transforming-growth-factor-beta and Encephalitis

Epilepsy is a chronic neurological disease characterized by an enduring propensity for generation of seizures. The pathogenic processes of seizure generation and recurrence are the subject of intensive preclinical and clinical investigations as their identification would enable development of novel treatments that prevent epileptic seizures and reduce seizure burden. Such treatments are particularly needed for pharmacoresistant epilepsies, which affect ~30% of patients. Neuroinflammation is commonly activated in epileptogenic brain regions in humans and is clearly involved in animal models of epilepsy. An increased understanding of neuroinflammatory mechanisms in epilepsy has identified cellular and molecular targets for new mechanistic therapies or existing anti-inflammatory drugs that could overcome the limitations of current medications, which provide only symptomatic control of seizures. Moreover, inflammatory mediators in the blood and molecular imaging of neuroinflammation could provide diagnostic, prognostic and predictive biomarkers for epilepsy, which will be instrumental for patient stratification in future clinical studies. In this Review, we focus on our understanding of the IL-1 receptor-Toll-like receptor 4 axis, the arachidonic acid-prostaglandin cascade, oxidative stress and transforming growth factor-β signalling associated with blood-brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures, neuronal cell loss and neurological comorbidities.

Topics: Animals; Arachidonic Acid; Biomarkers; Encephalitis; Epilepsy; Humans; Oxidative Stress; Prostaglandins; Receptors, Interleukin-1; Signal Transduction; Toll-Like Receptor 4; Transforming Growth Factor beta

Morbidities of aging and Alzheimer's disease (AD) have been related to defective functions of both T cells and macrophages leading to brain amyloidosis and inflammation. In AD patients, "inflammaging" may be associated with an increase of incompetent memory T cells and inflammatory cytokines produced by macrophages, whereas defective clearance of amyloid-beta 1-42 (Abeta) may be related to defective transcription of immune genes necessary for Abeta phagocytosis, beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase and Toll-like receptors. However, AD shows considerable heterogeneity of disease manifestations and mechanisms. The approaches to re-balancing Abeta immunity and inflammation are being pursued in transgenic animal models and peripheral blood mononuclear cells of patients. The regulatory signaling pathways of microglial phagocytosis and inflammation involving co-receptors and transforming growth factor-beta have been considerably clarified in animal studies. Natural immunostimulating therapies using vitamin D3 and curcuminoids have been developed in macrophages of AD patients. AD patients possess two types of macrophages: a majority has "Type I", which are improved by curcuminoids and vitamin D3; whereas a minority has "Type II" responding positively to vitamin D3 but not to curcuminoids. Other nutritional substances, such as plant polyphenols and omega-3 fatty acids, may inhibit inflammation and stimulate immunity. More invasive immune approaches involve Abeta vaccine and cytokine antagonists. Increased inflammation may represent the "first hit", and defective transcription of immune genes the "second hit" in the pathogenesis of AD.

Topics: Adjuvants, Immunologic; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholecalciferol; Curcumin; Encephalitis; Humans; Immunity, Innate; Macrophages; Phagocytosis; Transforming Growth Factor beta

Inflammation is an important part of the pathophysiology of traumatic brain injury. Although the central nervous system differs from the other organs because of the almost complete isolation from the blood stream mediated by the blood-brain barrier, the main steps characterizing the immune activation within the brain follow a scenario similar to that in other organs. The key players in these processes are the numerous immune mediators released within minutes of the primary injury. They guide a sequence of events including expression of adhesion molecules, cellular infiltration, and additional secretion of inflammatory molecules and growth factors, resulting in either regeneration or cell death. The question is this: to what extent is inflammation beneficial for the injured brain tissue, and how does it contribute to secondary brain damage and progressive neuronal loss? This review briefly reports recent evidence supporting the dual, the beneficial, or the deleterious role of neuroinflammation after traumatic brain injury.

Topics: Animals; Brain Injuries; Cytokines; Encephalitis; Humans; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-6; Leukocytes; Mice; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The inflammatory response in prion diseases is dominated by microglial activation. Contrary to their profile in vitro none of the pro-inflammatory cytokines interleukin-1beta, interleukin-6, or tumour necrosis factor-alpha are significantly upregulated in the ME7 model of prion disease. However, two major inflammatory mediators are elevated: transforming growth factor-beta1 and prostaglandin E2. This cytokine profile is the same as that reported for macrophages during phagocytosis of apoptotic cells and indeed transforming growth factor-beta1 and prostaglandin E2 are responsible for the downregulated phenotype of these macrophages. Transforming growth factor-beta1 may also have roles in extracellular matrix deposition and in amyloidogenesis and may play a direct role in disease pathogenesis. There is also now evidence to suggest that a peripheral infection, and its consequent systemic cytokine expression, may drive central nervous system cytokine expression and perhaps exacerbate disease.

