Interleukin-1 reduces food intake and body weight in rat by acting in the arcuate hypothalamus.

A reduction in food intake is commonly observed after bacterial infection, a phenomenon that can be reproduced by peripheral administration of Gram-negative bacterial lipopolysaccharide (LPS) or interleukin-1beta (IL-1ß), a pro-inflammatory cytokine released by LPS-activated macrophages. The arcuate nucleus of the hypothalamus (ARH) plays a major role in food intake regulation and expresses IL-1 type 1 receptor (IL-1R1) mRNA. In the present work, we tested the hypothesis that IL-1R1 expressing cells in the ARH mediate IL-1ß and/or LPS-induced hypophagia in the rat. To do so, we developed an IL-1ß-saporin conjugate, which eliminated IL-R1-expressing neurons in the hippocampus, and micro-injected it into the ARH prior to systemic IL-1ß and LPS administration. ARH IL-1ß-saporin injection resulted in loss of neuropeptide Y-containing cells and attenuated hypophagia and weight loss after intraperitoneal IL-1ß, but not LPS, administration. In conclusion, the present study shows that ARH NPY-containing neurons express functional IL-1R1s that mediate peripheral IL-1ß-, but not LPS-, induced hypophagia. Our present and previous findings indicate that the reduction of food intake after IL-1ß and LPS are mediated by different neural pathways.

Acute effects of steroid hormones and neuropeptides on human social-emotional behavior: a review of single administration studies.

Steroids and peptides mediate a diverse array of animal social behaviors. Human research is restricted by technical-ethical limitations, and models of the neuroendocrine regulation of social-emotional behavior are therefore mainly limited to non-human species, often under the assumption that human social-emotional behavior is emancipated from hormonal control. Development of acute hormone administration procedures in human research, together with the advent of novel non-invasive neuroimaging techniques, have opened up opportunities to systematically study the neuroendocrinology of human social-emotional behavior. Here, we review all placebo-controlled single hormone administration studies addressing human social-emotional behavior, involving the steroids testosterone and estradiol, and the peptides oxytocin and vasopressin. These studies demonstrate substantial hormonal control over human social-emotional behavior and give insights into the underlying neural mechanisms. Finally, we propose a theoretical model that synthesizes detailed knowledge of the neuroendocrinology of social-emotional behavior in animals with the recently gained data from humans described in our review.

The type 1 TNF receptor and its associated adapter protein, FAN, are required for TNFalpha-induced sickness behavior.

RATIONALE: During the course of an infection, the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) acts in the brain to trigger development of behavioral responses, collectively termed sickness behavior. Biological activities of TNFalpha can be mediated by TNF receptor type 1 (TNF-R1) and type 2 (TNF-R2). TNFalpha activates neutral sphingomyelinase through the TNF-R1 adapter protein FAN (factor associated with neutral sphingomyelinase activation), but a behavioral role of FAN in the brain has never been reported. OBJECTIVES: We hypothesized that TNFalpha-induced sickness behavior requires TNF-R1 and that FAN is a necessary component for this response. MATERIALS AND METHODS: We determined the role of brain TNF-R1 in sickness behavior by administering an optimal amount of TNFalpha intracerebroventricularly (i.c.v., 50 ng/mouse) to wild-type (WT), TNF-R1-, TNF-R2-, and FAN-deficient mice. Sickness was assessed by decreased social exploration of a novel juvenile, induction of immobility, and loss of body weight. RESULTS: TNF-R1-deficient mice were resistant to the sickness-inducing properties of i.c.v. TNFalpha, whereas both TNF-R2-deficient and WT mice were fully responsive. Furthermore, the complete absence of TNFalpha-induced sickness behavior in FAN-deficient mice provided in vivo evidence that FAN-dependent TNF-R1 signaling is critical for this central action of TNFalpha. CONCLUSIONS: This is the first report to demonstrate that TNFalpha-induced sickness behavior is fully mediated by TNF-R1 and that the adaptor protein FAN is a necessary intracellular intermediate for sickness behavior.

Uncoupling of interleukin-6 from its signalling pathway by dietary n-3-polyunsaturated fatty acid deprivation alters sickness behaviour in mice.

