Biomedical subjects

Jialin Zheng

Publications and source records attributed to Jialin Zheng.

15 recordsLinked to original sources

PubMed2006

HIV-1-infected and/or immune activated macrophages regulate astrocyte SDF-1 production through IL-1beta.

Stromal cell-derived factor 1 alpha (SDF-1alpha) and its receptor CXCR4 play important roles in the pathogenesis of human immunodeficiency virus type one (HIV-1)-associated dementia (HAD) by serving as a HIV-1 co-receptor and affecting cell migration, virus-mediated neurotoxicity, and neurodegeneration. However, the underlying mechanisms regulating SDF-1 production during disease are not completely understood. In this report we investigated the role of HIV-1 infected and immune competent macrophage, the principal target cell and mediator of neuronal injury and death in HAD, in regulating SDF-1 production by astrocytes. Our data demonstrated that astrocytes are the primary cell type expressing SDF-1 in the brain. Immune-activated or HIV-1-infected human monocyte-derived-macrophage (MDM) conditioned media (MCM) induced a substantial increase in SDF-1 production by human astrocytes. This SDF-1 production was directly dependent on MDM IL-1beta following both viral and immune activation. The MCM-induced production of SDF-1 was prevented by IL-1beta receptor antagonist (IL-1Ra) and IL-1beta siRNA treatment of human MDM. These laboratory observations were confirmed in severe combined immunodeficient (SCID) mice with HIV-1 encephalitis (HIVE). In these HIVE mice, reactive astrocytes showed a significant increase in SDF-1 expression, as observed by immunocytochemical staining. Similarly, SDF-1 mRNA levels were increased in the encephalitic region as measured by real time RT-PCR, and correlated with IL-1beta mRNA expression. These observations provide direct evidence that IL-1beta, produced from HIV-1-infected and/or immune competent macrophage, induces production of SDF-1 by astrocytes, and as such contribute to ongoing SDF-1 mediated CNS regulation during HAD.

AIDS Dementia Complex↗

PubMed2006

TRAIL-mediated apoptosis in HIV-1-infected macrophages is dependent on the inhibition of Akt-1 phosphorylation.

HIV-1 uses mononuclear phagocytes (monocytes, tissue macrophages, and dendritic cells) as a vehicle for its own dissemination and as a reservoir for continuous viral replication. The mechanism by which the host immune system clears HIV-1-infected macrophages is not understood. TRAIL may play a role in this process. TRAIL is expressed on the cell membrane of peripheral immune cells and can be cleaved into a soluble, secreted form. The plasma level of TRAIL is increased in HIV-1-infected patients, particularly those with high viral loads. To study the effect of elevated TRAIL on mononuclear phagocytes, we used recombinant human (rh) TRAIL and human monocyte-derived macrophages (MDM) as an in vitro model. Our results demonstrated rhTRAIL-induced apoptosis in HIV-1-infected MDM and inhibited viral replication, while having a reduced effect on uninfected MDM. HIV-1 infection significantly decreased Akt-1 phosphorylation; rhTRAIL exposure further decreased Akt-1 phosphorylation. Infection with a dominant-negative Akt-1 adenovirus potentiated rhTRAIL-induced apoptosis, while constitutively active Akt-1 blocked rhTRAIL-induced apoptosis in HIV-1-infected MDM. From this data we conclude the death ligand TRAIL preferentially provokes apoptosis of HIV-1-infected MDM, and the mechanism is reliant upon the inhibition of Akt-1 phosphorylation. Understanding this mechanism may facilitate the elimination of HIV-1-infected macrophages and lead to new therapeutic avenues for treatment of HIV-1 infection.

Apoptosis↗

PubMed2006

The phenotypic characterization of naturally occurring regulatory CD4+CD25+ T cells.

The homeostasis of the immune system depends on the balance between the immune response to an invaded pathogen and the immune tolerance to self antigens. Both central and peripheral tolerances are important mechanisms for the induction and maintenance of T cell tolerance. Recently, much attention has been paid to regulatory T cells (Treg), which play a significant role in maintaining peripheral immune tolerance. So far, there has been no satisfactory advance regarding the surface markers of Treg cells, as none is unique for Treg cells. In this review, we summarize some important molecules expressed in naturally occurring CD4+CD25+ Treg cells (nTreg), including forkhead/winged-helix family transcriptional repressor p3 (Foxp3), the tumor necrosis factor receptor (TNFR) family, CD28/CTLA4 molecules, chemokine receptors, Toll-like receptors (TLRs), membrane-bound TGF-beta and other molecules, such as neuropilin-1, lymphocyte activation gene-3 (LAG)-3 and granzyme. This review provides a collective view on current studies of nTreg cell activation and development related to the expression of molecules and cell phenotype markers, which is important for elucidation of nTreg cell origin, development and function.

Animals↗

PubMed2005

Cellular IAP1 regulates TRAIL-induced apoptosis in human fetal cortical neural progenitor cells.

