Sleep and Microbes.

Sleep is profoundly altered during the course of infectious diseases. The typical response to infection includes an initial increase in nonrapid eye movement sleep (NREMS) followed by an inhibition in NREMS. REMS is inhibited during infections. Bacterial cell wall components, such as peptidoglycan and lipopolysaccharide, macrophage digests of these components, such as muramyl peptides, and viral products, such as viral double-stranded RNA, trigger sleep responses. They do so via pathogen-associated molecular pattern recognition receptors that, in turn, enhance cytokine production. Altered sleep and associated sleep-facilitated fever responses are likely adaptive responses to infection. Normal sleep in physiological conditions may also be influenced by gut microbes because the microbiota is affected by circadian rhythms, stressors, diet, and exercise. Furthermore, sleep loss enhances translocation of viable bacteria from the intestine, which provides another means by which sleep-microbe interactions impact neurobiology.

The reciprocal link between sleep and immune responses.

Good sleep is necessary for both physical and mental health; sleep and immune responses are reciprocally and closely linked. Sleep loss impairs the immune response, while, on the other hand, the immune response, activated for instance by an infection, alters sleep. Sleep alterations induced by immune activation are mediated by cytokines such as interleukin-1. In the past, it was thought that cytokines were produced only by the immune system, and active only there as signaling molecules. Today it is clear that IL-1 and other cytokines are present and active in the healthy brain, where they physiologically interact with the brain circuits and the neurotransmitter systems (for instance the serotonergic, GABAergic, and cholinergic systems) that control sleep. These interactions are altered by immune response, and, as a result, non-rapid eye movement (NREM) sleep is increased and fragmented, whereas rapid eye movements (REM) sleep is inhibited.

Effects of i.c.v. administration of interleukin-1 on sleep and body temperature of interleukin-6-deficient mice.

Cytokines in brain contribute to the regulation of physiological processes and complex behavior, including sleep. The cytokines that have been most extensively studied with respect to sleep are interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6. Administration of these cytokines into laboratory animals, or in some cases into healthy human volunteers, increases the amount of time spent in non-rapid eye movement (NREM) sleep. Although antagonizing the IL-1 or TNF systems reduces the amount of time laboratory animals spend in NREM sleep, interactions among these three cytokine systems as they pertain to the regulation of physiological NREM sleep are not well understood. To further elucidate mechanisms in brain by which IL-1beta, TNFalpha, and/or IL-6 contribute to NREM sleep regulation, we injected recombinant murine interleukin-1beta (muIL-1beta) into C57BL/6J mice and into IL-6-deficient mice (IL-6 knockout, KO). IL-6 KO (B6.129S6-Il6(tm1Kopf); n=13) and C57BL/6J mice (n=14) were implanted with telemeters to record the electroencephalogram (EEG) and core body temperature, as well as with indwelling guide cannulae targeted to one of the lateral ventricles. After recovery and habituation, mice were injected intracerebroventricularly just prior to dark onset on different days with either 0.5 microl vehicle (pyrogen-free saline; PFS) or with 0.5 microl PFS containing one of four doses of muIL-1beta (2.5 ng, 5 ng, 10 ng, 50 ng). No mouse received more than two doses of muIL-1beta, and administration of muIL-1beta doses was counter-balanced to eliminate potential order effects. Sleep-wake behavior was determined for 24 h after injections. i.c.v. administration of muIL-1beta increased in NREM sleep of both mouse strains in a dose-related fashion, but the maximal increase was of greater magnitude in C57Bl/6J mice. muIL-1beta induced fever in C57Bl/6J mice but not in IL-6 KO mice. Collectively, these data demonstrate IL-6 is necessary for IL-1 to induce fever, but IL-6 is not necessary for IL-1 to alter NREM sleep.

Interleukin-1 inhibits firing of serotonergic neurons in the dorsal raphe nucleus and enhances GABAergic inhibitory post-synaptic potentials.

