Neurotropic effects cytokines and trophic factors

Cytokines and trophic factors (TF) are involved into the nervous system activity regulation that confirms by their secretion and receptors identification within nervous system. Cytokines and TF production increases tremendously in response to CNS alterations or other CNS pathologic events where they are modulated both alterative and protective effects. Authors observed the data of clinical and laboratory investigations concerning the cytokines and TF-neurotropic effects and also the original results dedicated to investigation of tumor necrosis factor-alpha and interleukin-1-beta influence on experimental seizure syndrome. The new data about cytokines and TF-neurotropic effects as well as their influence on the experimental seizure syndrome are reviewed. The clinical use of cytokines and TF-perspective is evaluated also.     

Cytokine and intracellular signaling regulation of tissue factor expression in astrocytes

There is evidence that inflammatory cytokines such as IL-1beta, TNFalpha, and IL-6 are involved in the pathogenesis of cerebrovascular disorders including stroke. One action of cytokines that contributes to diseases in peripheral tissues is upregulation of the procoagulant receptor tissue factor (TF). In the CNS, astrocytes are the primary cells that express TF; although little is known about how TF is regulated in these cells. Experiments were performed to evaluate the effect of cytokine treatment on TF activity in primary cultures of murine cortical astrocytes and in the human astrocytoma cell line (CCF). IL-1beta treatment induced a 2.5-fold increase in TF activity in the primary astrocytes and a 3-fold induction in the astrocytoma cells. TNFalpha treatment induced a 2.5-fold increase in TF activity in both the primary astrocytes and astrocytoma cells. IL-6 upregulated TF activity 2-fold in primary astrocytes, however, it had no effect on TF activity in the astrocytoma cells. The signaling pathways regulating TF expression in these cells were examined by using staurosporine, a broad spectrum inhibitor of serine-threonine protein kinases, and by examining the effects of intermediates in the sphingomyelin signaling pathway. Staurosporine inhibited IL-1beta-induced TF activity in the primary astrocytes but did not effect IL-1beta- or TNFalpha-induced TF activity in the astrocytoma cells. TF activity in the astrocytoma cells was upregulated 1.5-fold over constitutive levels by a ceramide analogue or the enzyme sphingomyelinase, however the ceramide analogue had no effect on TF activity in the primary astrocytes. These results suggest inflammatory cytokines can upregulate TF activity in astrocytes and the astrocytoma CCF cell line although the two cell types appear to utilize different signaling pathways to mediate TF expression. Further studies will be important to more completely define the signaling regulation of TF in astrocytes since alterations in brain TF levels may play a key role in CNS pathophysiology.     

One messenger shared by two systems: How cytokines directly modulate neurons

Cytokines are small, secreted proteins that are known for their roles in the immune system. An accumulating body of evidence indicates that cytokines also work as neuromodulators in the central nervous system (CNS). Cytokines can access the CNS through multiple routes to directly impact neurons. The neuromodulatory effects of cytokines maintain the overall homeostasis of neural networks. In addition, cytokines regulate a diverse repertoire of behaviors both at a steady state and in inflammatory conditions by acting on discrete brain regions and neural networks. In this review, we discuss recent findings that provide insight into how combinatorial codes of cytokines might mediate neuro-immune communications to orchestrate functional responses of the brain to changes in immunological milieus.     

SOCS家族在中枢神经系统的研究进展

细胞因子信号抑制因子（SOCS）家族是一类对细胞因子信号通路具有负反馈调节作用的蛋白分子,参与多种细胞因子、生长因子和激素的信号调节。细胞因子对中枢神经系统中的各种生物效应具有广泛多样的调节作用,SOCS家族的许多成员在发育时期和成年的脑内均有表达,SOCS家族不仅与细胞因子信号调节及中枢神经系统多种功能的调节密切相关,而且可能是神经发育和分化的重要调控因子,并参与神经免疫内分泌调节。本文综述了SOCS家族的发现、结构特点、脑内分布以及在中枢神经系统中的功能等方面的研究进展。     

