Pediatr Res. 2007 Apr;61(4):427-32. Polyunsaturated Fatty
Acid supplementation alters proinflammatory gene expression
and reduces the incidence of necrotizing enterocolitis
in a neonatal rat model. ·
Lu J, Jilling
T, Li D, Caplan
MS. Although supplementation of preterm formula with
polyunsaturated fatty acids (PUFA) has been shown to reduce the incidence
of necrotizing enterocolitis (NEC) in animal
models and clinical trials, the mechanisms remain elusive. We hypothesized
that the protective effect of PUFA on NEC may be due to the ability of PUFA
to suppress Toll-like receptor (TLR) 4 and platelet-activating factor receptor
(PAFR) gene expression (molecules that are important in the pathogenesis of
NEC) in epithelial cells. To investigate the efficacy of different PUFA
preparations on NEC in a neonatal rat model, we compared the incidence of
NEC among the four PUFA supplemented groups-A: arachidonic
acid and docosahexaenoic acid (AA+DHA), B: egg
phospholipids (EP), C: DHA, and D: control without PUFA. PUFA
supplementation reduced the incidence of NEC and inhibited intestinal PAFR
and TLR4 gene expression compared with the controls. To validate the in
vivo observations, IEC-6 cells were exposed to PAF after pretreatment with
AA or DHA. Both AA and DHA supplementation blocked PAF-induced TLR4 and
PAFR mRNA expression in these enterocytes. These
results suggest that PUFA modulates gene expression of key factors involved
in experimental NEC pathogenesis. These effects might in part explain the
protective effect of PUFA on neonatal NEC. ABBREVIATIONS:: PMID: 17515866 [PubMed - in
process] Proteins. 2007 Apr 1;67(1):41-52. Understanding
the regulation mechanisms of PAF receptor by agonists and antagonists:
molecular modeling and molecular dynamics simulation studies. ·
Gui
C, Zhu W, Chen G, Luo
X, Liew
OW, Puah
CM, Chen K, Jiang
H. Drug Discovery and Design Centre, Shanghai
Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai 201203, People's Republic of China. Platelet-activating factor receptor (PAFR) is a member
of G-protein coupled receptor (GPCR) superfamily.
Understanding the regulation mechanisms of PAFR by its agonists and
antagonists at the atomic level is essential for designing PAFR antagonists
as drug candidates for treating PAF-mediated diseases. In this study, a 3D
model of PAFR was constructed by a hierarchical approach integrating
homology modeling, molecular docking and molecular dynamics (MD)
simulations. Based on the 3D model, regulation mechanisms of PAFR by
agonists and antagonists were investigated via three 8-ns MD simulations on
the systems of apo-PAFR, PAFR-PAF and PAFR-GB.
The simulations revealed that binding of PAF to PAFR triggers the
straightening process of the kinked helix VI, leading to its activated
state. In contrast, binding of GB to PAFR locks PAFR in its inactive state.
(c) 2007 Wiley-Liss, Inc. PMID: 17243151 [PubMed -
indexed for MEDLINE J Pharmacol Exp Ther.
2007 Feb;320(2):728-37. Epub
2006 Nov 3. Platelet-activating
factor modulates activity of cyclic nucleotides in fetal ovine pulmonary
vascular smooth muscle. ·
Ibe
BO, Ameer
A, Portugal AM,
Renteria
L, Raj
JU. Division of Neonatology,
Department of Pediatrics, At birth, release of endogenous vasodilators such as
nitric oxide and prostacyclin facilitate
pulmonary vasodilation via the cyclic
nucleotides, cGMP and cAMP.
Interaction of cyclic nucleotides and platelet-activating factor
(PAF)-mediated responses in pulmonary vascular smooth muscle is not known.
We studied the effects of cGMP and cAMP on PAF-mediated responses in ovine fetal
intrapulmonary venous smooth muscle cells. Studies were done in hypoxia or normoxia with buffer with 8-Br-cGMP (BGMP) and
8-Br-cAMP (BAMP), as well as cGMP-dependent
protein kinase (PKG) and cAMP-dependent
protein kinase (PKA) inhibitors. All groups were
treated with 1 nM PAF and incubated for 30 min
for the binding assay or 20 min for measurement of inositol
1,4,5-phosphate (IP(3)) production. BGMP and BAMP
decreased PAF binding in normoxia by 63 and 14%,
respectively. Incubations with the PKG inhibitor
Rp-8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate sodium and the PKA inhibitor
Rp-adenosine-3',5'-cyclic monophosphorothioate
abrogated the inhibitory effects of BGMP and BAMP. PAF-stimulated IP(3) production was 8565 +/- 314 dpm/10(6) cells in
hypoxia and 5418 +/- 118 dpm/10(6) cells in normoxia,
a 40% decrease. BGMP attenuated PAF-stimulated IP(3)
production by 67 and 37% in hypoxia and normoxia,
respectively; the value for BAMP was 44% under both conditions.
