Cytokine involvement in viral permissiveness and the progression of HIV disease

Many viruses have evolved novel means of exploiting host defense mechanisms for their own survival. This exploitation may be best exemplified by the interrelationships between certain viruses and the host cytokine networks. Many viruses, including the human immunodeficiency virus type-1 (HIV-1), rely on the liberation and cellular action of host immune cytokines to expand their host cell range, to regulate their cellular expression, and to maintain their dormant state until the proper extracellular conditions arise. As again exemplified by HIV-1, viruses may also take an active role regulating cytokine expression and cell surface cytokine receptors. Because the viral life cycle, and in particular the HIV-1 life cycle, is so intertwined with cytokine regulatory networks, these networks represent potential points for therapeutic intervention. As our understanding of cellular cytokine pathways involved in viral infection and replication continues to expand, so too will our ability to design rational anti-viral therapies to alter multiple steps along the viral life cycle.     

Invited review: cytokine regulation of fever: studies using gene knockout mice.

Fever is defined as a regulated rise in body temperature. The regulation of this phenomenon is accomplished by the actions of two types of endogenous cytokines, some functioning as pyrogens and others as antipyretics. Previous data obtained with the use of traditional pharmacological techniques, such as the injection of neutralizing antibodies, implicate interleukin (IL)-1 and IL-6 as endogenous pyrogens or inducers of fever. In almost all instances in which the endogenous actions of IL-1 or IL-6 are antagonized, fevers are attenuated. Other cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and IL-10, are thought to act as endogenous antipyretics or inhibitors of fever. In several studies, the inhibition of TNF action has enhanced fever. Recently, mice genetically engineered to lack cytokines or their receptors in all tissues of the body have been used to examine the regulation of IL-1, IL-6, TNF, and IL-10 on fever. Data obtained with these mice shed new light on our understanding of cytokine interactions in fever and, in some instances, contradict data obtained with pharmacological methods. This review summarizes the responses of cytokine and cytokine receptor knockout mice to fevers induced by lipopolysaccharide, turpentine, and sepsis.     

The emerging role of Interleukin 27 in inflammatory arthritis and bone destruction

Although the causes of inflammatory arthritis elude us, aberrant cytokine expression has been linked to joint pathology. Consequently, several approaches in the clinic and/or in clinical trials are targeting cytokines, e.g. tumor necrosis factor (TNF), Interleukin 23 (IL-23) and Interleukin 17 (IL-17), with the goal of antagonizing their respective biologic activity through therapeutic neutralizing antibodies. Such, cytokine signaling-dependent molecular networks orchestrate synovial inflammation on multiple levels including differentiation of myeloid cells to osteoclasts, the central cellular players in arthritis-associated pathologic bone resorption. Hence, understanding of the cellular and molecular mechanisms elicited by synovial cytokine networks that dictate recruitment, differentiation and activation of osteoclast precursors and osteoclasts, respectively, is central to shaping novel therapeutic options for inflammatory arthritis patients. In this article we are discussing the complex signaling interactions involved in the regulation of inflammatory arthritis and it's associated bone loss with a focus on Interleukin 27 (IL-27). The present review will discuss the primary bone-degrading cell, the osteoclast, and on how IL-27, directly or indirectly, modulates osteoclast activity in autoimmune-driven inflammatory joint diseases.     

Comparative proteomic analyses of the parietal lobe from rhesus monkeys fed a high-fat/sugar diet with and without resveratrol supplementation,relative to a healthy diet: Insights into the roles of unhealthy diets and resveratrol on function

A diet consisting of a high intake of saturated fat and refined sugars is characteristic of a Western-diet and has been shown to have a substantial negative effect on human health. Expression proteomics were used to investigate changes to the parietal lobe proteome of rhesus monkeys consuming either a high fat and sugar (HFS) diet, a HFS diet supplemented with resveratrol (HFS+RSV), or a healthy control diet for 2 years. Here we discuss the modifications in the levels of 12 specific proteins involved in various cellular systems including metabolism, neurotransmission, structural integrity, and general cellular signaling following a nutritional intervention. Our results contribute to a better understanding of the mechanisms by which resveratrol functions through the up- or down-regulation of proteins in different cellular sub-systems to affect the overall health of the brain.     