Sickness behaviour is an adaptive behavioural response to the activation of the innate immune system. It is mediated by brain cytokine production and action, especially interleukin-6 (IL-6). Polyunsaturated fatty acids (PUFA) are essential fatty acids that are highly incorporated in brain cell membranes and display immunomodulating properties. We hypothesized that a decrease in n-3 (also known as omega3) PUFA brain level by dietary means impacts on lipopolysaccharide (LPS)-induced IL-6 production and sickness behaviour. Our results show that mice exposed throughout life to a diet containing n-3 PUFA (n-3/n-6 diet) display a decrease in social interaction that does not occur in mice submitted to a diet devoid of n-3 PUFA (n-6 diet). LPS induced high IL-6 plasma levels as well as expression of IL-6 mRNA in the hippocampus and cFos mRNA in the brainstem of mice fed either diet, indicating intact immune-to-brain communication. However, STAT3 and STAT1 activation, a hallmark of the IL-6 signalling pathway, was lower in the hippocampus of LPS-treated n-6 mice than n-3/n-6 mice. In addition, LPS did not reduce social interaction in IL-6-knockout (IL-6-KO) mice and failed to induce STAT3 activation in the brain of IL-6-KO mice. Altogether, these findings point to alteration in brain STAT3 as a key mechanism for the lack of effect of LPS on social interaction in mice fed with the n-6 PUFA diet. The relative deficiency of Western diets in n-3 PUFA could impact on behavioural aspects of the host response to infection.

In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL-1 beta in the murine brain.

The P2X(7) receptor (P2X(7)R) is a purinoceptor expressed predominantly by cells of immune origin, including microglial cells. P2X(7)R has a role in the release of biologically active proinflammatory cytokines such as IL-1 beta, IL-6 and TNFalpha. Here we demonstrate that when incubated with lipopolysaccharide (LPS), glial cells cultured from brain of P2X(7)R(-/-) mice produce less IL-1 beta compared to glial cells from brains of wild-type mice. This is not the case for TNFalpha and IL-6. Our results indicate a selective effect of the P2X7R gene deletion on release of IL-1 beta release but not of IL-6 and TNFalpha. In addition, we confirm that only microglial cells produce IL-1beta, and this release is dependent on P2X(7)R and ABC1 transporter. Because IL-1 beta is a key regulator of the brain cytokine network and P2X(7)R is an absolute requirement for IL-1 beta release, we further investigated whether response of brain cytokines to LPS in vivo was altered in P2X(7)R(-/-) mice compared to wild-type mice. IL-1 beta and TNFalpha mRNAs were less elevated in the brain of P2X(7)R(-/-) than in the brain of wild-type mice in response to systemic LPS. These results show that P2X7R plays a key role in the brain cytokine response to immune stimuli, which certainly applies also to cytokine-dependent alterations in brain functions including sickness behavior.

TNFalpha-induced sickness behavior in mice with functional 55 kD TNF receptors is blocked by central IGF-I.

A variety of pathogenic insults cause synthesis of tumor necrosis factor (TNF)alpha in the brain, resulting in sickness behavior. Here we used TNF-receptor (TNF-R)2-deficient and wild-type mice to demonstrate that the reduction in social exploration of a novel juvenile, the increase in immobility and the loss of body weight caused by central TNFalpha (i.c.v., 50 ng/mouse) are blocked by central pre-treatment with the multifunctional peptide, insulin-like growth factor (IGF-I; i.c.v., 300 ng/mouse). These results establish that sickness behavior induced by central TNFalpha via the TNF-R1 (p55) is directly opposed by IGF-I in the brain.

Inactivation of the cerebral NFkappaB pathway inhibits interleukin-1beta-induced sickness behavior and c-Fos expression in various brain nuclei.

The behavioral effects of peripherally administered interleukin-1beta (IL-1beta) are mediated by the production of cytokines and other proinflammatory mediators at the level of the blood-brain interface and by activation of neural pathway. To assess whether this action is mediated by NFkappaB activation, rats were injected into the lateral ventricle of the brain with a specific inhibitor of NFkappaB activation, the NEMO Binding Domain (NBD) peptide that has been shown previously to abolish completely IL-1beta-induced NFkappaB activation and Cox-2 synthesis in the brain microvasculature. NFkappaB pathway inactivation significantly blocked the behavioral effects of intraperitoneally administered IL-1beta in the form of social withdrawal and decreased food intake, and dramatically reduced IL-1beta-induced c-Fos expression in various brain regions as paraventricular nucleus, supraoptic nucleus, and lateral part of the central amygdala. These findings strongly support the hypothesis that IL-1beta-induced NFkappaB activation at the blood-brain interface is a crucial step in the transmission of immune signals from the periphery to the brain that underlies further events responsible of sickness behavior.

