In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.Anyone who has experienced a viral or bacterial infection knows what it means to feel sick. The behaviour of sick people changes dramatically; they often feel feverish and nauseated, ignore food and beverages, and lose interest in their physical and social environments. They tire easily and their sleep is often fragmented. In addition, they feel depressed and irritable, and can experience mild cognitive disorders ranging from impaired attention to difficulties in remembering recent events. Despite their negative impact on well-being, these symptoms of sickness are usually ignored. They are viewed as uncomfortable but banal components of infections 1 .Sickness is a normal response to infection, just as fear is normal in the face of a predator. It is characterized by endocrine, autonomic and behavioural changes and is triggered by soluble mediators that are produced at the site of infection by activated accessory immune cells. These mediators are known as pro-inflammatory cytokines, and include interleukin-1α and β (IL-1α and IL-1β), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). They coordinate the local and systemic inflammatory response to microbial pathogens. However, NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript these peripherally produced cytokines also act on the brain to cause the aforementioned behavioural symptoms of sickness. Recently, it has been suggested that 'sickness behaviour' 2, 3, a term used to describe the drastic changes in subjective experience and behaviour that occur in physically ill patients and animals, is an expression of a previously unrecognized motivational state. It is responsible for re-organizing perceptions and actions to enable ill individuals to cope better with an infection4.During the last five years, it has been established that pro-inflammatory cytokines induce not only symptoms of sickness, but also true major depressive disorders in physically ill patients with no previous history of mental disorders. Some of the mechanisms that might be responsible for inflammation-mediated sickness and depression have now been elucidated. These findings suggest that the brain-cytokine system, which is in essence a diffuse system, is the unsuspected conductor of the ensemble of neuronal circuits and neurotransmitters that organize physiologi...

Acute cognitive disorders are common in elderly patients with peripheral infections but it is not clear why. Here we injected old and young mice with Escherichia coli lipopolysaccharide (LPS) to mimic an acute peripheral infection and separated the hippocampal neuronal cell layers from the surrounding hippocampal tissue by laser capture microdissection and measured mRNA for several inflammatory cytokines (IL-1β, IL-6, and TNFα) that are known to disrupt cognition. The results showed that old mice had an increased inflammatory response in the hippocampus after LPS compared to younger cohorts. Immunohistochemistry further showed more microglial cells in the hippocampus of old mice compared to young adults, and that more IL-1β-positive cells were present in the dentate gyrus and in the CA1, CA2 and CA3 regions of LPS-treated old mice compared to young adults. In a test of cognition that required animals to effectively integrate new information with a preexisting schema to complete a spatial task, we found that hippocampal processing is more easily disrupted in old animals than in younger ones when the peripheral innate immune system is stimulated. Collectively, the results suggest that aging can facilitate neurobehavioral complications associated with peripheral infections probably by allowing the over expression of inflammatory cytokines in brain areas that mediate cognitive processing.

Dietary fiber (DF) is deemed to be a key component in healthy eating. DF is not a static collection of undigestible plant materials that pass untouched or unencumbered through the gastrointestinal (GI) tract; instead, DFs are a vast array of complex saccharide-based molecules that can bind potential nutrients and nutrient precursors to prevent their absorption. Some DFs are fermentable, and the GI tract catabolism leads to the generation of various bioactive materials, such as short-chain fatty acids (SCFAs), that can markedly augment the GI tract biomass and change the composition of the GI tract flora. The health benefits of DFs include the prevention and mitigation of type 2 diabetes, cardiovascular disease and colon cancer. By modulating food ingestion, digestion, absorption and metabolism, DFs reduce the risk of hyperlipidemia, hypercholesterolemia and hyperglycemia. Emerging research has begun to investigate the role of DFs in immunomodulation. If substantiated, DFs could facilitate many biologic processes, including infection prevention and the improvement of mood and memory. This review describes the accepted physiologic functions of DFs and explores their new potential immune-based actions.

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The cytokine IL-1 is critical to the pathogenesis of a variety of human conditions and diseases. Unlike most other cytokines, IL-1 is counterbalanced by two endogenous inhibitors. The functional significance of IL-1 receptor antagonist (IL-1RA) is well documented due to the clinical utilization of the recombinant human IL-1RA analog, anakinra. In contrast, much less is known about the type 2 IL-1 receptor (IL-1R2), which acts as a decoy receptor for IL-1. While IL-1R2 is structurally similar to the type 1 IL-1 receptor (IL-1R1) responsible for IL-1 signal transduction, its truncated cytoplasmic domain and lack of Toll-IL-1 receptor (TIR) region renders IL-1R2 incapable of transmembrane signaling. IL-1R2 competes with IL-1R1 for ligands and for the IL-1R1 co-receptor, IL-1 receptor accessory protein (IL-1RAP). Additionally, IL-1R2 exists in both a membrane bound and soluble form (sIL-1R2) that has biological properties similar to both a decoy receptor and a binding protein. Thus far, IL-1R2 has been implicated in arthritis, endometriosis, organ transplantation, sepsis/sickness behavior, diabetes, atherosclerosis, autoimmune inner ear disease (AIED), Alzheimer’s disease and ulcerative colitis. In this review, we will detail the functional properties of IL-1R2 and examine its role in human disease.

