Introduction

During acute or chronic infection and inflammation complex changes in a variety of physiological systems occur. In addition to changes in temperature or the induction of fever also behavioral changes like tiredness, flu-like symptoms and impaired concentration are common. During the last 20 to 30 years there is rapidly growing interest and also knowledge about the underlying mechanisms: One of the first important findings was the observation, that the hypothalamo-pituitary-adrenal (HPA) system is stimulated following the peripheral administration of interleukin-1 (IL-1) (Besedovsky, del Rey, Sorkin, and Dinarello 1986). After this basic finding in psychoneuroimmunological research further studies focused on the inflammatory cytokines such as IL-1 as major components in the interaction of peripheral immune function and central nervous system (CNS): These peptides belong to the huge number of cytokines which are involved in this brain-immune interaction (see Hopkins and Rothwell 1995; Rothwell and Hopkins 1995). In human research mainly cytokines of the cytokine families of interleukins, interferons (IFN), or the tumor necrosis factor (TNF) family have been investigated.

The induction of fever and neuroendocrine activation have been most intensively studied using animal models to study CNS-mediated host response parameters (Kluger 1991; Turnbull and Rivier 1999). The central role of inflammatory cytokines are well accepted, IL-1 and IL-6 as well as TNF-a are the most important molecules. Based on these findings it has been suggested that these cytokines also may be responsible for changes in complex brain functions during experimental models of infection and inflammation. In rodents a typical pattern of behavioral responses including reduced motor activity, decreased food intake, reduced exploratory behavior, social and sexual interaction, less intake of food and water, altered sleep, and impaired learning occurs. This syndrome has been called "sickness behavior" (Dantzer 2001; Yirmiya et al. 2000). These behavioral responses were classically induced by the injection of bacterial endotoxin. In more specific studies it has been shown that inflammatory cytokines released peripherally, such as IL-1P, IL-6, and TNF-a, also are able to cause the "sickness behavior." It was initially unclear how these big peptides circulating in the blood could influence CNS-structures behind the blood-brain barrier, but it was later demonstrated that a variety of major pathways are involved: In the periventricular organs passive diffusion of cytokines has been demonstrated. Additionally, active transport mechanisms and specific transport peptides to the brain do exist for most of the cytokines. Moreover, an activation of neural afferents like the vagus nerve by cytokines in the periphery is an important mechanism. Systemic inflammation has been shown to induce cytokine synthesis and release mainly from microglial cells within the brain (Rothwell and Hopkins 1995). It can be assumed that these pathways are also functional in humans. Hence, cytokine signals from the periphery are very likely to modulate complex human CNS function.

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