Topics: Animals; Central Nervous System; Cytokines; Dinoprostone; Encephalitis; Humans; Microglia; Prion Diseases; Reactive Oxygen Species; Transforming Growth Factor beta

Transforming growth factor-beta(1) (TGF-beta(1)) and interleukin (IL)-10 gene expression is equivocal in normal brain and upregulated in over a dozen central and peripheral diseases/disorders. The patterns of specific expression of cytokines differ in these diseases. Published data indicate that these cytokines are produced by and act on both neurons and glial cells. Although their actions are commonly viewed as 'anti-inflammatory', they protect neurons and downregulate the responses of glial cells to diseases/disorders in the absence of inflammation. Their actions counterbalance the actions of elevated IL-1 and/or tumor necrosis factor-alpha to maintain homeostasis. Their therapeutic potential will be realized by improving our understanding of their place in neural cytokine networks.

Topics: Animals; Anti-Inflammatory Agents; Brain; Encephalitis; Humans; Interleukin-10; Neuroimmunomodulation; Transforming Growth Factor beta; Up-Regulation

Lead (Pb) is a heavy metal with a proven neurotoxic effect. Exposure is particularly dangerous to the developing brain in the pre- and neonatal periods. One postulated mechanism of its neurotoxicity is induction of inflammation. This study analyzed the effect of exposure of rat pups to Pb during periods of brain development on the concentrations of selected cytokines and prostanoids in the forebrain cortex, hippocampus and cerebellum.. Administration of 0.1% lead acetate (PbAc) in drinking water ad libitum, from the first day of gestation to postnatal day 21, resulted in blood Pb in rat pups reaching levels below the threshold considered safe for humans by the Centers for Disease Control and Prevention (10 µg/dL). Enzyme-linked immunosorbent assay (ELISA) method was used to determine the levels of interleukins IL-1β, IL-6, transforming growth factor-β (TGF-β), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2). Western blot and quantitative real-time PCR were used to determine the expression levels of cyclooxygenases COX-1 and COX-2. Finally, Western blot was used to determine the level of nuclear factor kappa B (NF-κB).. In all studied brain structures (forebrain cortex, hippocampus and cerebellum), the administration of Pb caused a significant increase in all studied cytokines and prostanoids (IL-1β, IL-6, TGF-β, PGE2 and TXB2). The protein and mRNA expression of COX-1 and COX-2 increased in all studied brain structures, as did NF-κB expression.. Chronic pre- and neonatal exposure to Pb induces neuroinflammation in the forebrain cortex, hippocampus and cerebellum of rat pups.

Topics: Animals; Animals, Newborn; Biomarkers; Cerebellum; Dinoprostone; Disease Models, Animal; Encephalitis; Female; Hippocampus; Interleukin-1beta; Interleukin-6; Lead; Male; Pregnancy; Prenatal Exposure Delayed Effects; Prosencephalon; Rats; Thromboxane B2; Transforming Growth Factor beta

Zinc-α2-glycoprotein (ZAG) is a 42-kDa protein reported as an anti-inflammatory adipocytokine. Evidences from clinical and experimental studies revealed that brain inflammation plays important roles in epileptogenesis and seizure. Interestingly, closely relationship between ZAG and many important inflammatory mediators has been proven. Our previous study identified ZAG in neurons and found that ZAG is decreased in epilepsy and interacts with TGFβ and ERK. This study aimed to investigate the role of ZAG in seizure and explore its effect on seizure-related neuroinflammation.. We overexpressed AZGP1 in the hippocampus of rats via adeno-associated virus vector injection and observed their seizure behavior and EEG after pentylenetetrazol (PTZ) kindling. The level of typical inflammation mediators including TNFα, IL-6, TGFβ, ERK, and ERK phosphorylation were determined.. The overexpression of AZGP1 reduced the seizure severity, prolonged the latency of kindling, and alleviated epileptiform discharges in EEG changes induced by PTZ. Overexpression of AZGP1 also suppressed the expression of TNFα, IL-6, TGFβ, and ERK phosphorylaton in PTZ-kindled rats.. ZAG may inhibit TGFβ-mediated ERK phosphorylation and inhibit neuroinflammation mediated by TNFα and IL-6, suggesting ZAG may suppress seizure via inhibiting neuroinflammation. ZAG may be a potential and novel therapeutic target for epilepsy.