Pentoxifylline and insulin-like growth factor-I (IGF-I) abrogate kainic acid-induced cognitive impairment in mice.

Hippocampal insults involving neuroimmune mechanisms can impair learning and memory in a variety of tasks. The present study was designed to assess the effect of pentoxifylline, an inhibitor of tumor necrosis factor alpha (TNFalpha), and insulin-like growth factor-I (IGF-I) on kainate (KA)-induced impairment in spatial memory. Male mice received a subcutaneous injection of a dose of KA (15 mg/kg) that had no cytotoxic effect on hippocampal neurons as confirmed by Fluorojade B staining. This dose resulted in an impairment of spatial memory in a two-trial recognition task 11 days later. Intraperitoneal administration of pentoxifylline (200 mg/kg) abrogated this effect. Repeated intracerebroventricular injection of IGF-I (2 microg/mouse on day 1 followed by 1 microg/mouse on days 2-5) abrogated KA-induced deficits in spatial memory whereas acute IGF-I (2 microg/mouse on day 1 only) had mixed effects. These findings indicate that endogenous TNFalpha is probably involved in the detrimental effects of kainate on cognition and that exogenous IGF-I can oppose these effects, probably by antagonizing TNFalpha-induced neurotoxicity.

Dual effect of central injection of recombinant rat interleukin-4 on lipopolysaccharide-induced sickness behavior in rats.

Systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) has profound depressive effects on behavior that are mediated by the inducible expression of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor alpha (TNF), in the brain. To assess the regulatory effects of the anti-inflammatory cytokine IL-4 on LPS-induced sickness behavior, rats injected intra-peritoneally (i.p.) with LPS were administered intracerebroventricularly (i.c.v.) with IL-4. IL-4 (30 and 300 ng) potentiated the behavioral effects of LPS (175 microg/1000 g) when both molecules were co-injected. However, when IL-4 (30 ng) was injected 12 h prior to LPS, it blocked the depressing effects of LPS on social exploration. These results indicate that the regulation of cytokine-induced sickness behavior by IL-4 can be either inhibitory or stimulatory depending on the sequencing of IL-4 and LPS treatments.

Expression and regulation of interleukin-1 receptors in the brain. Role in cytokines-induced sickness behavior.

Sickness behavior refers to the coordinated set of behavior changes that develop in sick individuals during the course of an infection. At the molecular level, these changes are due to the effects of proinflammatory cytokines as interleukin-1 on the brain. The purpose of this article is not to review the entire field of cytokines and behavior, but rather to address the role of interleukin-1 receptors (IL-1Rs) in sickness behavior. We briefly describe the notion of sickness behavior and present the distribution of IL-1Rs in the central nervous system of the human, mouse and rat. We then bring arguments in favor of the functionality of the various subtypes of receptors and evaluate the nature of the signaling pathways activated by brain IL-1Rs to initiate central modifications leading to symptoms of sickness. Finally, modulation of IL-1 action on its receptor by various opposing factors including glucocorticoids and anti-inflammatory cytokines is discussed.

Molecular basis of sickness behavior.

Peripheral and central injections of lipopolysaccharide (LPS), a cytokine inducer, and recombinant proinflammatory cytokines such as interleukin-1 beta (IL-1 beta) induce sickness behavior in the form of reduced food intake and decreased social activities. Mechanisms of the behavioral effects of cytokines have been the subject of much investigation during the last 3 years. At the behavioral level, the profound depressing effects of cytokines on behavior are the expression of a highly organized motivational state. At the molecular level, sickness behavior is mediated by an inducible brain cytokine compartment that is activated by peripheral cytokines via neural afferent pathways. Centrally produced cytokines act on brain cytokine receptors that are similar to those characterized on peripheral immune and nonimmune cells, as demonstrated by pharmacologic experiments using cytokine receptor antagonists, neutralizing antibodies to specific subtypes of cytokine receptors, and gene targeting techniques. Evidence exists that different components of sickness behavior are mediated by different cytokines and that the relative importance of these cytokines is not the same in the peripheral and central cytokine compartments.

