Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells

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dc.contributor.authorFu, Yanen
dc.contributor.authorGlaros, Trevoren
dc.contributor.authorZhu, Mengen
dc.contributor.authorWang, Piangen
dc.contributor.authorWu, Zhanghanen
dc.contributor.authorTyson, John J.en
dc.contributor.authorLi, Liwuen
dc.contributor.authorXing, Jianghuaen
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2016-12-09T21:39:31Zen
dc.date.available2016-12-09T21:39:31Zen
dc.date.issued2012-05-01en
dc.description.abstractThe 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.en
dc.description.sponsorshipThis work was supported by the National Science Foundation grant DMS-0969417 and NIH grant AI099120 (JX), NIH grant AI064414 and an American Heart Grant-in-Aid (LL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.description.versionPublished versionen
dc.format.extent14 pagesen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationFu Y, Glaros T, Zhu M, Wang P, Wu Z, et al. (2012) Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells. PLoS Comput Biol 8(5): e1002526. doi:10.1371/journal.pcbi.1002526en
dc.identifier.doihttps://doi.org/10.1371/journal.pcbi.1002526en
dc.identifier.issn1553-734Xen
dc.identifier.issue5en
dc.identifier.urihttp://hdl.handle.net/10919/73639en
dc.identifier.urlhttp://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1002526en
dc.identifier.volume8en
dc.language.isoenen
dc.publisherPLOSen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000305964600033&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectBiochemical Research Methodsen
dc.subjectMathematical & Computational Biologyen
dc.subjectBiochemistry & Molecular Biologyen
dc.subjectRECEPTOR-ASSOCIATED KINASEen
dc.subjectNECROSIS-FACTOR-ALPHAen
dc.subjectFACTOR-KAPPA-Ben
dc.subjectNEGATIVE REGULATIONen
dc.subjectSIGNALING PATHWAYSen
dc.subjectSYSTEMS BIOLOGYen
dc.subjectGENE-EXPRESSIONen
dc.subjectINTERLEUKIN-1 RECEPTORen
dc.subjectMACROPHAGE ACTIVATIONen
dc.subjectINFLAMMATORY RESPONSEen
dc.titleNetwork Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cellsen
dc.title.serialPLOS Computational Biologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/Scienceen
pubs.organisational-group/Virginia Tech/Science/Biological Sciencesen
pubs.organisational-group/Virginia Tech/Science/COS T&R Facultyen
pubs.organisational-group/Virginia Tech/University Distinguished Professorsen

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