Topics: Adipokines; Animals; Brain Waves; Carrier Proteins; Convulsants; Cytokines; Disease Models, Animal; eIF-2 Kinase; Electroencephalography; Encephalitis; Gene Expression Regulation; Glycoproteins; Green Fluorescent Proteins; Hippocampus; Kindling, Neurologic; Male; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures; Signal Transduction; Time Factors; Transduction, Genetic; Transforming Growth Factor beta

Transplantation of mesenchymal stem cells (MSCs) has been shown to enhance the recovery of brain functions following ischemic injury. Although immune modulation has been suggested to be one of the mechanisms, the molecular mechanisms underlying improved recovery has not been clearly identified. Here, we report that MSCs secrete transforming growth factor-beta (TGF-β) to suppress immune propagation in the ischemic rat brain. Ischemic stroke caused global death of resident cells in the infarcted area, elevated the monocyte chemoattractant protein-1 (MCP-1) level, and evoked massive infiltration of circulating CD68+ immune cells through the impaired blood-brain barrier. Transplantation of MSCs at day 3 post-ischemia blocked the subsequent upregulation of MCP-1 in the ischemic area and the infiltration of additional CD68+ immune cells. MSC-conditioned media decreased the migration and MCP-1 production of freshly isolated immune cells in vitro, and this effect was blocked by an inhibitor of TGF-β signaling or an anti-TGF-β neutralizing antibody. Finally, transplantation of TGF-β1-silenced MSCs failed to attenuate the infiltration of CD68+ cells into the ischemic brain, and was associated with only minor improvements in motor function. These results indicate that TGF-β is key to the ability of MSCs to beneficially attenuate immune reactions in the ischemic brain. Our findings offer insight into the interactions between allogeneic MSCs and the host immune system, reinforcing the prospective clinical value of using MSCs in the treatment of neurological disorders involving inflammation-mediated secondary damage.

Topics: Animals; Antigens, CD; Blood-Brain Barrier; Brain Infarction; Calcium-Binding Proteins; Cell Movement; Cells, Cultured; Chemokine CCL2; Disease Models, Animal; Encephalitis; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Microfilament Proteins; Peroxidase; Rats; Rats, Sprague-Dawley; Time Factors; Transforming Growth Factor beta

We previously showed that lipopolysaccharide (LPS) and pro-inflammatory cytokines utilized different mechanisms for the production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) in cultured rat astrocytes. To further characterize these regulatory pathways, we tested the effects of inhibitory factors (anti-inflammatory cytokines, cellular cAMP, and glucocorticoid) on aspects of iNOS expression (from transcription to enzyme activity) during LPS- and cytokine-induced astrocyte NO production. Anti-inflammatory cytokines (transforming growth factor-beta and interleukin-4) suppressed both LPS- and cytokine-induced NO production by reducing iNOS protein expression without affecting mRNA levels. Increased cellular cAMP levels, induced by noradrenaline or forskolin, suppressed LPS-induced, but not cytokine-induced, NO production without affecting iNOS protein expression. The glucocorticoid analog, dexamethasone, suppressed LPS-induced, but not cytokine-induced, NO production by reducing iNOS promoter activity. These different mechanisms would allow the fine control of NO concentration in the brain, as well as accounting for the multiple roles of NO in brain physiology and pathology. Moreover, these mechanisms provide useful therapeutic targets for the treatment of neurodegenerative diseases.

Topics: Animals; Astrocytes; Brain; Cells, Cultured; Cyclic AMP; Cytokines; Dexamethasone; Encephalitis; Gene Expression Regulation, Enzymologic; Inflammation Mediators; Interleukin-4; Lipopolysaccharides; Nitric Oxide; Nitric Oxide Synthase Type II; Promoter Regions, Genetic; Rats; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta

Activation and mobilization of microglia are early events in the majority of brain pathologies. Among the signalling molecules that can affect microglial behaviour, we investigated whether nerve growth factor (NGF) was able to influence microglial motility. We found that NGF induced chemotaxis of microglial cells through the activation of TrkA receptor. In addition, NGF chemotactic activity was increased in the presence of low concentrations (< or =0.2 ng/ml) of transforming growth factor-beta (TGF-beta), which at this concentration showed chemotactic activity per se. On the contrary, NGF-induced microglial migration was reduced in the presence of chemokinetic concentration of TGF-beta (> or =2 ng/ml). Finally, both basal and NGF-induced migratory activity of microglial cells was increased after a long-term exposure of primary mixed glial cultures to 2 ng/ml of TGF-beta. Our observations suggest that both NGF and TGF-beta contribute to microglial recruitment. The chemotactic activities of these two pleiotropic factors could be particularly relevant during chronic diseases in which recruited microglia remove apoptotic neurons in the absence of a typical inflammatory reaction.