Effects of insulin-like growth factor-I on cytokine-induced sickness behavior in mice.

Central administration of insulin-like growth factor-I (IGF-I) attenuates sickness behavior in response to the cytokine inducer lipopolysaccharide. The present study was designed to determine the respective roles of the two main proinflammatory cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta), in these effects. Male CD1 mice were injected into the lateral ventricle (i.c.v.) of the brain with optimal amounts of either TNFalpha (50 ng) or IL-1beta (2 ng) that induce sickness behavior. Behavioral responses to IGF-I (0, .1, and 1 microg) also given i.c.v. were measured at various time intervals before and after treatment with the two proinflammatory cytokines. Mice treated with TNFalpha and IL-1beta lost body weight and displayed equivalent reductions in social exploration and instances of immobility. At the dose of .1 microg, IGF-I attenuated these signs of sickness in TNFalpha-but not in IL-1beta-treated mice. At the dose of 1 microg, IGF-I attenuated IL-1beta-induced immobility and the reduction in social exploration but had no effect on loss of body weight. These findings indicate that IGF-I is more potent in attenuating sickness behavior induced by TNFalpha than that caused by IL-1beta, which is consistent with the relative specificity of the TNFalpha/IGF-I interactions in the brain.

Interleukin-1beta mediates the memory impairment associated with a delayed type hypersensitivity response to bacillus Calmette-Guérin in the rat hippocampus.

Interleukin-1beta (IL-1beta) plays a major role in the initiation and exacerbation of brain inflammation, and its action is limited by the natural antagonist of IL-1 receptors, IL-1Ra. The aim of the present study was to test the hypothesis that IL-1beta mediates the functional consequences of inflammation during the course of delayed-type hypersensitivity response to bacillus Calmette-Guérin (BCG) in the hippocampus of Lewis rats. Animals were primed with an injection of BCG in the right hippocampus and challenged 4 weeks later with BCG administered subcutaneously. Concentrations of IL-1beta and IL-1Ra were measured by ELISA in the BCG injected hippocampus and compared to those measured in the contralateral hippocampus during the first 2 weeks post-challenge. IL-1beta levels increased in response to BCG challenge and peaked 12 days after challenge. The same variations appeared in the contralateral hippocampus but to a lesser extent. Hippocampal IL-1Ra levels increased in response to intrahippocampal injection of BCG. They further increased at days 6 and 9 post-challenge and decreased from day 12 back to baseline values on day 16. The increase in IL-1beta levels and the decline in IL-1Ra levels were associated with an impairment in spatial memory in a Y-maze on day 16 post-challenge, that was abrogated by chronic administration of IL-1Ra via a subcutaneously implanted osmotic minipump geared to deliver 7 mg IL-1Ra/day. These results show that overexpression of IL-1beta in the brain during the course of a chronic inflammation has deleterious consequences on cognitive processes, that are reversed by blockade of IL-1 receptors.

Cytokine-induced sickness behavior.

The behavioral repertoire of humans and animals changes dramatically following infection. Sick individuals have little motivation to eat, are listless, complain of fatigue and malaise, loose interest in social activities and have significant changes in sleep patterns. They display an inability to experience pleasure, have exaggerated responses to pain and fail to concentrate. Proinflammatory cytokines acting in the brain cause sickness behaviors. These nearly universal behavioral changes are a manifestation of a central motivational state that is designed to promote recovery. Exaggerated symptoms of sickness in cancer patients, such as cachexia, can be life-threatening. However, quality of life is often drastically impaired before the cancer becomes totally debilitating. Although basic studies in psychoneuroimmunology have defined proinflammatory cytokines as the central mediators of sickness behavior, a much better understanding of how cytokine and neurotransmitter receptors communicate with each other is needed. Advances that have been made during the past decade should now be extended to clinical studies in an attempt to alleviate sickness symptoms and improve quality of life for cancer patients.