title: Modeling the intra- and extracellular cytokine signaling pathway under heat stroke in the liver.
abstract: Heat stroke (HS) is a life-threatening illness induced by prolonged exposure to a hot environment that causes central nervous system abnormalities and severe hyperthermia. Current data suggest that the pathophysiological responses to heat stroke may not only be due to the immediate effects of heat exposure per se but also the result of a systemic inflammatory response syndrome (SIRS). The observation that pro- (e.g., IL-1) and anti-inflammatory (e.g., IL-10) cytokines are elevated concomitantly during recovery suggests a complex network of interactions involved in the manifestation of heat-induced SIRS. In this study, we measured a set of circulating cytokine/soluble cytokine receptor proteins and liver cytokine and receptor mRNA accumulation in wild-type and tumor necrosis factor (TNF) receptor knockout mice to assess the effect of neutralization of TNF signaling on the SIRS following HS. Using a systems approach, we developed a computational model describing dynamic changes (intra- and extracellular events) in the cytokine signaling pathways in response to HS that was fitted to novel genomic (liver mRNA accumulation) and proteomic (circulating cytokines and receptors) data using global optimization. The model allows integration of relevant biological knowledge and formulation of new hypotheses regarding the molecular mechanisms behind the complex etiology of HS that may serve as future therapeutic targets. Moreover, using our unique modeling framework, we explored cytokine signaling pathways with three in silico experiments (e.g. by simulating different heat insult scenarios and responses in cytokine knockout strains in silico).
authors.affiliation: Institute for Collaborative Biotechnologies, University of California Santa Barbara, Santa Barbara, California, United States of America ; Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Rodriguez-Fernandez
authors.forename: Benyamin
authors.initials: B
authors.lastname: Grosman
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Yuraszeck
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Helwig
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Leon
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Doyle
mesh_terms: D000818:Animals; D003198:Computer Simulation; D016207:Cytokines / Q000032:analysis / Q000097:blood / Q000276:immunology*; D005786:Gene Expression Regulation; D018883:Heat Stroke / Q000150:complications* / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics; D015398:Signal Transduction; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D014409:Tumor Necrosis Factor-alpha
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