Topics: Animals; Animals, Newborn; Cell Movement; Cells, Cultured; Chemotaxis; Coculture Techniques; Dose-Response Relationship, Drug; Encephalitis; Gliosis; Microglia; Nerve Growth Factor; Phagocytosis; Rats; Receptor, trkA; Signal Transduction; Transforming Growth Factor beta

Astrocyte production of tissue inhibitor of metalloproteinase (TIMP)-1 is important in central nervous system (CNS) homeostasis and inflammatory diseases such as HIV-1-associated dementia (HAD). TIMPs and matrix metalloproteinases (MMPs) regulate the remodeling of the extracellular matrix. An imbalance between TIMPs and MMPs is associated with many pathologic conditions. Our recently published studies uniquely demonstrate that HAD patients have reduced levels of TIMP-1 in the brain. Astrocyte-TIMP-1 expression is differentially regulated in acute and chronic inflammatory conditions. In this and the adjoining report (Gardner et al., 2006), we investigate the mechanisms that may be involved in differential TIMP-1 regulation. One mechanism for TIMP-1 downregulation is the production of anti-inflammatory molecules, which can activate signaling pathways during chronic inflammation. We investigated the contribution of transforming growth factor (TGF)-signaling in astrocyte-MMP/TIMP-1-astrocyte regulation. TGF-beta1 and beta2 levels were upregulated in HAD brain tissues. Co-stimulation of astrocytes with IL-1beta and TGF-beta mimicked the TIMP-1 downregulation observed with IL-1beta chronic activation. Measurement of astrocyte-MMP protein levels showed that TGF-beta combined with IL-1beta increased MMP-2 and decreased proMMP-1 expression compared to IL-1beta alone. We propose that one of the mechanisms involved in TIMP-1 downregulation may be through TGF-signaling in chronic immune activation. These studies show a novel extracellular regulatory loop in astrocyte-TIMP-1 regulation.

Topics: AIDS Dementia Complex; Astrocytes; Brain; Cells, Cultured; Collagenases; Down-Regulation; Encephalitis; Enzyme Precursors; Extracellular Matrix; Humans; Interleukin-1; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinases; Neuroimmunomodulation; Signal Transduction; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta; Up-Regulation

An inflammatory response has been hypothesised to be involved in the pathogenesis of primary dementias, above all Alzheimer's disease (AD). This study was aimed at evaluating interleukin (IL)-12 and a panel of related cytokine levels in paired CSF and sera of demented patients. IL-12 (p70 heterodimer and total IL-12 p40 chain), interferon (IFN)-gamma, IL-10 and transforming growth factor (TGF)-beta1 levels were measured in 30 patients with probable Alzheimer's disease (PrAD), 57 patients with other dementing disorders, including probable vascular dementia (PrVD), Parkinson's disease (PD) and normal pressure hydrocephalus (NPH), and 25 cognitively normal control subjects. In the presence of unchanged concentrations of IL-12, IFN-gamma and IL-10, the mean CSF level of TGF-beta1 and the correspondent TGF-beta1 index, but not the serum level, were significantly increased in PrAD compared to controls and PrVD, whereas no difference was found vs. NPH and PD. Our results support the pathophysiological role of TGF-beta1 system in AD.