The influence of kainic acid on core temperature and cytokine levels in the brain

Excitotoxic brain injury is associated with hyperthermia, and there are data showing beneficial effects of hypothermia on neurodegeneration and that hyperthermia facilitates the neurodegeneration. Cytokines are inflammatory proteins that seem to be involved in the neuroinflammation associated with epilepsy. Core temperature changes caused by the epileptogenic glutamate analogue kainic acid (KA) were investigated in relation to changes in levels of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), and the endogenous interleukin-1 receptor antagonist (IL-1ra). The temperature was measured every 10 min during the first hour, and at 90 and 120 min, and hourly until 8 h after KA-injection (10 mg/kg). The cytokines were measured in the hypothalamus, a site of temperature regulation, and in hippocampus, cerebellum, and frontal cortex. KA induced a brief hypothermia followed by hyperthermia. IL-1beta levels were increased after KA-administration in all brain regions examined and, excepting hippocampus, returned to baseline levels at 24 h. The hippocampal IL-1ra levels were significantly increased at 24 h, whereas no changes in IL-6 levels were observed. The changes in IL-1beta levels and in ratios between the levels of the three cytokines, may account for some of the temperature changes and the behavioural manifestations induced by KA.     

Human transferrin. Expression and iron modulation of chimeric genes in transgenic mice

Transferrin (TF) is a plasma protein that transports and is regulated by iron. The aim of this study was to characterize human TF gene sequences that respond in vivo to cellular signals affecting expression in various tissues and to iron administration. Chimeric genes were constructed containing 152, 622, and 1152 base pairs (bp) of the human TF5'-flanking region with the coding region of a reporter gene, CAT (chloramphenicol acetyltransferase), and introduced into the germ line of mice. Transgenes containing TF 5'-flanking sequences to -152 bp were expressed poorly in all tissues examined. In contrast, transgenes containing TF sequences to -622 or -1152 bp were expressed at high levels in brain and liver, greater than or equal to 1000-fold higher than tissues such as heart and testes. Liver and brain are major sites of endogenous TF mRNA synthesis, but liver mRNA levels are 10-fold higher than brain. A significant diminution of CAT enzymatic activity in liver accompanied iron administration in both TF(0.67) and TF(1.2)CAT transgenic mice, mimicking the decrease of transferrin in humans following iron overload. Levels of endogenous plasma transferrin also decreased in iron-treated transgenic mice. Transgenic mouse lines carrying human TF chimeric genes will be useful models for analyzing the regulation of human transferrin by iron and for determining the molecular basis of transferrin regulation throughout mammalian development into the aging process.     

Plant Based Bioreactors of Recombinant Cytokines (Review)

Cytokines are a family of signaling polypeptides involved in intercellular interactions in the process of the immune response, as well as in the regulation of a number of normal physiological functions. Cytokines are used in medicine for the treatment of cancer, immune disorders, viral infections, and other socially significant diseases, but the extent of their use is limited by the high production cost of the active agent. The development of this area of pharmacology is associated with the success of genetic engineering, which allows the production of significant amounts of protein by transgenic organisms. The review discusses the latest advances in the production of various cytokines with the use of genetically modified plants.     

Keratinocytes as targets for interleukin-10-related cytokines: a putative role in the pathogenesis of psoriasis

Cytokines are key factors in the cross talk between the immune system and other systems including hepatic, nervous, cardiac and cutaneous systems, leading to an adaptive and integrated response of the organism to stress. They are also involved in the regulation of many processes, including hematopoiesis, the immune response and inflammation. IL-10 is one of the most important anti-inflammatory cytokines. Five cytokines structurally related to IL-10 have been described and presently form this family of cytokines: IL-19, IL-20, IL-22, IL-24 and IL-26. In contrast to IL-10, these cytokines display pro-inflammatory activities in different tissues, including skin. Indeed, some of them induce an inflammatory keratinocyte gene expression profile and an epidermis histology resembling psoriatic lesions. In this review, we discuss recent knowledge about the effects of cytokines of the IL-10 family on keratinocytes and their potential role in psoriasis, a cutaneous inflammatory disease.     