In vitro electrophysiological data suggest that interleukin-1 may promote non-rapid eye movement sleep by inhibiting spontaneous firing of wake-active serotonergic neurons in the dorsal raphe nucleus (DRN). Interleukin-1 enhances GABA inhibitory effects. DRN neurons are under an inhibitory GABAergic control. This study aimed to test the hypothesis that interleukin-1 inhibits DRN serotonergic neurons by potentiating GABAergic inhibitory effects. In vitro intracellular recordings were performed to assess the responses of physiologically and pharmacologically identified DRN serotonergic neurons to rat recombinant interleukin-1beta. Coronal slices containing DRN were obtained from male Sprague-Dawley rats. The impact of interleukin-1 on firing rate and on evoked post-synaptic potentials was determined. Evoked post-synaptic potentials were induced by stimulation with a bipolar electrode placed on the surface of the slice ventrolateral to DRN. Addition of interleukin-1 (25 ng/mL) to the bath perfusate significantly decreased firing rates of DRN serotonergic neurons from 1.3 +/- 0.2 Hz (before administration) to 0.7 +/- 0.2 Hz. Electrical stimulation induced depolarizing evoked post-synaptic potentials in DRN serotonergic neurons. The application of glutamatergic and GABAergic antagonists unmasked two different post-synaptic potential components: a GABAergic evoked inhibitory post-synaptic potentials and a glutamatergic evoked excitatory post-synaptic potentials, respectively. Interleukin-1 increased GABAergic evoked inhibitory post-synaptic potentials amplitudes by 30.3 +/- 3.8% (n = 6) without affecting glutamatergic evoked excitatory post-synaptic potentials. These results support the hypothesis that interleukin-1 inhibitory effects on DRN serotonergic neurons are mediated by an interleukin-1-induced potentiation of evoked GABAergic inhibitory responses.

Interleukin 1beta enhances non-rapid eye movement sleep and increases c-Fos protein expression in the median preoptic nucleus of the hypothalamus.

Interleukin 1beta (IL-1) is a key mediator of the acute phase response in an infected host and acts centrally to coordinate responses to an immune challenge, such as fever and increased non-rapid eye movement (NREM) sleep. The preoptic area (POA) is a primary sleep regulatory center in the brain: the ventrolateral POA (VLPO) and median preoptic nucleus (MnPN) each contain high numbers of c-Fos protein immunoreactive (IR) neurons after sleep but not after waking. We hypothesized that IL-1 mediates increased NREM sleep through activation of these sleep-active sites. Rats injected intracerebroventricularly with IL-1 (10 ng) at dark onset spent significantly more time in NREM sleep 4-5 h after injection. This increase in NREM sleep was associated with increased numbers of Fos-IR neurons in the MnPN, but not in the VLPO. Fos IR in the rostral MnPN was significantly increased 2 h post IL-1 injection, although the percentage of NREM sleep in the preceding 2 h was the same as controls. Fos IR was also increased in the extended VLPO 2 h postinjection. Finally, Fos IR in the MnPN did not differ significantly between IL-1 and vehicle-treated rats that had been sleep deprived for 2 h postinjection, but it was increased in VLPO core. Taken together, these results suggest that Fos IR in the MnPN after IL-1 is not independent of behavioral state and may require some threshold amount of sleep for its expression. Our results support a hypothesis that IL-1 enhances NREM sleep, in part, through activation of neurons in the MnPN of the hypothalamus.

Serotonergic activation stimulates the pituitary-adrenal axis and alters interleukin-1 mRNA expression in rat brain.

Interactions between neurotransmitters and immunomodulators within the central nervous system may be functionally relevant for communication between the immune system and the brain. Previous studies indicate that cytokines such as interleukin-1 (IL-1) alter activity of the serotonergic system at multiple levels. This study tested the hypothesis that serotonergic activation modulates cytokine mRNA expression in brain. Serotonergic activation was induced by injecting rats intraperitoneally (i.p.) prior to dark onset with the serotonin precursor L-5-hydroxytryptophan (5-HTP; 100 mg/kg). Cytokine mRNA expression in discrete brain regions at selected time points was determined by means of ribonuclease protection assay. Plasma corticosterone concentrations were also measured to determine if the hypothalamic-pituitary-adrenal axis is activated in response to this treatment, which potentially could exert feedback regulating cytokine message expression in brain. Plasma corticosterone was elevated for 4 h after 5-HTP administration. At this time IL-1alpha mRNA expression was reduced in the hippocampus, hypothalamus, and brainstem, and IL-1beta mRNA was reduced in the hippocampus. Six hours after 5-HTP injection, IL-1beta mRNA increased in the hypothalamus. These results show that activation of the serotonergic system affects cytokine message expression in rat brain, possibly by actions of corticosterone.

Beta (CC)-chemokines as modulators of sleep: implications for HIV-induced alterations in arousal state.

