137 research outputs found
Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells
The innate immune system, acting as the first line of host defense, senses
and adapts to foreign challenges through complex intracellular and
intercellular signaling networks. Endotoxin tolerance and priming elicited by
macrophages are classic examples of the complex adaptation of innate immune
cells. Upon repetitive exposures to different doses of bacterial endotoxin
(lipopolysaccharide) or other stimulants, macrophages show either suppressed or
augmented inflammatory responses compared to a single exposure to the
stimulant. Endotoxin tolerance and priming are critically involved in both
immune homeostasis and the pathogenesis of diverse inflammatory diseases.
However, the underlying molecular mechanisms are not well understood. By means
of a computational search through the parameter space of a coarse-grained
three-node network with a two-stage Metropolis sampling approach, we enumerated
all the network topologies that can generate priming or tolerance. We
discovered three major mechanisms for priming (pathway synergy, suppressor
deactivation, activator induction) and one for tolerance (inhibitor
persistence). These results not only explain existing experimental
observations, but also reveal intriguing test scenarios for future experimental
studies to clarify mechanisms of endotoxin priming and tolerance.Comment: 15 pages, 8 figures, submitte
Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin
Recent genomic analyses of pathologically-defined tumor types identify βwithin-a-tissueβ disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies
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Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: The role for KDR and MMP-9
Interleukin-6 (IL-6) is involved in angiogenesis. However, the underlying mechanisms are unknown. Using human cerebral endothelial cell (HCEC), we report for the first time that IL-6 triggers HCEC proliferation and migration in a dose-dependent manner, specifically associated with enhancement of VEGF expression, up-regulated and phosphorylated VEGF receptor-2 (KDR), and stimulated MMP-9 secretion. We investigated the signal pathway of IL-6/IL-6R responsible for KDR's regulation. Pharmacological inhibitor of P13K failed to inhibit IL-6-mediated VEGF overexpression, while blocking ERK1/2 with PD98059 could abolish IL-6-induced KDR overexpression. Further, neutralizing endogenous VEGF attenuated KDR expression and phosphorylation, suggesting that IL-6-induced KDR activation is independent of VEGF stimulation. MMP-9 inhibitor GM6001 significantly decreases HCEC proliferation and migration (p < 0.05), indicating the crucial function of MMP-9 in promoting angiogenic changes in HCECs. We conclude that IL-6 triggers VEGF-induced angiogenic activity through increasing VEGF release, up-regulates KDR expression and phosphorylation through activating ERK1/2 signaling, and stimulates MMP-9 overexpression. (c) 2006 Elsevier Inc. All rights reserved
Participation of PI3K and ERK1/2 pathways are required for human brain vascular smooth muscle cell migration
Human brain vascular smooth muscle cell (HBVSMC) migration contributes to angiogenesis and several pathological processes in the brain. However, the molecular mechanism of angiogenesis, in which smooth muscle cell contributes, remains unclear. Our study investigates the role of vascular endothelial growth factor (VEGF) in the HBVSMC migration and elucidates the chemotactic signaling pathway mediating this action. We used the in vitro \u27scratch\u27 wound method to detect the HBVSMC migration. VEGF(165) (1-40ng/ml) induced the HBVSMC migration in a dose-dependent manner (P\u3c0.05). VEGF(165) does not induce HBVSMC proliferation. Wortmannin, a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly inhibited serine/threonine kinase Akt/protein kinase B (PKB) phosphorylation and reduced HBVSMC migration into the wound edge following VEGF(165) stimulation (P\u3c0.05). PD98059, an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, also significantly inhibited ERK1/2 phosphorylation and reduced the numbers of SMC migration. Parallel distance measurement showed that VEGF(165) induced HBVSMC migration significantly reduced due to inhibition of PI3K or ERK1/2 phosphorylation (P\u3c0.05). Our results demonstrate that VEGF(165) could induce HBVSMC migration but not proliferation in vitro. Inhibiting Akt/PKB or ERK1/2 phosphorylation could reduce VEGF(165) induced HBVSMC migration. We provide the first evidence that activation of PI3K or ERK1/2 pathways are a crucial event in VEGF(165) mediated signal transduction leading to HBVSMC migration
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Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling
Abnormal vascular remodeling mediated by inflammatory cells has been identified as a key pathologic component of various vascular diseases, including abdominal aortic aneurysms, brain arteriovenous malformations and atherosclerosis. Based on findings from observational studies that analysed human intracranial aneurysms and experimental studies that utilized animal models, an emerging concept suggests that a key component of the pathophysiology of intracranial aneurysms is sustained abnormal vascular remodeling coupled with inflammation. This concept may provide a new treatment strategy to utilize agents to inhibit inflammation or cytokines produced by inflammatory cells such as matrix metalloproteinases. Such an approach would aim to stabilize these vascular lesions and prevent future expansion or rupture
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