Cytokine, Sickness Behavior, and Depression

Abstract

SummarySufficient evidence is now available to accept the concept that the brain recognizes cytokines as molecular signals of sickness. Clarifying the way the brain processes information generated by the innate immune system is accompanied by a progressive elucidation of the cellular and molecular components of the intricate system that mediates cytokine-induced sickness behavior. We are still far, however, from understanding the whole. Among the hundreds of genes that proinflammatory cytokines can induce in their cellular targets, only a handful has been examined functionally. In addition, a dynamic view of the cellular interactions that occur at the brain sites of cytokine production and action is missing, together with a clarification of the mechanisms that favor the transition toward pathology.Anyone who has experienced an episode of viral or bacterial infection knows well the subjective feelings of sickness, in the form of malaise, lassitude, fatigue, numbness, coldness, muscle and joint aches, and reduced appetite. Because they are common, these symptoms usually are ignored by physicians. They are considered uncomfortable, but banal, components of the pathogen-induced debilitation process that affects sick individuals.This simplistic view has turned out to be incorrect. The psychologic and behavioral components of sickness represent, together with fever response and associated neuroendocrine changes, a highly organized strategy of the organism to fight infection [1]. This strategy, referred to as "sickness behavior," is triggered by the proinflammatory cytokines produced by activated cells of the innate immune system in contact with specific pathogen-associated molecular patterns (PAMPs). These cytokines include mainly interleukin (IL) 1 (IL-1α and IL-1β), IL-6, and tumor necrosis factor α (TNF-α).The mechanisms that mediate the behavioral effects of peripherally released cytokines have been elucidated during the past fifteen years. IL-1 and other cytokines act on the brain via two main communication pathways: (1) a neural route represented by the primary afferent neurons that innervate the body site where the infectious process takes place and (2) a humoral pathway that involves the production of proinflammatory cytokines by phagocytic cells in the circumventricular organs (CVOs) and choroid plexus in response to circulating PAMPs or cytokines, followed by the propagation of these immune signals into the brain parenchyma (Fig. 1) [2]. The objective of this review is to present the current knowledge on the way this communication system is organized and regulated and the implications of these advances for understanding brain physiology and pathology.

Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression

“…The role of both brain and peripheral inflammation as a factor contributing to depression has been supported by clinical and experimental evidence, such as the presence of both brain and peripheral markers of inflammation in major depression patients; high frequency of comorbidity between primary autoimmune disorders and mood impairments; antidepressant effectiveness of anti-inflammatory drugs; the occurrence of clinical symptoms of depression in patients undergoing chemokine immunotherapy; the evolvement of behavioral and neuroendocrine depressive impairments in experimental animals treated with proinflammatory compounds [17,40,41]. Among various factors of inflammation, IL-1β appears to have particularly strong association with depression [17,18,20,42].…”

“…Among various factors of inflammation, IL-1β appears to have particularly strong association with depression [17,18,20,42]. Recent studies have reported the association between the polymorphism of IL1-β promoter and major depression [43], and they have even implicated IL-β gene polymorphism (specifically its rs16944 variant, which results in the increased IL1-β levels) in the lack of response to SSRI [44].…”

“…The effects if IL-1ra led us to propose that the increased IL-1β signaling, which has been a well-established hallmark of temporal lobe epilepsy [15,16], may also be the upstream-most factor that via the hyperactivity of the HPA axis [17][18][19][20] leads to the development of depressive impairments [1]. It has been long suggested that epilepsy and depression share certain pathophysiological mechanisms [21,22].…”

“…It has been long suggested that epilepsy and depression share certain pathophysiological mechanisms [21,22]. Given the involvement of IL-1β in epilepsy on the one hand and in depression on the other hand [17,23], it is conceivable to suggest that this cytokine represents one of factors linking mechanisms of the 2 diseases.…”

Sick and Tired: Mood, Fatigue, and Inflammation in Cancer

“…Indeed, multiple studies in both animals and humans have demonstrated that administration of PICs is sufficient to induce the sickness response and conversely that PIC antagonists can block that response [10].…”