Sleep is altered early in the course of HIV infection, before the onset of AIDS, indicating effects of the virus on neural processes. Previous observations suggest HIV envelope glycoproteins are possible mediators of these responses. Because some beta (CC)-chemokine receptors serve as co-receptors for HIV and bind HIV envelope glycoproteins, we determined in this study whether selected CC chemokine ligands alter sleep and whether their mRNAs are detectable in brain regions important for sleep. CCL4/MIP-1beta, but not CCL5/RANTES, injected centrally into rats prior to dark onset increased non-rapid eye movements sleep, fragmented sleep, and induced fever. mRNA for the chemokine receptor CCR3 was detectable under basal conditions in multiple brain regions. These data suggest some CC chemokines may also be involved in processes by which HIV alters sleep.

Corticotropin-releasing hormone (CRH) as a regulator of waking.

Corticotropin-releasing hormone (CRH), expressed in widely distributed regions of the central nervous system (CNS), mediates the hypothalamic-pituitary-adrenal (HPA) axis and autonomic components of responses to stressors. Sleep, a fundamental CNS process, is altered in response to a variety of stressors. Although there is an extensive literature on the role of CRH in responses to stressors, there is relatively little information on the role of CRH in normal, spontaneous behavior. We hypothesize that CRH is involved in the regulation of waking in the absence of overt stressors. Some of the early evidence supporting this hypothesis was indirect. We summarize in this review studies from our laboratory and others that provide direct evidence that CRH is involved in the regulation of spontaneous waking. We also suggest on the basis of recent studies that some effects of CRH on waking and sleep may be mediated by actions within the CNS of the immunomodulatory cytokine interleukin (IL)-1. Collectively, these observations suggest that CRH contributes to the regulation of spontaneous waking in the absence of stressors, and also indicate a potential mechanism mediating complex alterations in sleep that occur in response to immune challenge.

Rat strains that differ in corticotropin-releasing hormone production exhibit different sleep-wake responses to interleukin 1.

Corticotropin-releasing hormone (CRH) is a mediator of responses to a variety of stressors, including immune challenge. CRH and the hypothalamic-pituitary-adrenal (HPA) axis constitute a negative feedback mechanism for actions of immunomodulators, such as interleukin (IL) 1. CRH is a potent inducer of waking, whereas IL-1 induces slow-wave sleep (SWS). We hypothesize that the complex changes in sleep-wake behavior during immune challenge are mediated in part by CRH and its antagonism of IL-1-induced enhancement of SWS. To further explore this hypothesis, we administered IL-1beta intracerebroventricularly into rats of genetically related strains that differ in CRH/HPA axis responsiveness to IL-1 and determined subsequent alterations in their sleep-wake behavior. Sprague-Dawley rats responded to central administration of IL-1 with alterations in sleep-wake behavior as previously reported; SWS increased, and rapid eye movement sleep (REMS) and waking decreased. CRH and the HPA axis of Lewis rats are reported to be hyporesponsive to challenge; the onset of the IL-1-induced increase in SWS was quicker and the peak magnitude of the response greater than in Sprague-Dawley rats. In contrast, Fischer 344 rats exhibit greater CRH release and HPA axis activation in response to IL-1. IL-1 induced a profound and transient increase in waking of Fischer 344 rats before SWS increased. The febrile responses to IL-1 of Fischer 344 and Lewis rats were identical and of greater magnitude than those observed in Sprague-Dawley rats. Pretreatment with the CRH receptor antagonist alpha-helical CRH(9-41) blocked the initial IL-1-induced increase in waking of Fischer 344 rats. CRH receptor blockade did not affect the IL-1-induced alterations in sleep-wake behavior of Lewis or Sprague-Dawley rats or brain temperature of any rat strain. These observations support the hypothesis that CRH is both a modulator of responses to IL-1 and is involved in the regulation of waking.

Cytokine- and microbially induced sleep responses of interleukin-10 deficient mice.

Interleukin (IL)-1 and tumor necrosis factor (TNF) promote slow-wave sleep (SWS), whereas IL-10 inhibits the synthesis of IL-1 and TNF and promotes waking. We evaluated the impact of endogenous IL-10 on sleep-wake behavior by studying mice that lack a functional IL-10 gene. Under baseline conditions, C57BL/6-IL-10 knockout (KO) mice spent more time in SWS during the dark phase of the light-dark cycle than did genetically intact C57BL/6 mice. The two strains of mice showed generally comparable responses to treatment with IL-1, IL-10, or influenza virus, but differed in their responses to lipopolysaccharide (LPS). In IL-10 KO mice, LPS induced an initial transient increase and a subsequent prolonged decrease in SWS, as well as profound hypothermia. These responses were not observed in LPS-treated C57BL/6 mice. These data demonstrate that in the absence of endogenous IL-10, spontaneous SWS is increased and the impact of LPS on vigilance states is altered. Collectively, these observations support a role for IL-10 in sleep regulation and provide further evidence for the involvement of cytokines in the regulation of sleep.

