Low levels of circulating inflammatory cytokines - Do they affect human brain functions?

Department of Psychology, Hebrew University of Jerusalem, Yerushalayim, Jerusalem, Israel
Brain Behavior and Immunity (Impact Factor: 5.89). 11/2002; 16(5):525-32. DOI: 10.1016/S0889-1591(02)00004-1
Source: OAI


Animal studies provide consistent evidence for the pivotal role of inflammatory cytokines in inducing sickness behavior during systemic infection and inflammation. Because depression in humans shows a considerable symptomatic overlap with sickness behavior, it has been hypothesized that cytokines are also involved in affective disorders. This view is supported by studies showing that therapeutic administration of inflammatory cytokines can induce typical major depression and by evidence that stimulated cytokine-release during experimental endotoxemia provokes transient deterioration in mood and memory. However, in these conditions, similar to the animal models of acute infections, huge amounts of cytokines produced in the periphery act on the brain. In contrast, during most clinical conditions where depression might involve cytokine actions, such as chronic infection and inflammation, only low amounts of cytokines are circulating. The present paper addresses the question whether and how low amounts of circulating cytokines act on the human brain. Evidence is presented that very low amounts of circulating cytokines are likely to influence brain functions, even under baseline conditions. It is also likely that low levels of cytokines affect the same brain function as high levels do. However, it is uncertain whether these effects go in the same direction. NonREM sleep, for example, is promoted by a slight increase in cytokine levels, but suppressed by prominent increases. Because no comparable data are available for mood and other brain functions, the answer to the question whether and how low circulating amounts of cytokines affect mood depends on further experimental studies.

