TNF α: A Trigger of Autonomic Dysfunction

Abstract

During disease, infection, or trauma, the cytokine tumor necrosis factor α (TNF α ) causes fever, fatigue, malaise, allodynia, anorexia, gastric stasis associated with nausea, and emesis via interactions with the central nervous system. Our studies have focused on how TNF α produces a profound gastric stasis by acting on vago-vagal reflex circuits in the brainstem. Sensory elements of this circuit (i.e., nucleus of the solitary tract [NST] and area postrema) are activated by TNF α . In response, the efferent elements (i.e., dorsal motor neurons of the vagus) cause gastroinhibition via their action on the gastric enteric plexus. We find that TNF α presynaptically modulates the release of glutamate from primary vagal afferents to the NST and can amplify vagal afferent responsiveness by sensitizing presynaptic intracellular calcium-release mechanisms. The constitutive presence of TNF α receptors on these afferents and their ability to amplify afferent signals may explain how TNF α can completely disrupt autonomic control of the gut. KeywordsImmune-neural interactions; Gastric stasis; Visceral malaise; Hypersensitivity; Potentiation; Allodynia; Illness behavior Immune system activation in response to infection or injury initiates a constellation of physiological and behavioral changes that include fever, fatigue, listlessness, loss of appetite, malaise, nausea, emesis, hypersensitivity to touch or pain, and significant changes in sleep patterns (Hermann, Holmes, and Rogers 2005). This Ȝsickness behaviorȝ represents an attempt by the host to reorganize its physiological priorities following injury or infection. For example with infection, an elevation in body temperature may help destroy the microorganisms, and the loss of appetite and emesis will minimize ingestion and cause elimination of pathogens and toxins. The reduction in activity caused by allodynia and increased sleep will act to immobilize the host, thus conserving available energy resources (Turrin and Plata-Salaman 2000).These physiological changes are caused by the endocrine-like and paracrine-like actions of signal molecules called cytokines. Cytokines are released by immune effector cells as well as a variety of nonimmune cell types (e.g., Guzik and others 2006;Muller and Meineke 2007). The production of cytokines by the immune system in response to infection or injury plays a critical role in coordinating the host's defense (e.g., Correa and others 2007;Kaisho and Akira 2006). The process is triggered by interactions with transmembrane proteins, Toll-like receptors that are mainly expressed on antigen-presenting cells such as macrophages or dendritic cells and provoke the release of proinflammatory cytokines (e.g., Copyright © 2008 Sage Publications Address correspondence to: Gerlinda E. Hermann and Richard C. Rogers, Laboratory of Autonomic Neurosciences, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA 70808 (HermanGE@pbrc.edu; RogersRC@pbrc.edu). NIH Public Access Brainstem Visceral Autonomic ControlThe dorsal vaga...

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