Factors altering the sleep of burned children.

Although few studies have been conducted on burn patients, they indicate that sleep of burned children is altered. We suggest in this review, on the basis of the limited data available that factors contributing to sleep disruption in burned individuals may be broadly categorized as pathophysiological responses to the injury, the pain and discomfort experienced by the patient and medications used to treat these symptoms, and the physical environment in the Burns Intensive Care Unit. The responses to thermal injury include alterations in circulating neuropeptides, hormones, and immune-active substances, many of which are known to regulate/modulate sleep. Medications for the management of pain and for treating symptoms of various injury-induced stress and anxiety disorders may also alter sleep. Finally, frequent disruptions of the patient by medical staff is but one of the many environmental factors that may contribute to disrupted sleep. Severe burns induce a hypermetabolic response that may result in peripheral wasting, that depletes substrates necessary for tissue repair, and is associated with reduced growth hormone. Burn-induced growth hormone insufficiency is aggressively treated to counteract peripheral wasting and to aid in wound healing of skin graft donor sites. We speculate that improvement of sleep quality would result in a less severe reduction in growth hormone due to the well documented relationship between slow-wave sleep onset and growth hormone secretion. Such improvement in spontaneous growth hormone secretion patterns may aid in recovery by supporting tissue repair and by minimizing the hypermetabolic response to thermal injury. The experiments to test such hypotheses remain to be conducted, yet the results of such experiments may provide the basis for beginning to answer the question of whether or not sleep aids in recovery from injury.

IL-1 is a mediator of increases in slow-wave sleep induced by CRH receptor blockade.

We hypothesize that corticotropin-releasing hormone (CRH), a regulator of the hypothalamic-pituitary-adrenal (HPA) axis, is involved in sleep-wake regulation on the basis of observations that the CRH receptor antagonist astressin, after a delay of several hours, reduces waking and increases slow-wave sleep (SWS) in rats. This delay suggests a cascade of events that begins with the HPA axis and culminates with actions on sleep regulatory systems in the central nervous system. One candidate mediator in the brain for these actions is interleukin (IL)-1. IL-1 promotes sleep, and glucocorticoids inhibit IL-1 synthesis. In this study, central administration of 12.5 microgram astressin into rats before dark onset reduced corticosterone 4 h after injection and increased mRNA expression for IL-1alpha and IL-1beta but not for IL-6 or tumor necrosis factor-alpha in the brain 6 h after injection. To determine directly whether IL-1 is involved in astressin-induced alterations in sleep-wake behavior, we then pretreated rats with 20 microgram anti-IL-1beta antibodies before injecting astressin. The increase in SWS and the reduction in waking that occur after astressin are abolished when animals are pretreated with anti-IL-1beta. These data indicate that IL-1 is a mediator of astressin-induced alterations in sleep-wake behavior.

Human immunodeficiency virus glycoprotein 160 induces cytokine mRNA expression in the rat central nervous system.

1. Elevated proinflammatory cytokines within the central nervous system (CNS) of individuals infected with human immunodeficiency virus (HIV) may contribute to altered CNS processes prior to the onset of AIDS. Most studies of HIV-induced alterations in cytokine expression within the CNS have focused on interleukin (IL)-1 and tumor necrosis factor (TNF). 2. We used a ribonuclease protection assay (RPA) to elucidate further the pattern of cytokine mRNA expression in the rat CNS in response to HIV envelope glycoprotein 160 (gp160). Male Sprague-Dawley rats were surgically implanted with a guide cannula directed into a lateral cerebral ventricle. HIV gp160 was injected intracerebroventricularly and rats were sacrificed immediately (time = 0) or at 1, 2, or 4 hr postinjection. Discrete brain regions were dissected, and peripheral glands removed. All tissues were frozen in liquid nitrogen until RNA extraction and assay. 3. IL-1beta IL-1alpha, TNF-alpha, and TNFbeta mRNAs were constitutively expressed in brain tissues. Central administration of gp160 dramatically increased mRNA expression for IL-1beta and TNFalpha in the hypothalamus, hippocampus, brainstem, and cerebellum. Furthermore, although mRNA expression for IL-5, IL-6, and IL-10 was never detected under basal conditions, these mRNAs were increased in brain tissue after administration of gp160. Peak expression in each brain region was detected 2 hr after administration. Multiple cytokine mRNAs were detected in peripheral tissues, but their expression was not altered by central administration of gp160. 4. Our results indicate that gp160 induces mRNA expression in brain for cytokines other than IL-1 and TNF. Screening for multiple cytokine mRNA in this manner provides extensive information concerning the particular cytokines that may be involved in HIV-induced pathologies and alterations in CNS processes.