Effect of prostaglandins and their precursors on the proliferation of human lymphocytes and their secretion of tumor necrosis factor and various interleukins

Cytokines, released by T cells, participate in inflammation and produce tissue injury. Excess production of cytokines such as interleukins (ILs) and tumor necrosis factor (TNF) is believed to be involved in the pathobiology of conditions such as septicemia and septic shock, collagen vascular diseases, glomerulonephritis etc. On the other hand, prostaglandins (PGs) are known to modulate inflammation, immune response, and T-cell response to antigens. But relatively little information is available on the effects of PGs and PG precursors on the release of cytokines. Here the authors present data which suggests that PGs including thromboxane B₂ (TXB₂) and their precursors such as dihomo-gamma linolenic acid (DGLA), arachidonic acid (AA) and eicosapentaenoic acid (EPA) can inhibit T-cell proliferation and influence their ability to secrete IL-2, IL-4, IL-6 and TNF in vitro. These results may have relevance to the use of PG-precursors in various inflammatory conditions including collagen vascular diseases.     

Interactions between the immune and neuroendocrine systems: clinical implications

The endocrine and immune systems are interrelated via a bidirectional network in which hormones affect immune function and, in turn, immune responses are reflected in neuroendocrine changes. This bidirectional communication is possible because both systems share a common "chemical language" that results from a sharing of common ligands (hormones and cytokines) and their specific receptors. Cytokines are important partners in this crosstalk. They play a role in modulating the hypothalamo-pituitary-adrenal (HPA) axis responses at all three levels: the hypothalamus, the pituitary gland and the adrenals. Acute effects of cytokines are produced at the central nervous system level, particularly the hypothalamus, whereas pituitary and adrenal actions are slower and are probably involved during prolonged exposure to cytokines such as during chronic inflammation or infection. Several mechanisms have been proposed by which peripheral cytokines may gain access to the brain. They include an active transport through the blood-brain barrier, a passage at the circumventricular organ level, as well as a neuronal pathway through the vagal nerve. The immune-neuroendocrine interactions are involved in numerous physiological and pathophysiological conditions and the interactions with the HPA axis may represent a mechanism through which the immune system, by stimulating the production of glucocorticoids, avoids an overshoot of inflammatory response. They may also be involved in the state of hypogonadism, of hypothyroidism and growth inhibition which can occur during inflammatory and infectious diseases. The crosstalk between the immune and endocrine systems is important to homeostasis, since the interactions can produce various appropriate adaptative responses when homeostasis is threatened.     

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.     

Caspase-3 inhibits growth in Saccharomyces cerevisiae without causing cell death

Cytokine-dependent regulation of tissue inhibitors of metalloproteinases (TIMPs) expression provides an important mechanism for controlling the activity of matrix metalloproteinases. We present data indicating that during inflammatory processes TIMP-1 and TIMP-3 may be involved in the proteolytic remodeling of subendothelial basement membrane of the brain microvascular system, a key step during leukocyte migration into the brain perivascular tissue. In brain endothelial cells the expression of TIMP-1 is dramatically up-regulated by major proinflammatory cytokines, with the combination of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha) exhibiting the strongest synergistic stimulation. Simultaneously, IL-1beta/TNF alpha almost completely blocks TIMP-3 expression. Both synergistic effects are dose-dependent within the concentration range 0.05-5 ng/ml of both cytokines and correlate with the expression of inducible nitric oxide synthase, an endothelial cell activation marker. Down-regulation of TIMP-3 expression is also detected in astrocytes treated with TNF alpha or IFN-gamma whereas oncostatin M as well as TNF alpha up-regulate TIMP-1 mRNA level. We propose that the cytokine-modified balance between TIMP-1 and TIMP-3 expression provides a potential mechanism involved in the regulation of microvascular basement membrane proteolysis.     

