Glial Cytokines as Neuropathogenic Factors in HIV Infection

Stanley, Laura; Mrak, Robert E.; Woody, Robert C.; Perrot, Linda J.; Zhang, Shuxing; Marshak, Daniel R.; Nelson, Stephen J.; Griffin, W. Sue T.

doi:10.1097/00005072-199405000-00003

Cited by 133 publications

(60 citation statements)

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“…The mechanisms through which GSK-3␤ activation may promote neuronal injury include phosphorylation of the microtubuleassociated protein Tau (Hoshi et al, 1995(Hoshi et al, , 1996Bhat et al, 2004). Consistent with this, Tau immunoreactive tangles are present in brains of individuals with advanced HIV-1 infection (Stanley et al, 1994). Thus, this signaling pathway is an attractive therapeutic target for treatment of HAD.…”

Section: Discussionmentioning

confidence: 69%

Neuroprotective Mechanisms of Lithium in Murine Human Immunodeficiency Virus-1 Encephalitis

Dou¹,

Ellison²,

Bradléy³

et al. 2005

J. Neurosci.

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Lithium (Li) has garnered considerable interest as a neuroprotective drug for a broad range of nervous system disorders. Its neuroprotective activities occur as a consequence of glycogen synthase kinase-3␤ (GSK-3␤) inhibition leading to downstream blockade of ␤-catenin and Tau phosphorylation. In the present study, we investigated Li-mediated neuroprotective mechanisms in laboratory and murine human immunodeficiency virus-1 (HIV-1) encephalitis (HIVE) models. In laboratory tests, Li protected neurons from neurotoxic secretions of HIV-1-infected monocyte-derived macrophages (MDMs). This neuroprotection was mediated, in part, through the phosphatidyl inositol 3-kinase/Akt and GSK-3␤ pathways. To examine the effects of Li treatment in vivo, MDMs were injected into the basal ganglia of severe combined immunodeficient mice and then Li was administered (60 mg/kg/d). Seven days after MDM injection, mice were killed and CNS tissue was collected and subjected to immunocytochemical and Western blot assays for leukocyte and neural antigens, GSK-3␤, and key kinase substrates such as ␤-catenin and Tau. Numbers of HIV-1 p24 antigen-positive MDMs were unaltered by Li treatment of HIVE mice. Similarly, the greatly increased extent of astrocyte and microglia activation in HIVE mice (10-fold and 16-fold, respectively, compared with unmanipulated controls) was also unaltered by Li. In contrast, Li restored HIVE-associated loss of microtubule-associated protein-2-positive neurites and synaptic density while reducing levels or activity of phospho-Tau Ser 202 , phospho-␤-catenin, and GSK-3␤. Electrophysiological recordings showed diminished long-term potentiation in hippocampal slices of HIVE mice that were restored by Li. Based on these data, the use of Li as an adjuvant for HIV-1-associated dementia is now being pursued.

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Section: Discussionmentioning

confidence: 69%

Neuroprotective Mechanisms of Lithium in Murine Human Immunodeficiency Virus-1 Encephalitis

Dou¹,

Ellison²,

Bradléy³

et al. 2005

J. Neurosci.

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“…Noncytotoxic defense mechanisms mediated through the production of soluble, inhibitory factors most likely contribute to the control of CNS infections. Although proinflammatory cytokines, such as TNF-␣ and IL-1␤, have been clearly implicated in neuronal damage (15)(16)(17)(18)(19), little is known about the regulatory effect of these cytokines on viral infections of the CNS or whether they possess beneficial, antiviral effects in brain cells. In response to viral infection, cytokines are secreted within the CNS from both activated glial cells and T lymphocyte infiltrates (20).…”

Section: Discussionmentioning

confidence: 99%

Decreased Cytomegalovirus Expression Following Proinflammatory Cytokine Treatment of Primary Human Astrocytes

