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PubMed1999

Class II transactivator and class II MHC gene expression in microglia: modulation by the cytokines TGF-beta, IL-4, IL-13 and IL-10.

Microglia are the resident macrophages of the brain, and when activated, have functions including cytokine production, phagocytosis and antigen presentation. The class II MHC genes encode proteins that present antigenic peptides to helper T cells, leading to T cell activation and the development of an antigen-specific immune response. Class II MHC gene expression is strictly regulated by the class II transactivator (CIITA) transcription factor. In this study, we investigated the effects of various immunomodulatory cytokines on IFN-gamma induction of class II MHC and CIITA gene expression in microglia, both primary microglia and a murine microglial cell line, EOC 20. By flow cytometry analysis we show that IFN-gamma-induced surface expression of class II MHC molecules on EOC 20 cells can be inhibited by the cytokines TGF-beta1, IL-4 and IL-10, but not IL-13. Using a ribonuclease protection assay, we have found that TGF-beta1, IL-4 and IL-10 act by inhibiting the expression of IFN-gamma-induced CIITA mRNA and, in turn, class II MHC mRNA. TGF-beta1, IL-4, and IL-10 inhibition of IFN-gamma-induced CIITA mRNA accumulation was not due to destabilization of CIITA mRNA, suggesting an effect at the level of transcription. In primary murine microglia, IL-10 and TGF-beta1 inhibited IFN-gamma-induced CIITA and class II MHC expression. However, a discordant effect of IL-4 was noted in that IL-4 enhanced IFN-gamma-induced CIITA and class II MHC expression in primary microglia. Although some differences are observed between EOC 20 cells and primary microglia in terms of responsiveness to TGF-beta, IL-4 and IL-10, CIITA and class II MHC gene expression are coordinately modulated.

Animals↗

PubMed1999

Microglia induce myelin basic protein-specific T cell anergy or T cell activation, according to their state of activation.

Microglial cells are non-professional antigen-presenting cells (APC) the function of which is still controversial. Here, we studied the function of microglia derived from H-2(u) mice. We show that these microglia express a low level of B7.2 and CD40 and, interestingly, lack surface expression of B7.1. Resting and IFN-gamma-activated microglia were unable to activate naive and primed myelin basic protein (MBP)-specific CD4(+) T cells in the presence of MBP and encephalomyelitic MBP Ac1-11 peptide. Furthermore, in the presence of Ac1-11 peptide, CD4(+) TCR-transgenic T cells became anergized. Microglia became professional APC only after a multistep activation process involving both stimulation through cytokines [granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-gamma] and cognate signaling (B7-CD28 and CD40-CD40 ligand interactions). As such they were able to present MBP to both unprimed and primed T cells. Co-culture of microglia with GM-CSF up-regulated co-stimulatory molecules, in particular B7.1. Additional activation with IFN-gamma induced MHC class II and CD40 up-regulation. CD40-CD40 ligand interaction significantly enhanced microglial ability to prime TCR-transgenic T cells and was essential for presentation of MBP to in vivo primed non-transgenic T cells. We propose that microglia may serve different functions under different inflammatory conditions, depending on the cytokine milieu and the type of cognate interaction they are involved in.

Animals↗

PubMed2000

Ceramide-enhanced urokinase-type plasminogen activator (uPA) release is mediated by protein kinase C in cultured microglia.

As described previously, a relatively high dose of neurotrophins increased the release of urokinase-type plasminogen activator (uPA) from cultured microglia. This biological response is suggested to be caused by ceramide, which is a metabolite of nerve growth factor low-affinity receptor (NGFRp75)-associated sphingomyelin turnover. Therefore, in the present study, we examined the effect of ceramide on the release of uPA from cultured microglia. Treatment of the cells with permeable C8-ceramide (D-erythro-Sphingosine, N-octanoyl-) enhanced uPA release in a dose-dependent manner. This effect of C8-ceramide was mimicked by treatment with bacterial sphingomyelinase. A pharmacological study using a specific PKC activator, phorbol-12-myristate-13-acetate, and a protein kinase C (PKC) inhibitor, bisindolylmaleimide, showed that PKC activation is required in order to release uPA from ceramide-stimulated microglia as well as from nonstimulated microglia. Further study using a specific conventional PKC (cPKC) activator, 1-oleoyl-2-acetyl-sn-glycerol (OAG), and a specific cPKC inhibitor, Gö 6976, suggested that PKC-delta and/or -epsilon is involved in uPA release. As opposed to the apoptotic pathway, however, no activation of c-Jun N-terminal kinase and nuclear factor kappa B was observed in C8-ceramide-stimulated microglia. The findings suggest that uPA release from microglia is regulated by a mechanism in which PKC-delta and/or -epsilon are activated and further signals are transduced subsequently.