5-Hydroxytryptophan, but not L-tryptophan, alters sleep and brain temperature in rats.

The precise role of serotonin (5-hydroxytryptamine) in the regulation of sleep is not fully understood. To further clarify this role for 5-hydroxytryptamine, the 5-hydroxytryptamine precursors L-tryptophan (40 and 80 mg/kg) and L-5-hydroxytryptophan (25-, 50-, 75-, 100 mg/kg) were injected intraperitoneally into freely behaving rats 15 min prior to dark onset, and subsequent effects on sleep-wake activity and cortical brain temperature were determined. L-5-hydroxytryptophan, but not L-tryptophan, induced dose-dependent changes in sleep-wake activity. During the 12-h dark period, non-rapid eye movement sleep was inhibited in post-injection hours 1-2 by the two lowest L-5-hydroxytryptophan doses tested, while the two highest doses induced a delayed increase in non-rapid eye movement sleep in post-injection hours 3-12. These highest doses inhibited non-rapid eye movement sleep during the subsequent 12-h light period. The finding that L-5-hydroxytryptophan, but not L-tryptophan, induced a dose-dependent and long-lasting decrease in cortical brain temperature regardless of whether or not non-rapid eye movement sleep was suppressed or enhanced contributes to a growing list of conditions showing that sleep-wake activity and thermoregulation, although normally tightly coupled, may be dissociated. The initial non-rapid eye movement sleep inhibition observed following low doses of L-5-hydroxytryptophan may be attributable to increased serotonergic activity since 5-hydroxytryptamine may promote wakefulness per se, whereas the delayed non-rapid eye movement sleep enhancement after higher doses may be due to the induction by 5-hydroxytryptamine of sleep-inducing factor(s), as previously hypothesized. The period of non-rapid eye movement sleep inhibition beginning 12 h after administration of L-5-hydroxytryptophan doses that increase non-rapid eye movement sleep is characteristic of physiological manipulations in which non-rapid eye movement sleep is enhanced. The results of the present study suggest that the complex effects of 5-HT on sleep depend on the degree and time course of activation of the serotonergic system such that 5-HT may directly inhibit sleep, yet induce a cascade of physiological processes that enhance subsequent sleep.

Pituitary CRH receptor blockade reduces waking in the rat.

We have previously hypothesized that corticotropin-releasing hormone (CRH) is involved in the regulation of physiological waking. Central administration of CRH receptor antagonists reduces spontaneous waking in the rat. Some of the responses to central administration of CRH receptor antagonists may be mediated by mechanisms involving the hypothalamic-pituitary-adrenal axis, either by direct actions on the hypothalamus or by actions at the level of the pituitary due to leakage of the antagonists from the cerebrospinal fluid to blood. To further clarify the role of the hypothalamic-pituitary-adrenal axis as a mediator of responses to CRH receptor blockade, we administered intravenously into freely behaving rats in their home recording cages two specific CRH receptor antagonists, astressin or alpha-helical CRH, and determined subsequent changes in waking and sleep. Our results indicate that both antagonists reduce spontaneous waking, but with different time courses. Astressin, a potent antagonist of pituitary CRH receptors, reduces waking during postinjection hours 9-10, whereas high doses of alpha-helical CRH reduce waking only during the first postinjection hour. These results indicate that some effects of CRH on sleep-wake behavior may be meditated by pituitary CRH receptors.

Blockade of 5-hydroxytryptamine (serotonin)-2 receptors alters interleukin-1-induced changes in rat sleep.