Cheeran

Gekker

et al. 2000

The Journal of Immunology

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Understanding the influence of immune effector mechanisms on CMV infection of the CNS may facilitate the development of immunotherapies for viral encephalitis. Using cultures of highly purified, fully permissive primary human astrocytes, proinflammatory cytokines, but not antiinflammatory cytokines or β-chemokines, were found to inhibit CMV expression, DNA synthesis, and replication. Treatment with certain proinflammatory cytokines 24 h before CMV infection markedly suppressed viral expression in astrocytes. TNF-α, IL-1β, and IFN-γ all inhibited CMV expression (70 ± 4.2%, 65 ± 3.4%, and 82 ± 3.6% inhibition of viral expression, respectively, n = 5). In contrast, no viral suppression was observed following IL-6 treatment. Suppressive activity was dependent on the addition of cytokines before CMV infection. Cytokine pretreatment did not affect CMV entry into primary astrocytes, and the observed cytokine-induced suppressive activity was not affected by the NO synthase inhibitor NG-monomethyl-l-arginine (NGMA). Instead, the suppressive effect appeared to be mediated through a mechanism involving inhibition of CMV major immediate early promoter activity. These results support the hypothesis that proinflammatory cytokines possess anti-CMV activity in brain cells and may lead to new interventions for CMV encephalitis based upon immunotherapy.

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“…Patients with acquired immunodeficiency syndrome (AIDS)-related dementia, cancer, or chronic inflammatory diseases often exhibit elevated levels of IL-1␤ co-occurring with cognitive impairment (Gallo et al, 1989;Griffin et al, 1989;Stanley et al, 1994;Meyers, 2000). IL-1␤ is the most consistently induced cytokine in the brain after peripheral immune stimulation and has a high density of receptors in the hippocampus .…”

Section: Role Of Il-1␤ In Memory Impairmentmentioning

confidence: 99%

Neonatal Infection-Induced Memory Impairment after Lipopolysaccharide in Adulthood Is Prevented via Caspase-1 Inhibition

Bilbo¹,

Biedenkapp²,

Der-Avakian³

et al. 2005

J. Neurosci.

226

229

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We have reported that neonatal infection leads to memory impairment after an immune challenge in adulthood. Here we explored whether events occurring as a result of early infection alter the response to a subsequent immune challenge in adult rats, which may then impair memory. In experiment 1, peripheral infection with Escherichia coli on postnatal day 4 increased cytokines and corticosterone in the periphery, and cytokine and microglial cell marker gene expression in the hippocampus of neonate pups. Next, rats treated neonatally with E. coli or PBS were injected in adulthood with lipopolysaccharide (LPS) or saline and killed 1-24 h later. Microglial cell marker mRNA was elevated in hippocampus in saline controls infected as neonates. Furthermore, LPS induced a greater increase in glial cell marker mRNA in hippocampus of neonatally infected rats, and this increase remained elevated at 24 h versus controls. After LPS, neonatally infected rats exhibited faster increases in interleukin-1␤ (IL-1␤) within the hippocampus and cortex and a prolonged response within the cortex. There were no group differences in peripheral cytokines or corticosterone. In experiment 2, rats treated neonatally with E. coli or PBS received as adults either saline or a centrally administered caspase-1 inhibitor, which specifically prevents the synthesis of IL-1␤, 1 h before a learning event and subsequent LPS challenge. Caspase-1 inhibition completely prevented LPS-induced memory impairment in neonatally infected rats. These data implicate IL-1␤ in the set of immune/inflammatory events that occur in the brain as a result of neonatal infection, which likely contribute to cognitive alterations in adulthood.

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Glial Cytokines as Neuropathogenic Factors in HIV Infection

Cited by 133 publications

References 0 publications

Neuroprotective Mechanisms of Lithium in Murine Human Immunodeficiency Virus-1 Encephalitis

Neuroprotective Mechanisms of Lithium in Murine Human Immunodeficiency Virus-1 Encephalitis

Decreased Cytomegalovirus Expression Following Proinflammatory Cytokine Treatment of Primary Human Astrocytes

Neonatal Infection-Induced Memory Impairment after Lipopolysaccharide in Adulthood Is Prevented via Caspase-1 Inhibition

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