Animals↗

PubMed2002

Microglia activation and cell death in response to diethyl-dithiocarbamate acute administration.

An increasing body of evidence suggests a role for activated microglia in the pathogenesis of neurodegenerative disorders. Hence, it would be useful to have a better understanding of the significance of microglial activation for neuronal damage. Unfortunately, most models of microglial activation use invasive or long-lasting insults, which make it difficult to evaluate the role played by microglia. We have instead developed a model for microglial activation by using brief exposure to the widely available neurotoxin diethyl-dithiocarbamate (DDTC). Despite evidence for the neurotoxic nature of this substance, microglia involvement has not been hitherto investigated. After acute i.p. administration of DDTC at two different doses, microglia were already activated in selected areas of the rat brain (hippocampal dentate gyrus, entorhinal-pyriform cortex and hypothalamus) after 1 hour, reaching a peak at 3-6 hours and subsided within 6-48 hours, depending on the brain region. Microglia activation was associated with interleukin-1 beta immunopositivity between 3 and 6 hours and with up-regulation of major histocompatibility complex class II expression between 24 and 48 hours. No significant changes in astrocyte immunostaining were detected between 6 hours and 6 days. The TUNEL procedure revealed the death of a limited number of cells in the above-mentioned structures that peaked at 6h and then declined rapidly. Cell death was detected in sites with major, minor, or no microglial activation, indicating that these two events can occur concomitantly or independently. The study shows that the administration of DDTC provides a useful model for studying the implications of region-specific reactivity of microglia and its differential interaction with neuronal damage.

Adjuvants, Immunologic↗

PubMed2003

Dynamics of microglia in the developing rat brain.

Entrance of mesodermal precursors into the developing CNS is the most well-accepted origin of microglia. However, the contribution of proliferation and death of recruited microglial precursors to the final microglial cell population remains to be elucidated. To investigate microglial proliferation and apoptosis during development, we combined proliferating cell nuclear antigen (PCNA) immunohistochemistry, in situ detection of nuclear DNA fragmentation (TUNEL), and caspase-3 immunohistochemistry with tomato lectin histochemistry, a selective microglial marker. The study was carried out in Wistar rats from embryonic day (E) 16 to postnatal day (P) 18 in cerebral cortex, subcortical white matter, and hippocampus. Proliferating microglial cells were found at all ages in the three brain regions and represented a significant fraction of the total microglial cell population. The percentage of microglia expressing PCNA progressively increased from the embryonic period (25-51% at E16) to a maximum at P9, when the great majority of microglia expressed PCNA (92-99%) in all the brain regions analyzed. In spite of the remarkable proliferation and expansion of the microglial population with time, the density of microglia remained quite constant in most brain regions because of the considerable growth of the brain during late prenatal and early postnatal periods. In contrast, apoptosis of microglia was detected only at certain times and was restricted to some ameboid cells in white matter and primitive ramified cells in gray matter, representing a small fraction of the microglial population. Therefore, our results point to proliferation of microglial precursors in the developing brain as a physiological mechanism contributing to the acquisition of the adult microglial cell population. In contrast, microglial apoptosis occurs only locally at certain developmental stages and thus seems less crucial for the establishment of the final density of microglia.

Animals↗

PubMed2002

Expression of functional NK-1 receptors in murine microglia.