Effects of Habitat-Forming Species Richness,Evenness, Identity,and Abundance on Benthic Intertidal Community Establishment and Productivity

In a context of reduced global biodiversity, the potential impacts from the loss of habitat-forming species (HFS) on ecosystem structure and functioning must be established. These species are often the main community primary producers and have a major role in the establishment of organisms through facilitation processes. This study focuses on macroalgae and mussels as HFS within an intertidal zone along the St. Lawrence estuary (Quebec, Canada). Over a 16-week period, we manipulated the in situ diversity profile (richness, evenness, identity, and abundance) of the dominant HFS (Fucus distichus edentatus, F. vesiculosus, and Mytilus spp.) in order to define their role in both the establishment of associated species and community primary production. Contrary to expectation, no general change in HFS richness, evenness, abundance, or identity on associated species community establishment was observed. However, over the study period, the HFS diversity profile modified the structure within the trophic guilds, which may potentially affect further community functions. Also, our results showed that the low abundance of HFS had a negative impact on the primary productivity of the community. Our results suggest that HFS diversity profiles have a limited short-term role in our study habitat and may indicate that biological forcing in these intertidal communities is less important than environmental conditions. As such, there was an opportunistic establishment of species that ensured rapid colonization regardless of the absence, or the diversity profile, of facilitators such as HFS.     

Vasopressin Inhibits LTP in the CA2 Mouse Hippocampal Area

Growing evidence points to vasopressin (AVP) as a social behavior regulator modulating various memory processes and involved in pathologies such as mood disorders, anxiety and depression. Accordingly, AVP antagonists are actually envisaged as putative treatments. However, the underlying mechanisms are poorly characterized, in particular the influence of AVP on cellular or synaptic activities in limbic brain areas involved in social behavior. In the present study, we investigated AVP action on the synapse between the entorhinal cortex and CA2 hippocampal pyramidal neurons, by using both field potential and whole-cell recordings in mice brain acute slices. Short application (1 min) of AVP transiently reduced the synaptic response, only following induction of long-term potentiation (LTP) by high frequency stimulation (HFS) of afferent fibers. The basal synaptic response, measured in the absence of HFS, was not affected. The Schaffer collateral-CA1 synapse was not affected by AVP, even after LTP, while the Schaffer collateral-CA2 synapse was inhibited. Although investigated only recently, this CA2 hippocampal area appears to have a distinctive circuitry and a peculiar role in controlling episodic memory. Accordingly, AVP action on LTP-increased synaptic responses in this limbic structure may contribute to the role of this neuropeptide in controlling memory and social behavior.     

Proteomic analysis of the dorsal and ventral hippocampus of rats maintained on a high fat and refined sugar diet

The typical Western diet, rich in high saturated fat and refined sugar (HFS), has been shown to increase cognitive decline with aging and Alzheimer's disease, and to affect cognitive functions that are dependent on the hippocampus, including memory processes and reversal learning. To investigate neurophysiological changes underlying these impairments, we employed a proteomic approach to identify differentially expressed proteins in the rat dorsal and ventral hippocampus following maintenance on an HFS diet. Rats maintained on the HFS diet for 8 weeks were impaired on a novel object recognition task that assesses memory and on a Morris Water Maze task assessing reversal learning. Quantitative label‐free shotgun proteomic analysis was conducted on biological triplicates for each group. For the dorsal hippocampus, 59 proteins were upregulated and 36 downregulated in the HFS group compared to controls. Pathway ana‐lysis revealed changes to proteins involved in molecular transport and cellular and molecular signaling, and changes to signaling pathways including calcium signaling, citrate cycle, and oxidative phosphorylation. For the ventral hippocampus, 25 proteins were upregulated and 27 downregulated in HFS fed rats. Differentially expressed proteins were involved in cell‐to‐cell signaling and interaction, and cellular and molecular function. Changes to signaling pathways included protein ubiquitination, ubiquinone biosynthesis, oxidative phosphorylation, and mitochondrial dysfunction. This is the first shotgun proteomics study to examine protein changes in the hippocampus following long‐term consumption of a HFS diet, identifying changes to a large number of proteins including those involved in synaptic plasticity and energy metabolism. All MS data have been deposited in the ProteomeXchange with identifier PXD000028.     

Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary disorders

Recently melanogenic paracrine or autocrine cytokine networks have been discovered in vitro between melanocytes and other types of skin cells. These include endothelin (ET)-1, granulocyte macrophage colony stimulating factor, membrane-type stem cell factor (SCF) and growth-related oncogene-alpha for interactions between keratinocytes and melanocytes, and hepatocyte growth factor and soluble type SCF for interactions between fibroblasts and melanocytes. These networks are also associated with corresponding receptors expressed on melanocytes, including ET B receptor and the SCF receptor, c-KIT. Consistent with in vitro findings on the melanogenic paracrine or autocrine cytokine networks, we have found that the up- or down-regulation of such networks is intrinsically involved in vivo in the stimulation of melanocyte functions in several epidermal hyper- or hypo-pigmentary disorders. These are ET-1/ET B receptor as well as membrane type SCF/c-KIT for ultraviolet B-melanosis, granulocyte macrophage colony stimulating factor for ultraviolet A-melanosis, ET-1/ET B receptor as well as membrane type SCF for lentigo senilis, growth related oncogene-alpha for Riehl's melanosis, sphingosylphosphorylcholine for hyperpigmentation in atopic dermatitis, ET-1 for seborrhoeic keratosis, soluble type SCF as well as hepatocyte growth factor for dermatofibroma and café-au-lait macules, and c-KIT for vitiligo vulgaris. These unveiled regulatory mechanisms involved in the abnormal up- or down-regulated levels of lesional melanocyte function provide new insights into therapeutic tools utilizing blockage of responsible cytokine networks.     

Therapeutic electrical stimulation of the central nervous system

The electrical effects on the nervous system have been known for long. The excitatory effect has been used for diagnostic purposes or even for therapeutic applications, like in pain using low-frequency stimulation of the spinal cord or of the thalamus. The discovery that High-Frequency Stimulation (HFS) mimics the effect of lesioning has opened a new field of therapeutic application of electrical stimulation in all places where lesion of neuronal structures, such as nuclei of the basal ganglia, had proven some therapeutic efficiency. This was first applied to the thalamus to mimic thalamotomy for the treatment of tremor, then to the subthalamic nucleus and the pallidum to treat some advanced forms of Parkinson's disease and control not only the tremor but also akinesia, rigidity and dyskinesias. The field of application is increasingly growing, currently encompassing dystonias, epilepsy, obsessive compulsive disease, cluster headaches, and experimental approaches are being made in the field of obesity and food intake control. Although the effects of stimulation are clear-cut and the therapeutic benefit is clearly recognized, the mechanism of action of HFS is not yet understood. The similarity between HFS and the effect of lesions in several places of the brain suggests that this might induce an inhibition-like process, which is difficult to explain with the classical concept of physiology where electrical stimulation means excitation of neural elements. The current data coming from either clinical or experimental observations are providing elements to shape a beginning of an understanding. Intra-cerebral recordings in human patients with artefact suppression tend to show the arrest of electrical firing in the recorded places. Animal experiments, either in vitro or in vivo, show complex patterns mixing inhibitory effects and frequency stimulation induced bursting activity, which would suggest that the mechanism is based upon the jamming of the neuronal message, which is by this way functionally suppressed. More recent data from in vitro biological studies show that HFS profoundly affects the cellular functioning and particularly the protein synthesis, suggesting that it could alter the synaptic transmission by reducing the production of neurotransmitters. It is now clear that this method has a larger field of application than currently known and that its therapeutical applications will benefit to several diseases of the nervous system. The understanding of the mechanism has opened a new field of research, which will call for reappraisal of the basic effects of electricity on the living tissues.     

