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1433 CYTOKINES and FEVER Bruno Conti, Iustin Tabarean, Cristina

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1433 CYTOKINES and FEVER Bruno Conti, Iustin Tabarean, Cristina [Frontiers in Bioscience 9, 1433-1449, May 1, 2004] CYTOKINES AND FEVER Bruno Conti, Iustin Tabarean, Cristina Andrei and Tamas Bartfai Harold L. Dorris Neurological Research Center, Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Cytokines as endogenous pyrogenic and antipyretic agents 3.1. Interleukin 1 beta and the Interleukin 1 system 3.2. Tumor Necrosis Factor 3.3. Interleukin 6 3.4. Interleukin 1Receptor Antagonist 3.5. Interleukin 10 4. LPS and TLR: confluence of IL-1 and LPS signaling 5. Actions of cytokines on the hypothalamic thermoregulation 5.1. Actions of peripheral cytokines 5.2. Actions of cytokines formed in the CNS 6. Effects of pyrogenic cytokines on the firing rate of neurons in the preoptic area/anterior hypothalamus area (POA/AH) 7. Conclusion 8. Acknowledgements 9. References 1. ABSTRACT Cytokines are highly inducible, secreted proteins temperature-sensitive neurons in the preoptic hypothalamic mediating intercellular communication in the nervous and region involved in thermoregulation, directly or via second immune system. Fever is the multiphasic response of mediators, remain to be fully elucidated. elevation and decline of the body core temperature regulated by central thermoregulatory mechanisms 2. INTRODUCTION localized in the preoptic area of the hypothalamus. The discovery that several proinflammatory cytokines act as Fever is an induced increase of the body core endogenous pyrogens and that other cytokines can act as temperature caused by a regulated elevation of the antipyretic agents provided a link between the immune and temperature set point evoked by changes in the neuronal the central nervous systems and stimulated the study of the activity of components localized in the preoptic area of the central actions of cytokines. The proinflammatory hypothalamus. Because fever can be induced by a cytokines interleukin 1 (IL-1), interleukin 6 (IL-6) and the multitude of substances administered peripherally ranging tumor necrosis factor alpha (TNF) as well as the from inorganic to organic compounds or microbial and antiinflammatory cytokines interleukin 1 receptor mammalian proteins, the existence of a common antagonist (IL-1ra) and interleukin 10 (IL-10) have been endogenous fever mediator was postulated. Eventually, the most investigated for their pyrogenic or antipyretic action. much sought “endogenous pyrogen“ was found to be The experimental evidence demonstrating the role of these identical to the leukocyte activating factor (LAF), now secreted proteins in modulating the fever response is as most commonly known as interleukin 1 (IL-1), one of the follows: 1) association between cytokine levels in serum prototypic proinflammatory cytokines (see (1) for review). and CSF and fever; 2) finding of the presence of cytokine This finding led the way to the identification of the pyretic receptors on various cell types in the brain and and antipyretic properties of several cytokines and to the demonstration of the effects of pharmacological application investigation of their role as an endogenous mediator of the of cytokines and of their neutralizing antibodies on the febrile response. fever response; 3) fever studies on cytokine- and cytokine receptor- transgenic models. Studies on the peripheral and In the present review, we summarize the the central action of cytokines demonstrated that peripheral experimental evidence demonstrating the action and the cytokines can communicate with the brain in several ways effects on fever of some of the most extensively including stimulation of afferent neuronal pathways and investigated cytokines. While several cytokines have been induction of the synthesis of a non cytokine pyrogen, i.e. investigated for their pyrogenic action, including ciliary PGE2, in endothelial cells in the periphery and in the brain. neurotrophic factor, interleukin 2, interleukin 12 and Cytokines synthesized in the periphery may act by crossing interferon alpha, we will focus on the action of the three the blood brain barrier and acting directly via neuronal major proinflammatory cytokines: interleukin 1beta (IL- cytokine receptors. The mechanisms that ultimately 1beta), interleukin 6 (IL-6), Tumor Necrosis Factor alpha mediate the central action of cytokines and of LPS on the (TNF); and on those of the antiinflammatory cytokines: IL- 1433 Cytokines and fever system, we will often distinguish between their peripheral and central actions. 