alpha induced
proliferation via its effect on estrone which increases the
17beta-estradiol:progesterone ratio [PMID 20036328]; indomethacin
selectively inhibits AKR1C3 without affecting AKR1C1 or AKR1C2; NSAID
and melatonin analogs are similarly valuable potential treatments for
breast cancer as AKR1C3 inhibitors [PMID 19010312]

PPARgamma may clear out homocysteine;; Diabetes and hyperhomocysteinemia
(HHcy) are two independent risk factors for glomeruloslerosis and renal
insufficiency. Although PPARgamma agonists such as ciglitazone (CZ) are
known to modulate diabetic nephropathy, the role of CZ in
diabetes-associated HHcy and renopathy is incompletely defined. We
tested the hypothesis that induction of PPARgamma by CZ decreases tissue
Hcy level; this provides a protective role against diabetic nephropathy.
C57BL/6J mice were administered alloxan to create diabetes. Mice were
grouped to 0, 1, 10, 12, and 16 wk of treatment; only 12- and 16-wk
animals received CZ in drinking water after a 10-wk alloxan treatment.
In diabetes, PPARgamma cDNA, mRNA, and protein expression were
repressed, whereas an increase in plasma and glomerular Hcy levels was
observed. CZ normalized PPARgamma mRNA and protein expression and
glomerular level of Hcy, whereas plasma level of Hcy remained unchanged.
GFR was dramatically increased at 1-wk diabetic induction, followed by
hypofiltration at 10 wk, and was normalized by CZ treatment. This result
corroborated with glomerular and preglomerular arteriole histology. A
steady-state increase of RVR in diabetic mice became normal with CZ
treatment. CZ ameliorated decrease bioavailability of NO in the diabetic
animal. Glomerular MMP-2 and MMP-9 activities as well as TIMP-1
expression were increased robustly in diabetic mice and normalized with
CZ treatment. Interestingly, TIMP-4 expression was opposite to that of
TIMP-1 in diabetic and CZ-treated groups. These results suggested that
diabetic nephropathy exacerbated glomerular tissue level of Hcy, and
this caused further deterioration of glomerulus. CZ, however, protected
diabetic nephropathy in part by activating PPARgamma and clearing
glomerular tissue Hcy [PMID 18780770]; PPARgamma activation also
activates innate antimicrobial defensins in the colon [PMID 20421464]

15d-PGJ(2) has a potential peripheral antinociceptive and
anti-inflammatory effect in the TMJ via PPAR-gamma activation. The
results also suggest that 15d-PGJ(2) induced-peripheral antinociceptive
response in the TMJ is mediated by kappa/delta opioid receptors by the
activation of the intracellular l-arginine/NO/cGMP/K(+)(ATP) channel
pathway. The pharmacological properties of the peripheral administration
of 15d-PGJ(2) highlight the potential use of this PPAR-gamma agonist on
TMJ inflammatory pain conditions [PMID 19647045]; 15d-PGJ2 inhibits
inflammatory hypernociception via PPAR-gamma activation. This effect
seems to be dependent on endogenous opioids and local macrophages [PMID
17928570]

The opioid growth factor (OGF) regulates cell proliferation of human
cancer cells through the cyclin-dependent kinase inhibitory pathway,
with mediation of this action by the OGF receptor (OGFr). The ubiquity
of the OGF-OGFr axis in human cancer is unknown. We used 31 human cancer
cell lines, representative of more than 90% of neoplasias occurring in
humans, and found that OGF and OGFr were detected in the cytoplasm and
nucleus by immunohistochemistry. The addition of OGF to cultures
depressed cell number up to 41%, whereas naltrexone (NTX) increased cell
proliferation by up to 44%, a total of 85% in the modulating capacity
for the OGF-OGFr axis. Neutralization of OGF by specific antibodies led
to a marked increase in cell number. Knockdown of OGFr by OGFr-siRNA
resulted in a significant increase in the number of cells, even in the
face of the addition of exogenous OGF. The cultures to which NTX was
added and subjected to OGFr-siRNA were similar to those with OGF-siRNA
alone. The OGF-OGFr axis, a physiological determinant of
cell-proliferative activity, is a ubiquitous feature of human cancer
cells. The identification of this native biological system in neoplasia
may be important in understanding the pathophysiology of neoplasia, and
in designing treatment modalities that utilize the body's own chemistry
[PMID 19675283]

Immunobiology. 2010 Jun 11

B lymphocyte proliferation is suppressed by the opioid growth
factor-opioid growth factor receptor axis: Implication for the treatment
of autoimmune diseases.
Zagon IS, Donahue RN, Bonneau RH, McLaughlin PJ.
Department of Neural and Behavioral Sciences, The Pennsylvania State
University, College of Medicine, Hershey, PA, United States.

Endogenous opioids are known to repress the incidence and progression of
autoimmune diseases. One native opioid peptide, [Met(5)]-enkephalin,
termed the opioid gowth factor (OGF), interacts with the OGF receptor
(OGFr) to suppress the expression of experimental autoimmune
encephalomyelitis. The present study examined the role of the OGF-OGFr
axis in the regulation of B lymphocyte proliferation. Murine B
lymphocytes were stimulated with lipopolysaccharide. Both OGF and OGFr
were present in all B lymphocytes. OGF had a dose-dependent effect on
growth, with cell number inhibited by up to 43% at 72h; no other
synthetic or native opioid altered cell proliferation. Exogenous OGF
depressed cell number in cultures treated with siRNAs for the classical
opioid receptors, MOR (mu), DOR (delta), and KOR (kappa), however this
peptide had no effect in preparations exposed to siRNA for OGFr. The
decrease in cell number by exogenous OGF was dependent on p16 or p21
cyclin-dependent inhibitory kinase pathways. Exposure to the opioid
antagonist, naltrexone, did not change cell number from control levels.
These results suggest that the OGF-OGFr axis is present and functional
in B lymphocytes, but this system is not an autocrine regulator of cell
proliferation. Thus, at least exogenous OGF and perhaps endogenous OGF
by paracrine/endocrine sources, can be an immunosuppressant. Modulation
of the OGF-OGFr axis may be a novel paradigm for the treatment of
autoimmune diseases. Copyright (c) 2010 Elsevier GmbH. All rights
reserved.

PMID: 20598772

<http://www.sciencedaily.com/releases/2010/08/100823162328.htm>

0 new messages