Interaction profiling methods to map protein and pathway targets of bioactive ligands

Recent advances in -omic profiling technologies have ushered in an era where we no longer want to merely measure the presence or absence of a biomolecule of interest, but instead hope to understand its function and interactions within larger signaling networks. Here, we review several emerging proteomic technologies capable of detecting protein interaction networks in live cells and their integration to draft holistic maps of proteins that respond to diverse stimuli, including bioactive small molecules. Moreover, we provide a conceptual framework to combine so-called ‘top-down’ and ‘bottom-up’ interaction profiling methods and ensuing proteomic profiles to directly identify binding targets of small molecule ligands, as well as for unbiased discovery of proteins and pathways that may be directly bound or influenced by those first responders. The integrated, interaction-based profiling methods discussed here have the potential to provide a unique and dynamic view into cellular signaling networks for both basic and translational biological studies.     

Comparing methods for metabolic network analysis and an application to metabolic engineering

Bioinformatics tools have facilitated the reconstruction and analysis of cellular metabolism of various organisms based on information encoded in their genomes. Characterization of cellular metabolism is useful to understand the phenotypic capabilities of these organisms. It has been done quantitatively through the analysis of pathway operations. There are several in silico approaches for analyzing metabolic networks, including structural and stoichiometric analysis, metabolic flux analysis, metabolic control analysis, and several kinetic modeling based analyses. They can serve as a virtual laboratory to give insights into basic principles of cellular functions. This article summarizes the progress and advances in software and algorithm development for metabolic network analysis, along with their applications relevant to cellular physiology, and metabolic engineering with an emphasis on microbial strain optimization. Moreover, it provides a detailed comparative analysis of existing approaches under different categories.     

Fenugreek improves diet-induced metabolic disorders in rats

Trigonella foenum-graecum L. (fenugreek) has been described earlier and its use in ancient medicinal practice is well known. The hypoglycemic effects of fenugreek have been studied in many animal models and diabetic patients. The purpose of this study was to examine the preventive efficiency of dietary fenugreek on diet-induced metabolic diseases in rats. The diets used in this study were a standard diet, a high-fat high-sucrose (HFS) diet, and a HFS diet containing 0.5?g/kg b.?w./day fenugreek based on the modified version of the AIN-93G purified diet, for 12 weeks, respectively. The rats fed the HFS diet containing fenugreek showed significantly lower fasting insulin levels and HOMA-IR than the rats fed the HFS diet. Therefore, fenugreek improved insulin sensitivity in rats. The triglyceride and total cholesterol levels in the plasma were significantly lower in the fenugreek-administered group. Moreover, distinct reductions of triglyceride, total cholesterol, free fatty acid, and phospholipid levels in the liver were found in the rats fed the HFS diet containing fenugreek. These results suggest that fenugreek enhanced insulin sensitivity at least partly by improving lipid metabolism disorders in the plasma and the liver in the rats induced by the HFS diet.     

An in vitro model for dengue virus infection that exhibits human monocyte infection, multiple cytokine production and dexamethasone immunomodulation

An important cytokine role in dengue fever pathogenesis has been described. These molecules can be associated with haemorrhagic manifestations, coagulation disorders, hypotension and shock, all symptoms implicated in vascular permeability and disease worsening conditions. Several immunological diseases have been treated by cytokine modulation and dexamethasone is utilized clinically to treat pathologies with inflammatory and autoimmune etiologies. We established an in vitro model with human monocytes infected by dengue virus-2 for evaluating immunomodulatory and antiviral activities of potential pharmaceutical products. Flow cytometry analysis demonstrated significant dengue antigen detection in target cells two days after infection. TNF-alpha, IFN-alpha, IL-6 and IL-10 are produced by in vitro infected monocytes and are significantly detected in cell culture supernatants by multiplex microbead immunoassay. Dexamethasone action was tested for the first time for its modulation in dengue infection, presenting optimistic results in both decreasing cell infection rates and inhibiting TNF-alpha, IFN-alpha and IL-10 production. This model is proposed for novel drug trials yet to be applied for dengue fever.     