Topics: Aged; Alzheimer Disease; Biomarkers; Brain; Cerebrospinal Fluid; Dementia, Vascular; Disease Progression; Encephalitis; Female; Humans; Hydrocephalus, Normal Pressure; Interferon-gamma; Interleukin-10; Interleukin-12; Male; Middle Aged; Parkinson Disease; Predictive Value of Tests; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

Both transforming growth factor-beta1 (TGF-beta1) and nitric oxide synthase-2 (NOS-2) are upregulated under various neuropathological states. Evidence suggests that TGF-beta1 can either attenuate or augment NOS-2 expression, with the prevailing effect dependent on the experimental paradigm employed and the cell-type under study. The purpose of the present study was to determine the effect of TGF-beta1 on astrocytic NOS-2 expression. In purified astrocyte cultures, TGF-beta1 alone did not induce NOS-2 or NO production. However, NO production induced by lipopolysaccharide (LPS) plus IFNgamma was enhanced by TGF-beta1 in a concentration-dependent manner between 10 and 1,000 pg/mL. The presence of IFNgamma was not necessary for this effect to occur, as TGF-beta1 enhanced NO production induced by LPS in a similar fashion. In cultures stimulated with LPS plus IFNgamma, the enhancement of NO production by TGF-beta1 was associated with a corresponding increase in NOS-2 mRNA and protein expression. Interestingly, immunocytochemical assessment of NOS-2 protein expression demonstrated that TGF-beta1 augmented astrocytic NO production, specifically by increasing the pool of astrocytes capable of expressing NOS-2 induced by either LPS (approximately threefold) or LPS plus IFNgamma (approximately sevenfold). In a broader sense, our results suggest that TGF-beta1 recruits a latent population of astrocytes to respond to stimulation by pro-inflammatory mediators.

Topics: Animals; Animals, Newborn; Astrocytes; Brain; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Interactions; Encephalitis; Inflammation Mediators; Interferon-gamma; Lipopolysaccharides; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

Traumatic brain injury (TBI) initiates a cascade of cellular and molecular responses including both pro- and anti-inflammatory. Although post-traumatic hypothermia has been shown to improve outcome in various models of brain injury, the underlying mechanisms responsible for these effects have not been clarified. In this study, inflammation cDNA arrays and semi-quantitative RT-PCR were used to detect genes that are differentially regulated after TBI. In addition, the effect of post-traumatic hypothermia on the expression of selective genes was also studied. Rats (n = 6-8 per group) underwent moderate fluid-percussion (F-P) brain injury with and without hypothermic treatment (33 degrees C/3 h). RNA from 3-h or 24-h survival was analyzed for the expression of IL1-beta, IL2, IL6, TGF-beta2, growth-regulated oncogene (GRO), migration inhibitory factor (MIF), and MCP (a transcription factor). The interleukins IL-1beta, IL-2, and IL-6 and TGF-beta and GRO were strongly upregulated early and transiently from 2- to 30-fold over sham at 3 h, with normalization by 24 h. In contrast, the expressions of MIF and MCP were both reduced by TBI compared to sham. Post-traumatic hypothermia had no significant effect on the acute expression of the majority of genes investigated. However, the expression of TGF-beta2 at 24 h was significantly reduced by temperature manipulation. The mechanism by which post-traumatic hypothermia is protective may not involve a general genetic response of the inflammatory genes. However, specific genes, including TGF-beta2, may be altered and effect cell death mechanisms after TBI. Hypothermia differentially regulates certain genes and may target more delayed responses underlying the secondary damage following TBI.

Topics: Animals; Antigens, CD; Brain Injuries; Chemokine CXCL1; Chemokines, CXC; Cytokines; Disease Models, Animal; Down-Regulation; Encephalitis; Gene Expression Regulation; Hypothermia, Induced; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Interleukins; Macrophage Migration-Inhibitory Factors; Male; Membrane Cofactor Protein; Membrane Glycoproteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta2

Mycoplasma pneumoniae sometimes causes central nervous system manifestations, which may involve the host immune response, as the organism does not directly damage neural cells, or release toxins. Therefore we measured the levels of interleukin-6, interleukin-8, interleukin-18, interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta1 in serum and cerebrospinal fluid samples from patients who manifested central nervous system manifestations during acute M. pneumoniae infection. The subjects were nine patients with early-onset encephalitis (central nervous system disease onset within 7 days from the onset of fever), four with late-onset encephalitis (onset at 8 days or later), three with encephalitis but without fever, and three with aseptic meningitis. Intrathecal elevations of interleukin-6 and interleukin-8 in all four types of central nervous system manifestations, and of interleukin-18 in late-onset encephalitis were observed. None of the cerebrospinal fluid samples contained detectable levels of interferon-gamma, tumor necrosis factor-alpha, or transforming growth factor-beta1. In conclusion, interleukin-6, interleukin-8, and interleukin-18 might be involved in the inflammatory process leading to the central nervous system manifestations caused by M. pneumoniae.