Cells of myeloid origin such as microglia have the potential to contribute significantly to the development of inflammatory responses in the CNS. The ability of the neuropeptide substance P to augment proinflammatory responses by other myeloid cell types such as macrophages and dendritic cells is well recognized. In the present study, we demonstrate the presence of mRNA encoding NK-1 (substance P) receptors in murine microglia cell lines. Importantly, we have utilized specific antibodies developed by our laboratory to detect the expression of the NK-1 receptor protein in murine microglia cell lines by Western blot analysis and flow cytometry. Furthermore, we have investigated the presence of this receptor on primary murine microglia and report the presence of authentic NK-1 receptors as determined by Western blot analysis and flow cytometry. In addition, we demonstrate that NK-1 receptors expressed on microglia are functional as demonstrated by the ability of nanomolar concentrations of substance P to initiate activation of the transcriptional activator, NF-kappaB. Given the weight of evidence supporting the role of substance P--substance P receptor interactions in the initiation of optimal proinflammatory responses by myeloid cells, the demonstration of authentic and functional NK-1 receptors in microglia identifies this neuropeptide as a potentially important contributor to CNS inflammatory responses during disease states.

Animals↗

PubMed2002

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit chemokine production in activated microglia.

Microglia react to even minor disturbances in CNS homeostasis and function as critical regulators of CNS inflammation. Activated microglia secrete inflammatory mediators such as cytokines and chemokines, which contribute to the pathophysiological changes associated with several neuroimmunologic disorders. Microglia-derived inflammatory chemokines recruit various populations of immune cells, which initiate and maintain the inflammatory response against foreign antigens. Entry and retention of activated immune cells in the CNS is a common denominator in a variety of traumatic, ischemic, and degenerative diseases. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two structurally related neuropeptides that function as potent anti-inflammatory factors in the periphery. Here we investigated the effects of VIP and PACAP on chemokine production by activated microglia. VIP and PACAP inhibit the expression of the microglia-derived CXC chemokines MIP-2 and KC, and of the CC chemokines MIP-1alpha, -1beta, MCP-1, and RANTES. The inhibition of chemokine gene expression correlates with an inhibitory effect of VIP/PACAP on NFkB binding. The VIP/PACAP inhibition of both chemokine production and of NFkB binding is mediated through the specific receptor VPAC1 and involves a cAMP-dependent intracellular pathway. Of biological significance is the fact that the inhibition of chemokine production by VIP/PACAP leads to a significant reduction in the chemotactic activity generated by activated microglia for peripheral leukocytes, i.e., neutrophils, macrophages, and lymphocytes. Because reduction in the number and activation of infiltrating leukocytes represents an important factor in the control of inflammation in the CNS, VIP and/or PACAP released by neurons during an inflammatory response could serve as neuronal survival factors by limiting the inflammatory process.

Animals↗

PubMed2003

Microglia activation influences dye coupling and Cx43 expression of the astrocytic network.

Under inflammatory conditions, activated microglia are capable of producing proinflammatory cytokines that are reported to influence cell-to-cell communication. The present study was performed to evaluate the influence of microglial activation on the coupling efficiency of the astroglial network. Primary astrocyte cultures of newborn rats were cocultured with either 5% (M5) or 30% (M30) microglia. Microglial activation (rounded phagocytotic phenotype) was investigated using the monoclonal anti-ED1 antibody, and immunofluorescence with a polyclonal anti-Cx43 antibody was used to study astroglial Cx43 expression and distribution. Functional coupling of astrocytes was evaluated by monitoring the transfer of microinjected Lucifer yellow into neighboring cells. The data obtained can be summarized as follows: astroglia/M30 cocultures contained significantly fewer resting microglia and significantly more activated microglia than the M5 cocultures; significantly reduced astroglial Cx43 staining was found in M30 cocultures concurrently with a reduced number of dye coupled astrocytes; and the positive correlation of percent activated microglia with reduced astroglial Cx43 expression was highly significant, indicating that the degree of intercellular communication in the astroglial network may be modulated by the activation of microglia under in vitro conditions.

Animals↗

PubMed2002

Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system.

Scavenger receptor class A (SR-A, CD204), scavenger receptor-BI (SR-BI), and CD36 are cell surface proteins that mediate cell adhesion to, and endocytosis of, various native and pathologically modified substances, and participate in intracellular signaling, lipid metabolism, and host defense against bacterial pathogens. Microglia, Mato cells, astrocytes, cerebral microvascular endothelial cells, cerebral arterial smooth muscle cells, and retinal pigment epithelial cells express one or more of these SR. Expression of SR-A and SR-BI by microglia is developmentally regulated. Neonatal microglia express SR-A and SR-BI, while microglia in normal mouse and human adult brain express neither. Astrocytes in adult brain express SR-BI. In Alzheimer's disease, microglial expression of SR-A is increased. Such findings, and evidence that SR-A and SR-BI mediate adhesion and endocytosis of fibrillar beta-amyloid by microglia and astrocytes, respectively, and that SR-A, SR-BI, and CD36 participate in secretion of reactive oxygen species by microglia, suggest roles for these receptors in homeostasis and neuropathology.