3. CYTOKINES AS ENDOGENOUS PYROGENIC AND ANTIPYRETIC AGENTS Cytokines are intercellular signaling proteins mainly produced by immuno-competent cells. Their primary function is the regulation and the coordination of immune responses. Expression of several cytokines and their receptors were also demonstrated in the central nervous system where they are produced by glial or neuronal cell types. In the CNS, cytokines are believed to function as possible trophic factors, which can directly affect neuronal function and which also participate in local inflammatory processes. Several cytokines, including IL- 1beta, IL-6, TNF, IL-1ra and IL-10 were also demonstrated to have pyretic or antipyretic effects. Such conclusions came primarily from three different experimental evidences demonstrating: a) association between the levels of these cytokines in the serum and/or in the cerebrospinal fluid (CSF) and fever; b) the effects of peripheral and central pharmacological application of the cytokine on core body temperature; c) cytokine action in studies on transgenic Figure 1. Convergence of IL-1 and LPS signaling. animals overexpressing or null mutated for a specific Schematic representation of how IL-1 and LPS action both cytokine or its receptor; d) cytokine action in experiment activate the same intracellular signal transduction pathway. employing specific neutralizing antibodies; e) autonomic IL-1 beta and the members of IL-1 family of ligands: IL- and behavioral responses in establishing and maintaining 1alpha/beta and IL-1ra act through the IL-1Type I receptor, fever response to cytokines and other pyrogens were also a heterodimer of the IL-1RI and its accessory protein instrumental. Although not a major mechanism of IL1RAcP. Binding of agonist, IL-1beta or IL-1alpha thermoregulation in homeothermic animals they can induces the recruitment of the cytosolic adaptor protein, regulate core body temperature by combined use of both MyD88 or its analogs and initiates the activation of the autonomic and behavioral mechanism: i.e. the animals may IRAK/TRAF pathway leading to the activation of the seek out cooler or warmer places during the different transcription factor NF-B and subsequently to phases of fever response to conserve the body’s energy transcriptional stimulation of multiple genes including reserve (2). those coding for COX2 and iNOS and, that are involved in the production of potent inflammatory mediators such as In evaluating the effects of cytokines, it is PGE2 and NO and to the auto induction of IL-1beta important to consider not only the experimental approach synthesis, respectively. LPS, bound to the LPS binding utilized, but also some peculiar features of these protein protein can activate the same transduction pathway upon molecules. Cytokines are among the most highly inducible stimulation of the TLR4 receptor belonging to the same proteins known. Their expression level can go from 10-15– family of Toll receptors as the IL-1type 1 receptor and 10-12 M, barely detectable levels, to 10-9–10-7 M in a matter utilizing the same IRAK/TRAF pathway leading to the of 30-90 minutes in response to bacterial, viral, activation of the transcription factor NF-B with inflammatory or stress stimuli. In addition, cytokines can transcriptional consequences as described above (see text regulate each others production. For instance, IL-1beta is for details). Thus LPS can act directly at TLR4 and/or it one of the most potent inducers of TNF as well as of IL-1ra can induce e.g. IL-1beta synthesis and then evoke similar and TNF is a powerful stimulator of IL-1beta production; responses via the IL-1type 1 receptor. Availability of LPS, finally both IL-1beta and TNF potently induce IL-6 (3, 4). LPS binding protein and of TLR4 are important in deciding Thus, while proinflammatory cytokines are normally how much of LPS signaling will occur through each branch synthesized and active in response to stimulation (i.e. of this bifurcated signaling leading to the production of the bacterial infection), their rapid and potent cross-induction same proinflammatory agents, IL-1beta, PGE2, NO renders the understanding of their hierarchical action difficult to investigate. In addition, their relevance with 1 receptor antagonist (IL-1ra) and interleukin 10 (IL-10). respect to the fever response also depends on the possible IL-1beta and IL-6 are considered to be endogenous presence and dose of bacterial or viral pyrogens. pyrogens, while IL-1ra and IL-10 have antipyretic action. Lipopolysaccharide (LPS) from Gram negative bacteria can TNF has been shown to have both pyrogenic and in fact activate the same intracellular signaling pathway as antipyretic effects depending on the experimental IL-1 and thus bypass its action if present at high dose (5). conditions. As these molecules can be synthesized and are Figure 1 illustrates the confluence of the IL-1 and LPS active in the immune as well as in the central nervous signaling via their respective Toll family receptor.
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