Topics: Adolescent; Child; Child, Preschool; Cytokines; Encephalitis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interferon-gamma; Interleukin-18; Interleukin-6; Interleukin-8; Male; Meningitis, Aseptic; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Microglia rapidly respond to CNS injury, yet the mechanisms leading to their activation and inactivation remain poorly defined. In particular, few studies have established how interactions between inflammatory mediators affect the innate immune response of microglia. To begin to establish how microglia integrate signals from multiple inflammatory mediators, we examined the effects of interleukin 1beta (IL-1beta), interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), interferon gamma (IFN-gamma), and transforming growth factor beta1 (TGFbeta1) on both newborn and bulk-isolated adult microglia. To assess the functional state of the cells, we assayed the expression of cyclooxygenase 2 (Cox-2), interleukin 6, and tumor necrosis factor alpha, and two protein tyrosine kinases that have been implicated in microglial responses to activational stimuli, HCK and FAK. These studies demonstrated that IL-1beta, TNFalpha, IL-6, but not IFN-gamma increase the expression of Cox-2, whereas they all increase the expression of HCK and FAK. In these studies, TGFbeta1 either had no effect, or it decreased basal levels of these proteins. TGFbeta1 blocked activation by IL-1beta when given prior to, or simultaneously with, IL-1beta. TGFbeta1 blocked the induction of the tyrosine kinases, Cox-2, and the induction of IL-6 and TNFalpha mRNAs. However, TGFbeta1 was ineffective in antagonizing the induction of Cox-2 by either IL-6 or TNFalpha. We conclude that the TGFbeta receptor signaling cascades intersect with IL-1, but they may not interact with IL-6 or TNFalpha signaling pathways that lead to activation.

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Cells, Cultured; Chemotaxis; Cyclooxygenase 2; Drug Interactions; Encephalitis; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Inflammation Mediators; Interleukin-1; Interleukin-6; Isoenzymes; Male; Microglia; Prostaglandin-Endoperoxide Synthases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-hck; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Up-Regulation

When the brain suffers injury, microglia migrate to the damaged sites and become activated. These activated microglia are not detected several days later and the mechanisms underlying their disappearance are not well characterized. In this study, we demonstrate that interleukin (IL)-13, an anti-inflammatory cytokine, selectively induces cell death of activated microglia in vitro. Cell death was detected 4 days after the coaddition of IL-13 with any one of the microglial activators, lipopolysaccharide (LPS), ganglioside, or thrombin. This cell death occurred in a time-dependent manner. LPS, ganglioside, thrombin, or IL-13 alone did not induce cell death. Among anti-inflammatory cytokines, IL-4 mimicked the effect of IL-13, while TGF-beta did not. Cells treated with IL-13 plus LPS, or IL-13 plus ganglioside, showed the characteristics of apoptosis when analyzed by electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Electron micrographs also showed microglia engulfing neighboring dead cells. We propose that IL-13 and IL-4 induce death of activated microglia, and that this process is important for prevention of chronic inflammation that can cause tissue damage.

Topics: Animals; Animals, Newborn; Brain Injuries; Cell Death; Cell Size; Cells, Cultured; Encephalitis; Ethidium; Fluoresceins; Fluorescent Dyes; Gangliosides; Gliosis; In Situ Nick-End Labeling; Intercalating Agents; Interleukin-13; Interleukin-4; Lipopolysaccharides; Microglia; Microscopy, Electron; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

Apoptosis of autoaggressive T cells in the central nervous system (CNS) is an effective, nonphlogistic mechanism for the termination of autoimmune inflammation in experimental autoimmune encephalomyelitis (EAE). The clearance of apoptotic leukocytes by tissue-specific phagocytes is a critical event in the resolution of the inflammatory attack. To investigate the role of microglia in the removal of apoptotic cells and potential regulatory mechanisms of microglial phagocytosis, an in vitro phagocytosis assay was established, using Lewis rat microglia. Microglia exhibited a high capacity for the uptake of apoptotic autologous thymocytes, as well as apoptotic encephalitogenic myelin basic protein (MBP)-specific T cells, in contrast to nonapoptotic target cells. Pretreatment of microglia with interferon-gamma (IFN-gamma) raised the proportion of microglia capable of phagocytosing apoptotic cells to 75% above the untreated controls. The increased phagocytic activity was selective for apoptotic target cells and was not dependent on phosphatidylserine-mediated recognition mechanisms. In contrast, preincubation of microglia with interleukin-4 (IL-4) inhibited the uptake of apoptotic cells, whereas tumor-necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) did not alter phagocytosis. Phagocytic clearance of apoptotic inflammatory cells by microglia may be an important mechanism for the termination of autoimmune inflammation in the CNS. Augmentation of microglial phagocytosis by the Th-1-type cytokine IFN-gamma suggests a feedback mechanism for the accelerated clearance of the inflammatory infiltrate in the CNS.