Animals↗

PubMed2003

Hematopoietic prostaglandin D synthase is expressed in microglia in the developing postnatal mouse brain.

Hematopoietic prostaglandin D synthase (HPGDS) is a PGD(2)-synthesizing enzyme and is expressed in antigen-presenting cells, mast cells, and other immunocompetent cells. We here report the HPGDS expression in microglia and the migration pathway of microglia in the developing mouse brain as detected by HPGDS immunohistochemistry. Expression of HPGDS mRNA peaked at postnatal day (PND) 10, decreased gradually thereafter, and reached a plateau at PND 20. The mRNAs for target molecules of PGD(2), i.e., DP receptor (DPR) and CRTH2 receptor, showed developmental profiles overlapped to that of HPGDS. Most of the HPGDS(+) cells at PND 10 had morphological characteristics of ameboid microglia and gave positive immunostaining with microglia-specific markers such as RCA-1, F4/80, or ER-MP12. These specific markers became less detectable later on, but HPGDS was still expressed even in resting microglia. Thus, HPGDS is a useful marker for investigation of microglial development. Spaciotemporal evaluation of microglial development and migration with HPGDS immunostaining revealed the following three major possible migration pathways of microglia in the postnatal brain: from the lateral ventricle via subventricular zones to brain parenchyma; from the leptomeninges around the cerebellopontine angle to the cerebellar white matter; and from the overlying leptomeninges to the hippocampus, basal forebrain, and brainstem.

Aging↗

PubMed2005

Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways.

This study evaluated the role of thrombin-activated microglia in the neurodegeneration of mesencephalic cultures. Immunocytochemical and biochemical evidence indicated that in co-cultures consisting of rat cortical microglia and mesencephalic neurons, thrombin led to nonselective loss of mesencephalic neurons. Accompanying neurodegeneration, microglial activation was obvious, evidenced by expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and by increasing production of TNF-alpha and nitric oxide (NO). In mesencephalic neurons treated with conditioned media (CM) taken from thrombin-activated microglia, the number of dopaminergic neurons was significantly attenuated. The neurotoxicity of the CM was diminished when it was derived from microglia co-treated with thrombin and either an extracellular signal-regulated kinase 1/2 (ERK1/2) pathway inhibitor (PD98059) or a p38-mitogen-activated protein kinase (p38-MAPK) inhibitor (SB203580). Moreover, jun N-terminal kinase (JNK) and p38-MAPK were activated in mesencephalic neurons treated with CM of thrombin-activated microglia. Inhibition of JNK and p38-MAPK rescued the dopaminergic neurons. Collectively, these results indicate that thrombin-activated microglia induce neurodegeneration in cultured mesencephalic neurons and that the MAPKs actively participate in both microglial activation and neurodegeneration. The present data carefully suggest that microglial activation triggered by thrombin may be involved in the neuropathological processes of dopaminergic neuronal cell death that occur in Parkinson's disease.

Animals↗

PubMed2006

Lipopolysaccharide-activated SHP-1-deficient motheaten microglia release increased nitric oxide, TNF-alpha, and IL-1beta.

Accumulating evidence suggests a deleterious role for activated microglia in facilitating neuronal death by producing neurocytotoxic substances during injury, infection, or neurodegenerative diseases. After cochlear ablation, abnormal microglial activation accompanied by increased neuronal loss within the auditory brainstem occurs in motheaten (me/me) mice deficient in the protein tyrosine phosphatase SHP-1. To determine whether abnormally activated microglia contribute to neuronal death in me/me mice, primary microglial cultures from me/me and wild-type mouse cortices were stimulated by the bacterial endotoxin lipopolysaccharide (LPS) to evaluate the secretion of the neurotoxic mediators nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). Me/me microglia release significantly greater amounts of all three mediators compared with wild-type microglia. However, the increased release of these compounds in microglia lacking SHP-1 does not appear to occur through activation of extracellular signal-regulated kinase (ERK), p38 kinase subgroups of mitogen-activated protein (MAP) kinases, or increases in NF-kappaB-inducing kinase (NIK). These results suggest that abnormal microglial activation and release of neurotoxic compounds may potentiate neuronal death in deafferented cells and can thus potentiate neurodegeneration in the me/me brainstem. Our data also indicate that SHP-1 is engaged in signaling pathways in LPS-activated microglia, but not through regulation of the ERK and p38 MAP kinases.

