Modeling the Intra- and Extracellular Cytokine Signaling Pathway under Heat Stroke in the Liver

Maria Rodriguez-Fernandez,Bryan G Helwig,Lisa R Leon,Theresa M Yuraszeck,Francis J Doyle Iii,Benyamin Grosman,Meijing Wang

doi:10.1371/journal.pone.0073393

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).

Highlights

Heat stroke (HS) is a life-threatening illness characterized by profound central nervous system dysfunction, severely elevated core temperature, as well as organ and tissue damage resulting from environmental heat exposure [1]
Mathematical Model of the Cytokines Network The primary mechanisms represented in this model are the following: activation of various transcription factors (TFs) by stimulation via a set of external and internal signals triggered by heat stress; regulation of cytokine and cytokine receptor gene transcription involved in the network by means of these TFs; translation of mRNA into proteins; transport of the soluble proteins to the pericellular milieu; binding of plasma cytokines to their cognate receptors; and signaling back to the TFs
Four TFs were assumed to be the primary regulators of this network, namely, heat shock factor 1 (HSF-1), nuclear factor-kB (NF-kB), activator protein 1 (AP-1), and signal transducer and activator of transcription 3 (STAT-3)

Summary

Introduction

Heat stroke (HS) is a life-threatening illness characterized by profound central nervous system dysfunction, severely elevated core temperature, as well as organ and tissue damage resulting from environmental heat exposure [1]. Environmental heat exposure is one of the most deadly natural hazards in the United States with ,200 deaths per year. Clinical and experimental evidence suggests that the pathophysiological responses to HS are the result of a systemic inflammatory response syndrome (SIRS) that ensues following HS collapse. The SIRS is regarded as a response to bacteria and/or endotoxin leakage across ischemicdamaged gut epithelial barrier membranes, which stimulates cytokine and other inflammatory pathways that are thought to mediate a variety of pathophysiological responses. Cytokines are important regulators of the acute-phase response (APR) to inflammation/injury and have been implicated as mediators of the SIRS with HS [6]

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