Topics: Animals; Animals, Newborn; Apoptosis; Cells, Cultured; Cytokines; Encephalitis; Interferon-gamma; Interleukin-4; Microglia; Myelin Basic Protein; Phagocytosis; Phosphatidylserines; Rats; Rats, Inbred Lew; T-Lymphocytes; Thymus Gland; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Subarachnoid hemorrhage (SAH) elicits an inflammatory response in the subarachnoid space, which is mediated by the release of various cytokines. To assess their involvement in post-hemorrhagic complications, we determined the source and time-course of the release of inflammatory cytokines and acute-phase proteins in cerebrospinal fluid (CSF) following SAH. Concentrations of interleukin (IL)- 1beta, IL-6, transforming growth factor-beta1 (TGF-beta1) and C-reactive protein (CRP) in CSF of 36 patients with SAH were measured by enzyme-linked immunoabsorbent assay (ELISA). Floating cells collected from the CSF were centrifuged four to six days after SAH, and examined immunohistochemically. Intracellular IL-1beta and IL-6 were examined by flow cytometric analysis. The molecular weight of TGF-beta1 in CSF of 30 patients was examined by Western blot analysis. The TGF-beta1 levels of patients who had undergone ventriculoperitoneal (VP) shunt (n = 19) was significantly higher than nonshunt group (n = 16). The CRP levels of VP shunt group was significantly higher than nonshunt group. IL-6 concentration was maximal within day 0-1 and it was secreted by neutrophils and monocytes. ELISA showed consistently low levels of IL-1beta, whereas a proportion of monocytes and lymphcytes were IL- 1beta-positive by flow cytometric analysis. TGF-beta1 levels were also maximal on day 0-1 according to ELISA, although it tended to be in the inactive form derived from platelets. A 25 kDa band of TGF-1 was detectable for at least 13 days after SAH, which may have been secreted in part by neutrophils and monocytes. CRP levels in CSF peaked on day 2-3. The present results suggest that leukocytes induced by SAH play an important role in post-hemorrhagic inflammation in the subarachnoid space by releasing IL-6 and TGF-beta1. The CRP and TGF-beta1 levels in CSF are strongly concerned with communicating hydrocephalus after SAH.

Topics: Adult; Aged; Aged, 80 and over; Blotting, Western; C-Reactive Protein; Cerebrospinal Fluid; Chemotaxis, Leukocyte; Cytokines; Encephalitis; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Immunohistochemistry; Interleukin-1; Interleukin-6; Leukocytes; Male; Middle Aged; Monocytes; Neutrophils; Subarachnoid Hemorrhage; Transforming Growth Factor beta

Transforming growth factor-beta1 is a multifunctional peptide with increased expression during Alzheimer's disease and other neurodegenerative conditions which involve inflammatory mechanisms. We examined the autoregulation of transforming growth factor-beta1 and transforming growth factor-beta receptors and the effects of transforming growth factor-beta1 on complement C1q in brains of adult Fischer 344 male rats and in primary glial cultures. Perforant path transection by entorhinal cortex lesioning was used as a model for the hippocampal deafferentation of Alzheimer's disease. In the hippocampus ipsilateral to the lesion, transforming growth factor-beta1 peptide was increased >100-fold; the messenger RNAs encoding transforming growth factor-beta1, transforming growth factor-beta type I and type II receptors were also increased, but to a smaller degree. In this acute lesion paradigm, microglia are the main cell type containing transforming growth factor-beta1, transforming growth factor-beta type I and II receptor messenger RNAs, shown by immunocytochemistry in combination with in situ hybridization. Autoregulation of the transforming growth factor-beta1 system was examined by intraventricular infusion of transforming growth factor-beta1 peptide, which increased hippocampal transforming growth factor-beta1 messenger RNA levels in a dose-dependent fashion. Similarly, transforming growth factor-beta1 increased levels of transforming growth factor-beta1 messenger RNA and transforming growth factor-beta type II receptor messenger RNA (IC(50), 5pM) and increased release of transforming growth factor-beta1 peptide from primary microglia cultures. Interactions of transforming growth factor-beta1 with complement system gene expression are also indicated, because transforming growth factor-beta1 decreased C1qB messenger RNA in the cortex and hippocampus, after intraventricular infusion, and in cultured glia. These indications of autocrine regulation of transforming growth factor-beta1 in the rodent brain support a major role of microglia in neural activities of transforming growth factor-beta1 and give a new link between transforming growth factor-beta1 and the complement system. The auto-induction of the transforming growth factor-beta1 system has implications for transgenic mice that overexpress transforming growth factor-beta1 in brain cells and for its potential role in amyloidogenesis.

