Molecular Pathways Resultant in Fever due to Inhibitory Effects of Binding PGE2 to Glucocorticoid Receptors

Abstract

AbstractThermoregulation is crucial to homeostasis, but the mechanisms of its dysfunction are still largely mysterious, including fever, which is generally the most disconcerting sign of a serious infection or disease. Theories on body temperature dynamics that aim to explain a fever, such as changes in an internal setpoint, have been proposed, but none can identify the fundamental molecular pathways that produce a fever. Moreover, causative substances, pyrogens such as prostaglandin E2 (PGE2), have not been associated with receptors at the hypothalamus, which is responsible for autonomic control of temperature, and therefore no molecular path has been previously identified that can elucidate the causative reason for fever. Here, molecular pathways resultant in fever are identified for the first time. Based on recent developments made by this lab, which has shown that PGE2 possesses similar binding affinity as the hormone cortisol (CORT) at the critical ligand binding domain (LBD) of glucocorticoid receptors (GR); mathematical modeling and a case study for validation is used to present that competitive inhibition of CORT by PGE2 as the fundamental reason for dysfunctional dynamics of body temperature, including fever. The model characterizing temperature is in the form of a multivariable feedback controller comprised of a superposition of proportional and derivative terms of temperature, CORT, and PGE2 concentration at the hypothalamus thereby linking the cardiovascular, immune, and neural systems. The model constitutes a framework of linear equations that describes a closed-loop system of body temperature effects in response to infectious agents, triggering events, and other causal factors. The model is validated by examination of the transient and spectral characteristics of a three-day case history involving temperature trajectories after physical activity protocols in response to a standard vaccination of pneumococcal and influenza species. The framework for the development of the molecular pathways of fever is further proposed as extensible to other signs and symptoms of disease and emotional dysfunction whose causative source is competitive inhibition of PGE2 and CORT at the LBD of GR.Graphical Abstract