transforming-growth-factor-beta and AIDS-Dementia-Complex

Cytokines are widely considered to function as major mediators of neuropathogenesis of HIV-1 infection. This view is based on a large amount of data obtained in vitro, in animal models and in human brain tissue obtained postmortem. Evidence for the involvement of interleukin-1 and transforming growth factor-beta 1, summarized here, indicates that these cytokines likely control HIV-1 expression in the brain and astrocytosis, the two hallmarks of brain in AIDS patients. Although the data do not reveal the precise time course of molecular and cellular changes in vivo, they strongly suggest a complex pattern of interactions whose ordering in time determines when and where HIV-1 is expressed in the brain. Further kinetic data are therefore urgently needed to shed light on the heterogeneity of HIV-1 expression in the brain.

Topics: AIDS Dementia Complex; Animals; Astrocytes; HIV Infections; HIV-1; Humans; Interleukin-1; Nervous System Diseases; Rats; Transforming Growth Factor beta; Virus Replication

The Transforming Growth Factor-betas (TGF-beta) are a group of multifunctional proteins whose cellular sites of production and action are widely distributed throughout the body, including the central nervous system (CNS). Within the CNS, various isoforms of TGF-beta are produced by both glial and neural cells. When evaluated in either cell culture or in vivo models, the various isoforms of TGF-beta have been shown to have potent effects on the proliferation, function, or survival of both neurons and all three glial cell types, astrocytes, microglia and oligodendrocytes. TGF-beta has also been shown to play a role in several forms of acute CNS pathology including ischemia, excitotoxicity and several forms of neurodegenerative diseases including multiple sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease.

Topics: AIDS Dementia Complex; Alzheimer Disease; Animals; Astrocytes; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Gene Expression; Humans; Ischemia; Microglia; Multiple Sclerosis; Neurodegenerative Diseases; Oligodendroglia; Parkinson Disease; Transforming Growth Factor beta

Topics: AIDS Dementia Complex; HIV; Humans; Meningitis, Viral; Transforming Growth Factor beta; Virus Replication

This chapter has summarized studies showing that cells of the immune system and glial cells of the CNS use many of the same cytokines as communication signals. Activated astrocytes and microglia are the principal sources of these cytokines in the CNS, although oligodendrocytes are capable of expressing IL-1 and TGF-beta. There is a complex circuitry of interactions mediated by cytokines, especially in the event of blood-brain barrier damage and lymphoid/mononuclear cell infiltration into the CNS. Infiltrating activated macrophages produce cytokines such as IL-1, TNF-alpha, and IL-6, which would trigger glial cells to produce their own cytokines. The activation of astrocytes and microglia to secrete proinflammatory cytokines such as IL-1, TNF-alpha, IL-6, and GM-CsF may contribute to the propagation of intracerebral immune and inflammatory responses initiated by immune cells, as well as enhancement of HIV-1 expression in the CNS. The cytokine cascades ongoing in the CNS could ultimately be suppressed due to the presence of immunosuppressive cytokines such as TGF-beta. Whether immune and inflammatory responses within the CNS are propagated or suppressed depends on a number of parameters, including (a) the activational status of these cells, (b) cytokine receptor levels on glial and immune cells, (c) the presence of cytokines with both immune-enhancing and immune-suppressing effects (IFN-gamma, IL-1, TNF-alpha, IL-6, TGF-beta, CsFs), (d) the concentration and location of these cytokines in the CNS, and (e) the temporal sequence in which a particular cell is exposed to numerous cytokines (see Fig. 1). The ultimate outcome of immunologic and inflammatory events in the CNS, as well as HIV expression, will be determined, in part, by an interplay of the above parameters.

Topics: AIDS Dementia Complex; Brain; Cytokines; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-1; Interleukin-6; Neuroglia; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Excessive glutamate neurotransmission has been implicated in neuronal injury in many disorders of the central nervous system (CNS), including human immunodeficiency virus (HIV)-associated dementia. Gp120IIIB is a strain of a HIV glycoprotein with specificity for the CXCR4 receptor that induces neuronal apoptosis in in vitro models of acquired immunodeficiency syndrome (AIDS)-induced neurodegeneration. Since the catabolism of the neuropeptide N-acetylaspartylglutamate (NAAG) by glutamate carboxypeptidase (GCP) II increases cellular glutamate, an event associated with excitotoxicity, we hypothesized that inhibition of GCP II may prevent gp120IIIB-induced cell death. Furthermore, through GCP II inhibition, increased NAAG may be neuroprotective via its agonist effects at the mGlu(3) receptor. To ascertain the therapeutic potential of GCP II inhibitors, embryonic day 17 hippocampal cultures were exposed to gp120IIIB in the presence of a potent and highly selective GCP II inhibitor, 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). 2-PMPA was found to abrogate gp120IIIB-induced toxicity in a dose-dependent manner. Additionally, 2-PMPA was neuroprotective when applied up to 2 h after the application of gp120IIIB. The abrogation of apoptosis by 2-PMPA was reversed with administration of mGlu(3) receptor antagonists and with antibodies to transforming growth factor (TGF)-beta. Further, consistent with the localization of GCP II, 2-PMPA failed to provide neuroprotection in the absence of glia. GCP II activity and its inhibition by 2-PMPA were confirmed in the hippocampal cultures using radiolabeled NAAG and high-performance liquid chromatography (HPLC) analysis. Taken together, these data suggest that GCP II is involved in mediating gp120-induced apoptosis in hippocampal neurons and GCP II inhibitors may have potential in the treatment of neuronal injury related to AIDS.

