Cytokine signaling in endothelial cells

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Title Cytokine signaling in endothelial cells
Publication Type dissertation
School or College School of Medicine
Department Pathology
Author Modur, Vijayanand R.
Date 1996-06
Description Endothelial cells mediate the inflammatory response by coordinating localization and activation of leukocytes via a concerted expression of adhesion molecules and cytokines. Adhesion molecule and cytokine gene expression occurs following activation of specific signaling pathways by endothelial cell agonists. The MAP kinase signaling pathways consist of a cascade of kinases that phosphorylate transcription factors to activate specific genes. The major MAP kinase pathways are the 'ERK' or 'growth' pathway and the 'stress' pathway. NF-?B, another mediator of endothelial gene expression, is normally sequestered by the I?B in the cytoplasm. However, certain stimuli cause degradation of I?B that results in NF-?B nuclear translocation. In the nucleus NF-?B activates transcription from NF-?B dependent promoters of adhesion molecule and cytokine genes. The major aim of this study was to describe signaling mechanisms involved in the induction of adhesion molecules and cytokines by the use of receptor and nonreceptor endothelial cell agonists. The nonreceptor agonists brown recluse spider venom and bacterial sphingomyelinase induced a pattern of gene expression distinct from tumor necrosis factor (TNF). Since TNF activation of NF-?B and MAP kinase was theorized to be downstream of sphingomyelin breakdown due to a TNF receptor associated sphingomyelinase, the results with nonreceptor sphingomyelin breakdown were intriguing. On elucidation of signaling pathways, TNF sends at least two signals. Sphingomyelin breakdown to ceramide activates the ERK MAP kinase pathway, and ceramide-independent activation of stress MAP kinases and NF-?B nuclear translocation. Another novel receptor agonist oncostatin M (OSM) was found to induce a pattern of gene expression distinct from both TNF and bacterial sphingomyelinase. At low concentrations, OSM caused potent ERK activation, but at higher concentrations it caused NF?B nuclear translocation in addition to ERK activation. This unmasked NF-?B-dependent and -independent mechanisms of endothelial cell adhesion molecule and cytokine expression. Furthermore, the above agonists did not induce the same characteristic responses in gene induction and signaling in transformed endothelial cells, showing that alteration in signaling pathways associated with cell transformation alters gene expression. In conclusion, integration of different signals at the promoters of adhesion molecule and cytokine genes mediates a coordinated inflammatory response by endothelial cells.
Type Text
Publisher University of Utah
Subject Cellular signal transduction; Cytokines; Endothelium
Subject MESH Signal Transduction; Cytokines; Endothelium
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Cytokine signaling in endothelial cells Spencer S. Eccles Health Sciences Library.
Rights Management © Vijayanand R. Modur.
Format application/pdf
Format Medium application/pdf
Format Extent 2,953,725 bytes
Identifier undthes,4073
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available)
Funding/Fellowship Nora Eccles Tredwell Foundation; United States Public Health grant NIHLBI#P50 HL 50153
Master File Extent 2,953,769 bytes
ARK ark:/87278/s6tt4svg
Setname ir_etd
ID 191924
Reference URL https://collections.lib.utah.edu/ark:/87278/s6tt4svg
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