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    • "by experimentally induced endotoxemia, which provided evidence that appetite in humans decreased with mounting immune response (Pollmächer et al., 2002). Control steers fed on average 9.7 min per meal, with a frequency of approximately 12 meals per day, whereas BRD case steers fed on average between 7.6 and 8.9 min, with a frequency of 9.7 (d −7) to 12.5 (d −5) per day. "
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    ABSTRACT: Bovine respiratory disease (BRD), which can cause substantial losses for feedlot operations, is often difficult to detect based solely on visual observations. The objectives of the current study were to determine a BRD case identification based on clinical and laboratory parameters and assess the value of feeding behavior for early detection of BRD. Auction-derived, mixed-breed beef steers (n = 213) with an average arrival weight of 294 kg were placed at a southern Alberta commercial feedlot equipped with an automated feed bunk monitoring system. Feeding behavior was recorded continuously (1-s intervals) for 5 wk after arrival and summarized into meals. Meals were defined as feeding events that were interrupted by less than 300 s non-feeding. Meal intake (g) and meal time (min) were further summarized into daily mean, minimum, maximum and sum, and together with frequency of meals per day, were fit into a discrete survival time analysis with a conditional log-log link. Feedlot staff visually evaluated (pen-checked) health status twice daily. Within 35 d after arrival, 76% (n = 165) of the steers had one or more clinical signs of BRD (reluctance to move, crusted nose, nasal or ocular discharge, drooped ears or head and gaunt appearance). While 41 blood samples could not be processed due to immediate freezing, for 124 of these steers, complete and differential blood cell count, total serum protein, plasma fibrinogen, serum concentration of haptoglobin (HP) and serum amyloid A (SAA) were determined. The disease definition for BRD was a rectal temperature ≥ 40.0°C, at least two clinical signs of BRD, and HP > 0.15 mg/mL. It was noteworthy that 94% of the 124 steers identified by the feedlot staff with clinical signs of BRD had HP > 0.15 mg/mL. An increase in mean meal intake, frequency and mean inter-meal interval time between meals was associated with a decreased hazard for developing BRD 7 d before visual identification (P < 0.001). Furthermore, increased mean mealtime, frequency and mean inter-meal interval time between meals were associated with a decreased BRD hazard up to 7 d before feedlot staff noticed clinical symptoms (P < 0.001). In conclusion, mean intake per meal as well as mean meal time and frequency of meals could be used to predict the hazard of BRD in feedlot cattle 7 d before visual detection and could be considered in commercial feedlot settings once a predictive algorithm has been developed.
    Full-text · Article · Jan 2015 · Journal of Animal Science
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    • "As above, CNS measured cytokines may originate native or infiltrated cells in the CNS or peripheral cytokines could be transported across the BBB [51,52]. While we find that the brain of Munc18-OE mice presents an imbalance of immune and inflammatory systems, further studies including activity experiments should be carried out to identify the sources of the altered inflammatory signals observed in transgenic mice. "
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    ABSTRACT: Background An accumulating body of evidence points to the significance of neuroinflammation and immunogenetics in schizophrenia, and an imbalance of cytokines in the central nervous system (CNS) has been suggested to be associated with the disorder. Munc18-overexpressing mice (Munc18-OE) have provided a model for the study of the alterations that may underlie the symptoms of subjects with schizophrenia. The aim of the present study was to elucidate the involvement of neuroinflammation and cytokine imbalance in this model. Methods Cytokines were evaluated in the cortex and the striatum of Munc18-OE and wild-type (WT) mice by enzyme-linked immunosorbent assay (ELISA). Protein levels of specific microglia and macrophage, astrocytic and neuroinflammation markers were quantified by western blot in the cortex and the striatum of Munc18-OE and WT mice. Results Each cytokine evaluated (Interferon-gamma (IFN-γ), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-2 (IL-2) and CCL2 chemokine) was present at higher levels in the striatum of Munc18-OE mice than WT. Cortical TNF-α and IL-2 levels were significantly lower in Munc18-OE mice than WT mice. The microglia and macrophage marker CD11b was lower in the cortexes of Munc18-OE mice than WT, but no differences were observed in the striatum. Glial Fibrillary Acidic Protein (GFAP) and Nuclear Factor-kappaB (NF-κB)p65 levels were not different between the groups. Interleukin-1beta (IL-1β) and IL-6 levels were beneath detection limits. Conclusions The disrupted levels of cytokines detected in the brain of Munc18-OE mice was found to be similar to clinical reports and endorses study of this type for analysis of this aspect of the disorder. The lower CD11b expression in the cortex but not in the striatum of the Munc18-OE mice may reflect differences in physiological activity. The cytokine expression pattern observed in Munc18-OE mice is similar to a previously published model of schizophrenia caused by maternal immune activation. Together, these data suggest a possible role for an immune imbalance in this disorder.
    Full-text · Article · Jul 2014 · Journal of Neuroinflammation
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    • "While higher inflammatory and pathophysiological levels of cytokines are implicated in a range of neuropsychiatric and neurodegeneration diseases, it is now equally evident that, within the central nervous system (CNS), cytokines, including the chemoattractant cytokines (chemokines), mediate physiological signaling functions far beyond and independent of their traditional roles in inflammation and disease (Hopkins and Rothwell, 1995; Rothwell and Hopkins, 1995; Reichenberg et al., 2001; Pollmächer et al., 2002; Wilson et al., 2002; Adler and Rogers, 2005; Adler et al., 2006; McAfoose and Baune, 2009; Hoshiko et al., 2012; Williamson and Bilbo, 2013). In particular , pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNF-α) have all been implicated in cardinal cellular and molecular processes of longterm hippocampal-dependent memory consolidation including synaptic plasticity, synaptic scaling and neurogenesis (Malenka and Bear, 2004; Bruel-Jungerman et al., 2007a,b; Turrigiano, 2007; Baier et al., 2009; McAfoose and Baune, 2009; Bachstetter et al., 2011; Ben Menachem-Zidon et al., 2011; Yirmiya and Goshen, 2011; del Rey et al., 2013; Gemma and Bachstetter, 2013). "
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    ABSTRACT: Several cytokines and chemokines are now known to play normal physiological roles in the brain where they act as key regulators of communication between neurons, glia and microglia. In particular, cytokines and chemokines can affect cardinal cellular and molecular processes of hippocampal-dependent long-term memory consolidation including synaptic plasticity, synaptic scaling and neurogenesis. The chemokine, CX3CL1 (fractalkine), has been shown to modulate synaptic transmission and long-term potentiation (LTP) in the CA1 pyramidal cell layer of the hippocampus. Here, we confirm widespread expression of CX3CL1 on mature neurons in the adult rat hippocampus. We report an up-regulation in CX3CL1 protein expression in the CA1, CA3 and dentate gyrus of the rat hippocampus 2 h after spatial learning in the water maze task. Moreover, the same temporal increase in CX3CL1 was evident following long-term potentiation-inducing theta-burst stimulation in the dentate gyrus. At physiologically relevant concentrations, CX3CL1 inhibited LTP maintenance in the dentate gyrus. This attenuation in dentate LTP was lost in the presence of GABAA receptor/chloride channel antagonism. CX3CL1 also had opposing actions on glutamate-mediated rise in intracellular calcium in hippocampal organotypic slice cultures in the presence and absence of GABAA receptor/chloride channel blockade. Using primary dissociated hippocampal cultures, we established that CX3CL1 reduces glutamate-mediated intracellular calcium rises in both neurons and glia in a dose dependent manner. In conclusion, CX3CL1 is up-regulated in the hippocampus during a brief temporal window following spatial learning the purpose of which may be to regulate glutamate-mediated neurotransmission tone. Our data supports a possible role for this chemokine in the protective plasticity process of synaptic scaling.
    Full-text · Article · Jul 2014 · Frontiers in Cellular Neuroscience
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