GH and IGF-I control over 80% of postnatal growth. We recently established that TNFalpha impairs the ability of IGF-I to increase protein synthesis and promote expression of myogenin in myoblasts. Here we extend these results by showing that ceramide, a second messenger in both TNFalpha and IL-1beta receptor signaling pathways, is a key downstream sphingosine-based lipid that leads to IGF-I resistance. A cell-permeable ceramide analog, C2-ceramide, inhibits IGF-I-induced protein synthesis by 65% and blocks the ability of IGF-I to increase expression of two key myogenic factors, myogenin and MyoD. Identical results were obtained with both TNFalpha and IL-1beta (1 ng/ml). Consistent with these data, neutral sphingomyelinase (N-SMase), an enzyme that catalyzes formation of ceramide from sphingomyelin, blocks IGF-I-induced protein synthesis and expression of both myogenin and MyoD. The possibility that cytokine-induced ceramide production is required for disruption of IGF-I biologic activity was confirmed by treating C2C12 myoblasts with inhibitors of all three ceramide-generating pathways. A N-SMase inhibitor, glutathione, as well as an acidic sphingomyelinase (A-SMase) inhibitor, D609, reverse the cytokine inhibition of IGF-I-induced protein synthesis by 80% and 45%, respectively. Likewise, an inhibitor of de novo ceramide synthesis, FB1, causes a 50% inhibition. Similarly, all three inhibitors significantly impair the ability of both TNFalpha and IL-1beta to suppress IGF-I-driven expression of myogenin. These experiments establish that ceramide, derived both from sphingomyelin and de novo synthesis, is a key intermediate by which proinflammatory cytokines impair the ability of IGF-I to promote protein synthesis and expression of critical muscle-specific transcription factors.

The prevalence of childhood obesity has risen dramatically and coincident with this upsurge is a growth in adverse childhood psychological conditions including impulsivity, depression, anxiety and attention deficit/hyperactive disorder (ADHD). Due to confounds that exist when determining causality of childhood behavioral perturbations, controversy remains as to whether overnutrition and/or childhood obesity is important. Therefore, we examined juvenile mice to determine if biobehaviors were impacted by a short-term feeding (1–3 wks) of a high-fat diet (HFD). After 1 wk of a HFD feeding, mouse burrowing and spontaneous wheel running were increased while mouse exploration of the open quadrants of a zero maze, perfect alternations in a Y-maze and recognition of a novel object were impaired. Examination of mouse cortex, hippocampus and hypothalamus for dopamine and its metabolites demonstrated increased homovanillic acid (HVA) concentrations in the hippocampus and cortex that were associated with decreased cortical BDNF gene expression. In contrast, pro-inflammatory cytokine gene transcripts and serum IL-1α, IL-1β, TNF-α and IL-6 were unaffected by the short-term HFD feeding. Administration to mice of the psychostimulant methylphenidate prevented HFD-dependent impairment of learning/memory. HFD learning/memory impairment was not inhibited by the anti-depressants desipramine or reboxetine nor was it blocked in IDO or IL-1R1 knockout mice. In sum, a HFD rapidly impacts dopamine metabolism in the brain appearing to trigger anxiety-like behaviors and learning/memory impairments prior to the onset of weight gain and/or pre-diabetes. Thus, overnutrition due to fats may be central to childhood psychological perturbations such as anxiety and ADHD.

Chronic inflammation appears to play a critical role in type 2 diabetes and its complications. Here we tested the hypothesis that this inflammatory dysregulation affects the IL-1β system and has functional consequences in the brain. Diabetic, db/db, and nondiabetic, db/+, mice were administered i.p. LPS, a potent cytokine inducer, at a dose of 100 μg/kg/mouse. db/db mouse innate immune-associated sickness behavior was 14.8, 33, 44.7, and 34% greater than that of db/+ mice at 2, 4, 8, and 12 h, respectively. When a fixed dose of LPS was used (5 μg/mouse), db/db mouse sickness was again enhanced 18.4, 22.2, and 14.5% at 4, 8, and 12 h as compared with db/+ mice. In diabetic mice, peritoneal macrophages produced more IL-1β in response to LPS, and peritoneal levels of IL-1β induced by LPS were increased. Importantly, IL-1R antagonist and type 2 IL-1 receptor (IL-1R2) failed to up-regulate in response to LPS in db/db mice. Finally, both peripheral and central administration of IL-1β, itself, induced sickness in db/db mice that mimicked the effects of peripheral LPS and was significantly greater than that seen in db/+ mice. Taken together, these results indicate that IL-1β-mediated innate immunity is augmented in db/db mice both at the periphery and in the brain, and the mechanism is due to diabetes-associated loss of IL-1β counterregulation.