Animals↗

PubMed2006

Differential activation of microglia in neurogenic versus non-neurogenic regions of the forebrain.

Proliferation decreases in the neurogenic subventricular zone (SVZ) of mice after aspiration lesions of the cerebral cortex. We hypothesized that microglial activation may contribute to this given microglial activation attenuates neurogenesis in the hippocampus. Using CD45, CD11b, IB4, and IL-6 immunohistochemistry (IHC), BrdU IHC, and fluorescent bead tracking of peripheral monocytes into the brain, we compared microglial activation in the SVZ to non-neurogenic forebrain regions. SVZ microglia exhibited greater constitutive activation and proliferation than did microglia in non-neurogenic regions. In contrast to the SVZ, the dentate gyrus (DG) contained relatively few CD45(+) cells. After aspiration cerebral cortex lesions, microglia became activated in the cerebral cortex, corpus callosum, and striatum. SVZ microglial activation did not increase, and similarly, microglia in the DG were less activated after injury than in adjacent non-neurogenic regions. We next showed that SVZ microglia are not categorically refractory to activation, since deep cortical contusion injuries increased SVZ microglial activation. Macrophages migrate into the brain during development, but it is unclear if this is recapitulated after injury. Infiltration of microbead-labeled macrophages into the brain did not change after injury, but resident SVZ microglia were induced to migrate toward the injury. Our data show that both constitutive and postlesion levels of microglial activation differ between neurogenic and non-neurogenic regions.

Animals↗

PubMed1993

Early and rapid de novo synthesis of Alzheimer beta A4-amyloid precursor protein (APP) in activated microglia.

Upon acute activation, microglia, the immuneffector cells of the brain parenchyma, express the amyloid precursor protein (APP) that is otherwise prominent in pathological structures related to Alzheimer's disease. In this disease complex amyloid-bearing neuritic plaques contain beta A4-amyloid protein, the APP, and numerous inflammatory proteins. The accompanying activation of microglia has mostly been viewed as a secondary reaction to amyloid deposits. Activation of microglia was performed in a graded fashion. Transection of peripheral nerves such as the facial or sciatic nerve causes a microglial reaction within hours in the nucleus of origin or in projection areas of the CNS. A predominantly glial up-regulation of APP mRNA and protein could be detected as early as 6 h post lesion not only at the site of affected neuronal cell bodies but also in corresponding projection areas. Its time course suggests rapid transneuronal signalling to glial cells in the projection area. Light and electron microscopy demonstrate that microglia, which are cells of mononuclear phagocyte lineage and comprise up to 20% of all glial cells, are the dominant source for non-neuronal APP expression. Ultrastructurally, brain perivascular cells within the basal lamina constitutively express APP and thus are a possible source of vascular amyloid. Additionally, microglia express leukocyte-derived (L)-APP mRNA and protein that have recently been described in mononuclear cells of the immune system. Increased L-APP expression may serve as a potential marker for glial/microglial activation. Such immune-mediated amyloidogenesis initiated by microglia might have implications for the treatment of neurodegenerative diseases.

Amyloid beta-Protein Precursor↗

PubMed1995

Phagocytic microglia during delayed neuronal loss in the facial nucleus of the rat: time course of the neuronofugal migration of brain macrophages.