Topics: AIDS Dementia Complex; Animals; Apoptosis; Cells, Cultured; Dipeptides; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glutamate Carboxypeptidase II; Hippocampus; HIV Envelope Protein gp120; Neuroglia; Neurons; Neuroprotective Agents; Organophosphorus Compounds; Rats; Receptors, Metabotropic Glutamate; 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

Topics: Adult; AIDS Dementia Complex; Cytokines; Female; Humans; Interferon-alpha; Male; Middle Aged; Transforming Growth Factor beta; Transforming Growth Factor beta1

The effects of anti-inflammatory drugs on glial immunity and neuropathology were determined in a severe combined immune deficiency (SCID) mouse model of HIV-1 encephalitis. HIV-1-infected human monocyte-derived macrophages (MDM) are stereotactically inoculated into basal ganglia resulting in a multinucleated giant cell encephalitis. A platelet activating factor antagonist and a matrix metalloproteinase inhibitor, which also inhibits tumor necrosis factor alpha release, were administered to animals at the time of the MDM inoculation. The drugs administered in combination markedly reduced brain inflammation, astrogliosis and microglia activation. These findings demonstrate that reduction of brain inflammatory responses, independent of viral replication, can affect HIVE pathology in an animal model system of disease.

Topics: AIDS Dementia Complex; Animals; Benzyl Compounds; Cell Survival; Dexamethasone; Disease Models, Animal; Drug Combinations; Gliosis; HIV-1; Humans; In Vitro Techniques; Interleukin-1; Interleukin-8; Leucine; Macrophages; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, SCID; Microglia; Neurons; Pentoxifylline; Platelet Activating Factor; Protease Inhibitors; Succinates; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Mechanisms involved in the pathogenesis of the AIDS-dementia complex are still unclear. The dichotomy between a small number of HIV-infected cells in the brain and their marked dysfunction could be related to a cellular amplification and/or activation of cerebral viral load by several cytokines. This link between cytokines and viral load could play a role in the generation of the clinical dementia syndrome. We have studied cerebral levels of transforming growth factor-beta1 and interferon-alpha, both in the mild and severe AIDS-dementia complex and also compared these cytokines with HIV RNA load in patients with different degrees of dementia. Our data indicate that production of different cytokines characterized the expression of clinical dementia. In the mild AIDS-dementia complex, there was a significant inverse correlation between interferon-alpha and transforming growth factor-beta1 (r = - 0.743; p < 0.001), and HIV-RNA was present in inverse proportion to transforming growth factor beta1 (r = - 0.751; p < 0.001). In patients with severe AIDS-dementia, transforming growth factor-beta1 was undetectable, while interferon-alpha level were higher than in mild AIDS dementia and correlated positively to cerebral HIV-RNA. No significant difference was evident between these cytokines in the serum of ADC patients and in the control samples. Our study suggests that a relationship is possible between productive HIV infection in the cerebral nervous system and a heterogenous and different expression of the immune response via a complex interaction of cytokines with a differential modulation of the dementia phenotype.

Topics: Adult; AIDS Dementia Complex; Brain; Female; HIV; Humans; Interferon-alpha; Male; Middle Aged; RNA, Viral; Transforming Growth Factor beta; Viral Load

Activated macrophages produce quinolinic acid (QUIN), a neurotoxin, in several inflammatory brain diseases including AIDS dementia complex. We hypothesized that IL1-beta, IL6, transforming growth factor (TGF-beta2 and platelet activating factor could increase macrophage QUIN production. And that the HIV-1 proteins Nef, Tat and gp41 may also increase synthesis of QUIN by macrophages. At 72 h there were significant increases in QUIN production in the cells stimulated with PAF (914 +/- 50 nM) and Nef (2781 +/- 162 nM), with somewhat less production by Tat stimulation (645 +/- 240 nM). The increases in QUIN production approximated in vitro concentrations of QUIN shown to be neurotoxic and correlated closely with indoleamine 2,3-dioxygenase induction. IL1-beta, IL6, TGF-beta2 and gp41 stimulation produced no significant increase in QUIN production. These results suggest that some of the neurotoxicity of PAF, nef and tat may be mediated by QUIN.