Topics: Alzheimer Disease; Animals; Brain; Cerebral Cortex; Complement C1q; Denervation; Disease Models, Animal; Encephalitis; Hippocampus; Homeostasis; Male; Microglia; Perforant Pathway; Rats; Rats, Inbred F344; Receptors, Transforming Growth Factor beta; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

An inflammatory reaction, essential for defence against infection and for wound repair, may also induce irreversible tissue damage. It appears that the central nervous system has developed its own immunosuppressive strategy in order to limit the destructive effects of inflammation. To clarify this point, we have characterized in one unique model of inflammation induced in the rat by intracerebral lipopolysaccharide injection the kinetics of the inflammatory reaction, the participation of immunitary and glial cells and of three growth factors. Among these molecules, brain-derived neurotrophic factor mRNA expression was found decreased following LPS injection. No striking differences were observed in the brain parenchyma after stab lesion or inflammatory lesion apart from an increase in the number of monocytes/macrophages recruited early to the lesion area. Macrophages were later accumulated around the lesion when astroglia and microglia reactions occurred. Some of the macrophages and microglia expressed major histocompatibility complex class II antigens on their surface whereas no T or B lymphocytes were observed in the brain parenchyma. However, a subpopulation of CD3- and CD4-negative CD8-positive cells, likely natural killer cells, was observed around the lesion site; this recruitment was inhibited by the highest dose of LPS. This study therefore supports the hypothesis of a suppression of some aspects of cell-mediated immunity in the brain, mechanisms which need to be further characterized.

Topics: Animals; Antigens, CD; Blotting, Northern; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Encephalitis; Female; Glial Fibrillary Acidic Protein; Histocompatibility Antigens Class II; Immunohistochemistry; Injections; Lipopolysaccharides; Nerve Growth Factors; Nerve Tissue Proteins; Rats; Rats, Inbred Lew; Transforming Growth Factor beta; Wounds, Stab

Borna disease is a virus-induced, immune-mediated encephalomyelitis based on a delayed-type hypersensitivity reaction. The severity of clinical symptoms after intracerebral infection of rats with Borna disease virus was reduced after treatment with transforming growth factor (TGF-beta 2). Intraperitoneal injection of the recombinant molecule, rTGF-beta 2, started on the day of infection at a dose of either 1 micrograms given every day or every other day for 8 consecutive days or 2 micrograms every third day, was found to result in the absence of typical Borna disease symptoms at 14 days after infection in most of the TGF-beta-treated rats, a time point at which all infected control animals not treated with rTGF-beta 2 showed distinct signs of Borna disease. The inhibition of the disease was paralleled by a significant reduction of the inflammatory reaction in the brain. However, the efficacy of treatment with rTGF-beta 2 was transient, because after day 21 only a slight or no reduction of the inflammatory reaction and, consequently, symptoms of Borna disease could be observed. Immunohistologic investigations revealed reduced CD4+ T cell numbers and no changes in macrophage counts in encephalitic lesions of rTG-beta treated rats. However, CD8+ cells were markedly decreased in the encephalitic lesions. Furthermore, the expression of MHC class II Ag was significantly reduced in the brain of rTGF-beta 2 treated Borna disease virus-infected rats, whereas MHC class I Ag expression was not. Most treated animals showed a reduction of Borna disease virus-specific serum antibodies, the result of an inhibition of the IgG response. The results presented here suggest a distinct influence of rTGF-beta 2 on T cell-mediated immune functions during the early phase of Borna disease virus-induced encephalomyelitis.

Topics: Animals; Antigens, Viral; Borna Disease; Borna disease virus; Brain; CD8 Antigens; Encephalitis; Hippocampus; Hypersensitivity, Delayed; Immunity, Cellular; Rats; Rats, Inbred Lew; T-Lymphocyte Subsets; Transforming Growth Factor beta