Molecular aspects of bile formation and cholestasis

Recent insights into the cellular and molecular mechanisms that control the function and regulation of hepatobiliary transport have led to a greater understanding of the physiological significance of bile secretion. Individual carriers for bile acids and other organic anions in both liver and intestine have now been cloned from several species. In addition, complex networks of signals that regulate key enzymes and membrane transporters located in cells that participate in the metabolism or transport of biliary constituents are being unraveled. This knowledge has major implications for the pathogenesis of cholestatic liver diseases. Here, we review recent information on molecular aspects of hepatobiliary secretory function and its regulation in cholestasis. Potential implications of this knowledge for the design of new therapies of cholestatic disorders are also discussed.     

Cytokine genes and disease susceptibility

Complex networks of cytokines interact in a dynamic way to homeostatically regulate immune responses and other biological pathways. It is, therefore, not surprising that variation in cytokine level has been correlated with disease susceptibility and process. A fundamental issue is whether such variation is a primary cause for disease or reflects secondary inflammatory change. This can be unravelled by investigating cytokine gene polymorphism to determine whether a genetic basis for cytokine dysregulation is associated with disease. Thousands of disease association studies investigating cytokine gene polymorphisms have been reported although many have not been replicated. This is largely due to lack of statistical power, poor definition of clinical phenotype and lack of matching between cases and controls. An appropriate study design should include: Any genetic analysis of cytokine genes in disease studies should also take into account the fact that cytokines rarely manifest their effects in isolation but rather work in complex regulatory networks. Thus, gene-gene and gene-environment interactions may be at the centre of any disease association. Statistical methods are now being introduced to determine such relationships and this should ultimately allow a more accurate estimate of disease risk for individuals with particular cytokine gene profiles.     

Characterization of thymic cell subpopulations involved in IL-1- or GM-CSF-induced IL-6 production.

IL-6 has been demonstrated by in vitro studies to be a cytokine involved in thymocyte activation We show herein that thymocytes cultured at high concentrations in the absence of comitogen respond to IL-1 and, to a lesser degree, to GM-CSF, by producing IL-6. This phenomenon disappears rapidly with decreasing cell densities, suggesting the involvement of a minor cellular component of the thymus which may be solely responsible for or cooperate in IL-6 production. We have analysed several thymic subpopulations for IL-6 production and show that accessory cells, and eventually their precursors, are the major if not exclusive, producers of this cytokine. Mature steroid-resistant thymocytes do not secrete IL-6. Production of IL-6 by total CD4-CD8- thymic cells is largely reduced by the depletion of mature accessory cells which express I-A and Mac-1 antigens. As shown previously, accessory cell precursors within the CD4-CD8- compartment are induced to differentiate into M phi and DC in response to IL-1 and GM-CSF. We provide evidence that this maturation is associated with IL-6 production. Thymic DC and phagocytic cells of the thymic reticulum (P-TR) in vitro produce high levels of IL-6 which are enhanced by GM-CSF or IL-1. These factors have a synergistic effect on IL-6 production by total thymocytes, and on CD4-CD8- cells that are not depleted for mature I-A+ Mac-1+ accessory cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytokines and cytokine networks target neurons to modulate long-term potentiation

Cytokines play crucial roles in the communication between brain cells including neurons and glia, as well as in the brain-periphery interactions. In the brain, cytokines modulate long-term potentiation (LTP), a cellular correlate of memory. Whether cytokines regulate LTP by direct effects on neurons or by indirect mechanisms mediated by non-neuronal cells is poorly understood. Elucidating neuron-specific effects of cytokines has been challenging because most brain cells express cytokine receptors. Moreover, cytokines commonly increase the expression of multiple cytokines in their target cells, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Here, we review evidence on both direct and indirect-mediated modulation of LTP by cytokines. We also describe novel approaches based on neuron- and synaptosome-enriched systems to identify cytokines able to directly modulate LTP, by targeting neurons and synapses. These approaches can test multiple samples in parallel, thus allowing the study of multiple cytokines simultaneously. Hence, a cytokine networks perspective coupled with neuron-specific analysis may contribute to delineation of maps of the modulation of LTP by cytokines.