Topics: AIDS Dementia Complex; Enzyme Induction; Gene Products, nef; Gene Products, tat; HIV Envelope Protein gp41; Humans; Interferon-gamma; Interleukin-1; Interleukin-6; Macrophages; nef Gene Products, Human Immunodeficiency Virus; Platelet Activating Factor; Quinolinic Acid; tat Gene Products, Human Immunodeficiency Virus; Transforming Growth Factor beta; Transforming Growth Factor beta2; Tryptophan Oxygenase

The transforming growth factor-beta family of polypeptides includes three related isoforms with pervasive effects on immune system function. In this study, the authors evaluated human brains with human immunodeficiency virus (HIV)-1 encephalitis for transforming growth factor beta (TGFbeta)1, TGFbeta2, and TGFbeta3 immunoreactivity using isoform-specific polyclonal antibodies and avidin-biotin immunohistochemistry. Normal brains and those with progressive multifocal leukoencephalopathy, toxoplasma encephalitis, and cryptococcal meningitis were used as controls. In normal controls, TGFbeta1, TGFbeta2, and TGFbeta3 immunoreactivity were confined to arachnoid cells and blood vessels. In 9 of 10 cases of HIV-1 encephalitis, all three isoforms were also detected in arachnoid cells. In addition, variable, predominantly TGFbeta2 and TGFbeta3 immunoreactivity were also detected in reactive astrocytes and mononuclear cells of white matter lesions. Extensive TGFbeta3 immunoreactivity was also detected in multinucleated giant cells in one case. In a case of cryptococcal meningitis, all three isoforms were detected in arachnoid cells and macrophages. Lesions of progressive multifocal leukoencephalopathy and toxoplasma encephalitis also exhibited TGFbeta1, TGFbeta2, and TGFbeta3 immunostaining in reactive astrocytes. These findings suggest that TGFbeta isoforms are present in HIV-1 encephalitis and may participate in the pathogenesis of this and other inflammatory central nervous system (CNS) lesions associated with acquired immunodeficiency syndrome (AIDS).

Topics: Adult; AIDS Dementia Complex; Brain; Case-Control Studies; Female; HIV-1; Humans; Immunohistochemistry; Male; Meninges; Middle Aged; Tissue Distribution; Transforming Growth Factor beta

Cytokines are potent factors mediating interactions between the immune and nervous systems. Cytokines released by macrophages/microglia, the predominant immune cell within the brain, have been proposed to modulate neuronal survival and death. In human immunodeficiency virus-encephalitis (HIVE), cytokines could modulate neurologic damage if nervous system cells possessed appropriate receptors. We hypothesized that the populations of neurons vulnerable to the toxic effects of cytokines in HIVE might contain specific receptors for these molecules. We examined the distribution of cytokine receptors in the human brain utilizing fluorescent-labeled cytokines combined with confocal laser microscopy imaging. Phycoerythrin-conjugated interleukin-1 beta and phycoerythrin-Avidin/biotin conjugated transforming growth factor beta 1 labeled dendritic processes of neurons in the neocortex. Labeling was abolished by pre-incubation with unlabeled cytokines. In cases with moderate HIVE, an average 35% increase in intensity of labeling was observed compared to cases without HIVE or with cases with severe HIVE. The patterns of interleukin 2 labeling were not altered in HIVE. These results suggest that neurons susceptible to cytokine-mediated damage during the progression of HIVE display abnormal patterns of cytokine receptor labeling.

Topics: Adult; AIDS Dementia Complex; Analysis of Variance; Autopsy; Brain; Cells, Cultured; Frontal Lobe; HIV Infections; Humans; Interleukin-1; Macrophages; Monocytes; Neurons; Receptors, Cytokine; Reference Values; Transforming Growth Factor beta

The multifunctional cytokine, transforming growth factor beta (TGF-beta), was identified by immunocytochemistry in the brain tissues of four patients with acquired immune deficiency syndrome (AIDS), but not in control brain tissue. The TGF-beta staining was localized to cells of monocytic lineage as well as astrocytes, especially in areas of brain pathology. In addition, the brain tissues from the AIDS patients contained transcripts for human immunodeficiency virus 1 (HIV-1) by in situ hybridization, suggesting a correlation between the presence of HIV-1 in the brain and the expression of TGF-beta. However, the expression of TGF-beta was not limited to HIV-1-positive cells, raising the possibility of alternative mechanisms for the induction of TGF-beta in these AIDS patients' brains. To investigate these mechanisms, purified human monocytes were infected in vitro with HIV-1 and were shown to secrete increased levels of TGF-beta. In addition, HIV-1-infected monocytes released a factor(s) capable of triggering cultured astrocytes that are not infected with HIV-1 to secrete TGF-beta. The release of TGF-beta, which is an extremely potent chemotactic factor, may contribute to the recruitment of HIV-1-infected monocytic cells, enabling viral spread to and within the central nervous system (CNS). Moreover, TGF-beta augments cytokine production, including cytokines known to be neurotoxic. The identification of TGF-beta within the CNS implicates this cytokine in the immunopathologic processes responsible for AIDS-related CNS dysfunction.

Topics: AIDS Dementia Complex; Astrocytes; Blotting, Northern; Brain; HIV-1; Humans; In Vitro Techniques; Macrophages; Male; Monocytes; RNA, Messenger; Transforming Growth Factor beta