Pretreatment with PKG or PKA inhibitor abrogated BGMP and BAMP inhibition
of IP(3) release. PAF receptor (PAFr) protein expression decreased in normoxia, but pretreatment with 10 nM
PAF up-regulated PAFr expression. Pretreatment
with PAF decreased expression and activities of PKG or PKA proteins in normoxia and hypoxia. Our data demonstrate the
existence of cGMP/cAMP-PAF cross-talk in
pulmonary vascular smooth muscle cells, which may be one mechanism by which
PAFr-mediated vasoconstriction is down-regulated
at birth. PMID: 17085546 [PubMed -
indexed for MEDLINE tion. Differential Regulation of CD40-Mediated TNF
Receptor-Associated Factor Degradation in B Lymphocytes. B Cell Maturation Antigen, the Receptor
for a Proliferation-Inducing Ligand and B
Cell-Activating Factor of the TNF Family, Induces Antigen Presentation in B
Cells. ICAM-1 gene expression in endothelial cells: Effects on the
inhibition of STAT3 phosphorylation.
Moore
CR, Bishop GA.
Interdisciplinary Graduate Program in Immunology.
Engagement of CD40 on murine B cells by its ligand CD154 induces the binding of TNFR-associated
factors (TRAFs) 1, 2, 3, and 6, followed by the
rapid degradation of TRAFs 2 and 3. TRAF
degradation occurs in response to signaling by other TNFR superfamily members, and is likely to be a normal
regulatory component of signaling by this receptor family. In this study,
we found that receptor-induced TRAF degradation limits TRAF2-dependent CD40
signals to murine B cells. However, TRAFs 1 and 6 are not degraded in response to CD40
engagement, despite their association with CD40. To better understand the
mechanisms underlying differential TRAF degradation, mixed protein domain
TRAF chimeras were analyzed in murine B cells.
Chimeras containing the TRAF2 zinc (Zn) domains induced effective
degradation, if attached to a TRAF domain that binds to the PXQXT motif of
CD40. However, the Zn domains of TRAF3 and TRAF6 could not induce
degradation in response to CD40, regardless of the TRAF domains to which
they were attached. Our data indicate that TRAF2 serves as the master
regulator of TRAF degradation in response to CD40 signaling, and this
function is dependent upon both the TRAF Zn domains and receptor binding
position.
PMID: 16148124 [PubMed - in process]
Yang M, Hase
H, Legarda-Addison
D, Varughese
L, Seed B, Ting AT.
B cell maturation Ag (BCMA), a member of the TNFR superfamily
expressed on B cells, binds to a proliferation-inducing ligand
(APRIL) and B cell-activating factor of the TNF family (BAFF) but the
specific B cell responses regulated by BCMA remain unclear. This study
demonstrates that ligation of A20 B cells transfected with BCMA induces the expression of CD40,
CD80/B7-1, CD86/B7-2, MHC class II, and CD54/ICAM-1, which subsequently
enhances the presentation of OVA peptide Ag to DO11.10 T cells. BCMA
expression in murine splenic
B cells can be induced with IL-4 and IL-6, allowing subsequent treatment
with APRIL or agonist anti-BCMA to similarly induce Ag presentation. A
comparative analysis of hybrid receptors of TNFR2 fused to the cytoplasmic domains of APRIL/BAFF receptors found that
only BCMA, but not transmembrane activator and
calcium-modulator and cyclophilin ligand interactor or BAFF-R,
is capable of activating Ag presentation. Although all three receptors can
trigger NF-kappaB signaling, only BCMA activates
the JNK pathway conferring on BCMA the specific ability to activate this Ag
presentation response.
PMID: 16116167 [PubMed - in process]
Resveratrol suppresses IL-6-induced
Wung
BS, Hsu MC, Wu CC, Hsieh CW.
Department of Applied Microbiology,
Resveratrol, a polyphenolic
phytoaxelin present in red wine, has been
suggested to protect against atherosclerosis and cardiovascular disease
because of its antioxidant effects. Intercellular adhesion molecule
(ICAM-1), induced by cytokines, has been hypothesized to play a role in the
early events during atherosclerosis. In this study we tested the effects of
resveratrol upon both IL-6-induced ICAM-1 gene
expression and its underlying signaling pathways in endothelial cells (ECs). Resveratrol was found
to inhibit both TNFalpha- and IL-6-induced ICAM-1
gene expression at the promoter, transcriptional and protein levels. Resveratrol also abrogates the tyr705 phosphorylation of STAT3 in IL-6-treated ECs, in a dose- and time-dependent manner. Although quercetin had similar effects, resveratrol
showed higher inhibitory properties following 2-4 h pretreatments. Resveratrol has been shown to induce the activity of
endothelial nitric oxide synthase (eNOS) and increase NO production. Consistent with this,
the treatment of ECs with a NO donor (SNAP)
reduces IL-6-induced STAT3 phosphorylation.
Conversely, exposure of ECs to a NOS inhibitor
reversed the effects of resveratrol upon
IL-6-induced STAT3 phosphorylation. Furthermore, ECs transfected with
constitutively active Rac1 (RacV12) showed increases in ICAM-1 promoter
activity, intracellular reactive oxygen species (ROS) levels and STAT3 phosphorylation, and these increases were attenuated by
resveratrol treatment. In summary, we demonstrate
for the first time that resveratrol inhibits
IL-6-induced ICAM-1 gene expression, in part, by interfering with Rac-mediated pathways via the attenuation of STAT3 phosphorylation. This study therefore provides
important new insights that may contribute to the proposed beneficial
effects of resveratrol in endothelial responses
to cytokines during inflammation.
PMID: 16150460 [PubMed - as supplied by
publisher]