The injection of Fluoro-Gold (FG) into the whisker pad of rats yields a stable fluorescent labeling of the motoneurons in the lateral facial subnucleus. Following resection of 8-10 mm of the facial nerve, the microglia phagocytose the FG-preloaded neurons and assume the label. Employing this vital labeling of microglia in situ we studied the fate of same after completion of phagocytic activity. Starting at 56 days post resection (DPR) the FG-labeled microglia spread out from the lateral facial subdivision and invaded the entire facial nucleus. The quantitative analysis of this redistribution of the fluorescent marker revealed a prolonged increase in the number of labeled microglia strictly proportional to the delayed loss of neurons. The differentiation between microglia and shrunken neurons was performed with the new method of immunoquenching: the staining of vibratome sections with anti-rat neuron-specific enolase (NSE) combined with an ABC-HRP kit and DAB as detector totally extinguished (quenched) all fluorescence from the pre-labeled facial motoneurons. The fluorescent microglia were additionally stained with GSA I-B4 and OX-42, which should completely quench all fluorescence in the section. However, a few small round cells, always closely opposed to neuronal perikarya, still fluoresced. These NSE-negative, GSA I-B4 and OX-42 negative, but fluorescent cells may represent a new, immunologically uncharacterized microglial cell type, that participates in neuronophagia.

Animals↗

PubMed1995

Resident microglia and hematogenous macrophages as phagocytes in adoptively transferred experimental autoimmune encephalomyelitis: an investigation using rat radiation bone marrow chimeras.

Hematogenous macrophages are known to be involved in the induction of tissue damage in the central nervous system (CNS) as well as of clinical symptoms in experimental autoimmune encephalomyelitis (EAE). Although resident microglia can become phagocytic under certain circumstances, little is known about the role of these cells in brain inflammation in vivo. We thus studied EAE in the model of radiation bone marrow chimeras that allows us to distinguish donor-derived hematogenous cells from resident effector cells. Inflammation in the CNS was qualitatively and quantitatively similar in chimeras compared to fully histocompatible Lewis rats. Although activated resident microglial cells were outnumbered four- to sevenfold in EAE lesions by hematogenous macrophages, the number of resident microglia with ingested myelin was equal to that of macrophages containing myelin debris. Phagocytic resident microglia, expressing the macrophage activation marker ED1, showed ramified as well as amoeboid morphology. From our studies the following conclusions can be drawn. First, a considerable proportion of resident microglia upregulated ED1. Second, resident microglia provide a small but substantial source of brain macrophages in EAE as compared to the large influx of macrophages. Third, our results suggest that microglia, due to their strategic position within the CNS, are more effective in removal of myelin debris compared to hematogenous macrophages.

Animals↗

PubMed2001

Role of microglia in glioma biology.

Microglia, a type of differentiated tissue macrophage, are considered to be the most plastic cell population of the central nervous system (CNS). In response to pathological conditions, resting microglia undergo a stereotypic activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation. Considering their immune effector function, it is not surprising to see microglia accumulation in almost every CNS disease process, including malignant brain tumors or malignant gliomas. Although the function of these cells in CNS inflammatory processes is being studied, their role in malignant glioma biology remains unclear. On one hand, microglia may represent a CNS anti-tumor response, which is inactivated by local secretion of immunosuppressive factors by glioma cells. On the other hand, taking into account that microglia are capable of secreting a variety of immunomodulatory cytokines, it is possible that they are attracted by gliomas to promote tumor growth. A better understanding of microglia-glioma interaction will be helpful in designing novel immune-based therapies against these fatal tumors.

Animals↗

PubMed2002

Existence of functional beta1- and beta2-adrenergic receptors on microglia.

We examined the expression and function of beta-adrenergic receptor (beta-AR) subtypes in both isolated primary rat microglia and a rat microglial cell line. RT-PCR analyses revealed that microglia expressed beta(1)- and beta(2)-ARs but not beta(3)-ARs, whereas rat primary peritoneal macrophages expressed only beta(2)-ARs. Stimulation of beta-ARs on microglia by norepinephrine (NE) resulted in an increase in the level of intracellular cAMP and the subsequent expression of interleukin-1beta mRNA. These effects were prevented by propranolol. Similar results were obtained with other selective beta(1)-AR agonists and antagonists. beta(2)-ARs on microglia were also functional. It is possible that noradrenergic innervations participate in the control of microglial functions via beta(1)-ARs on microglia in the brain, because NE has high affinity for beta(1)- and beta(3)-ARs but little or no affinity for beta(2)-ARs. It seems physiologically significant that microglia can be controlled by NE, which predominates over epinephrine in the brain, whereas macrophages in peripheral tissues can be controlled by epinephrine, which is at higher levels in peripheral tissues.

Adrenergic beta-1 Receptor Agonists↗