The role of cytokines in oncology

The availability of sufficient quantities of recombinant human cytokines and promising preclinical data have led to their introduction into clinical trials. Cytokines have potential as new therapeutic agents in a variety of hematological disorders as well as in solid tumors. Only a few of the still increasing number of these glycoprotein hormones have been studied in humans so far, either as single agents or in combination with chemotherapy and other cytokines. Their clinical effects, beneficial role in supportive care, and use in the treatment of certain cancer patients are reviewed.     

β cell membrane remodelling and procoagulant events occur in inflammation‐driven insulin impairment: a GLP‐1 receptor dependent and independent control

Inflammation and hyperglycaemia are associated with a prothrombotic state. Cell‐derived microparticles (MPs) are the conveyors of active procoagulant tissue factor (TF) and circulate at high concentration in diabetic patients. Liraglutide, a glucagon‐like peptide (GLP)‐1 analogue, is known to promote insulin secretion and β‐cell preservation. In this in vitro study, we examined the link between insulin impairment, procoagulant activity and plasma membrane remodelling, under inflammatory conditions. Rin‐m5f β‐cell function, TF activity mediated by MPs and their modulation by 1 μM liraglutide were examined in a cell cross‐talk model. Methyl‐β‐cyclodextrine (MCD), a cholesterol depletor, was used to evaluate the involvement of raft on TF activity, MP shedding and insulin secretion as well as Soluble N‐éthylmaleimide‐sensitive‐factor Attachment protein Receptor (SNARE)‐dependent exocytosis. Cytokines induced a two‐fold increase in TF activity at MP surface that was counteracted by liraglutide. Microparticles prompted TF activity on the target cells and a two‐fold decrease in insulin secretion via protein kinase A (PKA) and p38 signalling, that was also abolished by liraglutide. Large lipid raft clusters were formed in response to cytokines and liraglutide or MCD‐treated cells showed similar patterns. Cells pre‐treated by saturating concentration of the GLP‐1r antagonist exendin (9‐39), showed a partial abolishment of the liraglutide‐driven insulin secretion and liraglutide‐decreased TF activity. Measurement of caspase 3 cleavage and MP shedding confirmed the contribution of GLP‐1r‐dependent and ‐independent pathways. Our results confirm an integrative β‐cell response to GLP‐1 that targets receptor‐mediated signalling and membrane remodelling pointing at the coupling of insulin secretion and inflammation‐driven procoagulant events.     

“Inflammatory” Cytokines

If cytokines are constitutively expressed by and act on neurons in normal adult brain, then we may have to modify our current view that they are predominantly inflammatory mediators. We critically reviewed the literature to determine whether we could find experimental basis for such a modification. We focused on two "proinflammatory" cytokines, interleukin (IL)-1 and tumor necrosis factor-alpha (TNFalpha) because they have been most thoroughly investigated in shaping our current thinking. Evidence, although equivocal, indicates that the genes coding for these cytokines and their accessory proteins are expressed by neurons, in addition to glial cells, in normal brain. Their expression is region- and cell type-specific. Furthermore, bioactive cytokines have been extracted from various regions of normal brain. The cytokines' receptors selectively are present on all neural cell types, rendering them responsive to cytokine signaling. Blocking their action modifies multiple neural "housekeeping" functions. For example, blocking IL-1 or TNFalpha by several independent means alters regulation of sleep. This indicates that these cytokines likely modulate in the brain behavior of a normal organism. In addition, these cytokines are likely involved in synaptic plasticity, neural transmission, and Ca2+ signaling. Thus, the evidence strongly suggests that these cytokines perform neural functions in normal brain. We therefore propose that they should be thought of as neuromodulators in addition to inflammatory mediators.