Recent data suggest that interleukin-1-induced enhancement of non-rapid eye movement sleep is mediated, in part, by the serotonergic system. To determine if sleep changes induced by interleukin-1 are mediated by a specific serotonergic receptor subtype, we evaluated interleukin-1 effects on sleep in rats pretreated with the 5-hydroxytryptamine (serotonin)-2 receptor antagonist ritanserin. Ritanserin (0.63 mg/kg, intraperitoneally) by itself did not alter sleep-wake behavior, although it did reduce cortical brain temperature. Interleukin-1 (5 ng, intracerebroventricularly) enhanced non-rapid eye movement sleep, suppressed rapid eye movement sleep, and induced a moderate febrile response. Pretreatment with ritanserin completely blocked the febrile response to interleukin-1 and abolished the interleukin-1-induced enhancement in non-rapid eye movement sleep that occurred during postinjection hours 3-4, without altering interleukin-1 effects on rapid eye movement sleep. The present data suggest that serotonin may partially mediate interleukin-1 effects on sleep by interacting with 5-hydroxytryptamine (serotonin)-2 receptors. These results also suggest that interactions between the serotonergic system and interleukin-1 may be important in regulating sleep-wake behavior.

Human immunodeficiency virus glycoproteins 160 and 41 alter sleep and brain temperature of rats.

Sleep is altered during all stages at which it has been recorded during chronic human immunodeficiency virus (HIV) infection, including the long latent phase before the development of AIDS; the mechanisms for such alterations are not known. The HIV envelope glycoprotein (gp) 120 alters sleep of rats in a manner somewhat similar to the alterations that occur in humans infected with HIV. To further determine which components of the virus may be responsible for altered behavior, we administered centrally into rats prior to dark onset recombinant HIV gp160 or gp41. Both glycoproteins increased non-rapid eye movements sleep, fragmented sleep, altered slow frequency components of the electroencephalogram, and induced modest febrile responses. These results complement and extend those previously obtained after gp120; HIV envelope glycoproteins are capable of altering sleep.

Hypothalamic serotonergic activity correlates better with brain temperature than with sleep-wake cycle and muscle tone in rats.

The activity of the serotonergic system varies in phase with the sleep-wake cycle, which is associated with changes in several physiological functions, including electroencephalographic activity, brain temperature, and locomotion. The aim of the present study was to clarify which of these parameters correlates better with serotonergic activity in spontaneous conditions. Voltammetric recordings by telemetry of serotonergic metabolism in the medial preoptic area and polygraphic recordings of sleep-wake activity (by means of electroencephalographic delta band, brain cortical temperature and neck electromyographic activity recordings) were simultaneously performed in freely moving rats. Univariate analyses of variance revealed that each variable under investigation was statistically correlated with serotonergic metabolism. When the variables were entered into the model simultaneously, both partial correlation and step-wise multiple regression analyses indicated that the highest correlation exists between serotonergic metabolism and brain cortical temperature. The present data show that serotonergic activity in the medial preoptic area is closely linked to physiological changes in brain temperature.

Sleep as a behavioral model of neuro-immune interactions.

The central nervous system, by a variety of mechanisms engages in constant surveillance of the peripheral immune system. Alterations in the status of the peripheral immune system induced by an invading pathogen for example, are quickly detected by the central nervous system, which then responds by altering physiological processes and behavior in an attempt to support the immune system in its efforts to eliminate the pathogen. Sleep is one of several behaviors that are dramatically altered in response to infection. Immune-active substances such as the pro-inflammatory cytokines interleukin-1 and tumor necrosis factor, either directly or indirectly via interactions with neurotransmitters or neurohormones are involved in the regulation of sleep. Because these cytokines increase during infection, they are likely candidates for mediating the profound alterations in sleep that occur during infection. Since regulation of behavior is the function of the central nervous system, infection-induced alterations in behavior provide a unique model for the study of neuro-immune interactions.

IL-10 as a mediator in the HPA axis and brain.

Certain functional interactions between the nervous, endocrine, and immune systems are mediated by cytokines. The pro-inflammatory cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF) were among the first to be recognized in this regard. A modulator of these cytokines, IL-10, has been shown to have a wide range of activities in the immune system; in this review, we describe its production and actions in the hypothalamic-pituitary-adrenal (HPA) axis. IL-10 is produced in pituitary, hypothalamic, and neural tissues in addition to lymphocytes. IL-10 enhances corticotropin releasing factor (CRF) and corticotropin (ACTH) production in hypothalamic and pituitary tissues, respectively. Further downstream in the HPA axis endogenous IL-10 has the potential to contribute to regulation of glucocorticosteroid production both tonically and following stressors. Our studies and those of others reviewed here indicate that IL-10 may be an important endogenous regulator in HPA axis activity and in CNS pathologies such as multiple sclerosis. Thus, in addition to its more widely recognized role in immunity, IL-10's neuroendocrine activities described here point to its role as an important regulator in communication between the immune and neuroendocrine systems.