Neural stem/progenitor cells (NPCs) are present in the developing and adult central nervous system. NPC apoptosis is an important aspect of normal brain development. We show that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 is highly expressed on human NPCs derived from fetal cortex, yet TRAIL induces only minimal levels of apoptosis in NPCs. Caspase-8 mRNA and protein, an important factor in the TRAIL-mediated death pathway, is present at low levels in human NPCs. In contrast, inhibitors of apoptosis proteins (IAP), such as c-IAP1, are highly expressed. The transcription inhibitor actinomycin D sensitized human NPCs to TRAIL-induced apoptosis. Further, inhibition of cellular inhibitors of apoptosis protein 1 (c-IAP1) expression by small interfering RNA (siRNA) increased TRAIL-mediated caspase-3 activation and apoptosis; thus, c-IAP1 protects NPCs against TRAIL-induced apoptosis and suppresses caspase-3 activation. These findings illustrate the mechanisms for NPC resistance to apoptotic agonists such as TRAIL, and demonstrate a potentially important mechanism in CNS disease states.

Apoptosis↗

PubMed2005

The role of TNF related apoptosis-inducing ligand in neurodegenerative diseases.

A hallmark of all forms of neurodegenerative diseases is impairment of neuronal functions, and in many cases neuronal cell death. Although the etiology of neurodegenerative diseases may be distinct, different diseases display a similar pathogenesis, for example abnormal immunity within the central nervous system (CNS), activation of macrophage/microglia and the involvement of proinflammatory cytokines. Recent studies show that neurons in a neurodegenerative state undergo a highly regulated programmed cell death, also called apoptosis. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, has been shown to be involved in apoptosis during many diseases. As one member of a death ligand family, TRAIL was originally thought to target only tumor cells and was not present in CNS. However, recent data showed that TRAIL was unregulated in HIV-1-infected and immune-activated macrophages, a major disease inducing cell during HIV-1-associated dementia (HAD). TRAIL is also induced on neuron by beta-amyloid protein, an important pathogen for Alzheimer's disease. In this review, we summarize the possible common aspects that TRAIL involved those neurodegenerative diseases, TRAIL induced apoptosis signaling in the CNS cells, and specific role of TRAIL in individual diseases.

AIDS Dementia Complex↗

PubMed2004

Stromal cell-derived factor 1-mediated CXCR4 signaling in rat and human cortical neural progenitor cells.

Stromal cell-derived factor 1 (SDF-1) and the chemokine receptor CXCR4 are highly expressed in the nervous system. Knockout studies have suggested that both SDF-1 and CXCR4 play essential roles in cerebellar, hippocampal, and neocortical neural cell migration during embryogenesis. To extend these observations, CXCR4 signaling events in rat and human neural progenitor cells (NPCs) were examined. Our results show that CXCR4 is expressed in abundance on rat and human NPCs. Moreover, SDF-1alpha induced increased NPCs levels of inositol 1,4,5-triphosphate, extracellular signal-regulated kinases 1/2, Akt, c-Jun N-terminal kinase, and intracellular calcium whereas it diminished cyclic adenosine monophosphate. Finally, SDF-1alpha can induce human NPC chemotaxis in vitro, suggesting that CXCR4 plays a functional role in NPC migration. Both T140, a CXCR4 antagonist, and pertussis toxin (PTX), an inactivator of G protein-coupled receptors, abrogated these events. Ultimately, this study suggested that SDF-1alpha can influence NPC function through CXCR4 and that CXCR4 is functional on NPC.

Animals↗

PubMed2004

TNF-related apoptosis-inducing ligand mediates human neuronal apoptosis: links to HIV-1-associated dementia.

TNF-related apoptosis-inducing ligand (TRAIL) is a type II integral membrane protein that interacts with multiple receptors and cell types including neurons. In this report, TRAIL protein levels were increased in human monocyte-derived macrophages (MDM) after HIV-1 infection and immune activation. In HIV-1 encephalitic (HIVE) human brain tissue, TRAIL-expressing macrophages were found in association with active caspase-3 positive neurons. Cytotoxic TRAIL receptors 1 and 2 were expressed on neurons in primary human fetal cultures and HIV-1 encephalitic brain tissue. Furthermore, TRAIL induced a dose-dependent effect on neuronal apoptosis. These results support a role for TRAIL in mononuclear phagocyte (MP)-mediated neurotoxicity in HIV-1-associated dementia (HAD).

AIDS Dementia Complex↗

PubMed2004

Mitochondrial glutaminase enhances extracellular glutamate production in HIV-1-infected macrophages: linkage to HIV-1 associated dementia.

Dysfunction in mononuclear phagocyte (MP, macrophages and microglia) immunity is thought to play a significant role in the pathogenesis of HIV-1 associated dementia (HAD). In particular, elevated extracellular concentrations of the excitatory neurotransmitter glutamate, produced by MP as a consequence of viral infection and immune activation, can induce neuronal injury. To determine the mechanism by which MP-mediated neuronal injury occurs, the concentration and rates of production of extracellular glutamate were measured in human monocyte-derived macrophage (MDM) supernatants by reverse phase high-performance liquid chromatography (RP-HPLC). Measurements were taken of supernatants from MDM infected with multiple HIV-1 strains including ADA and DJV (macrophage tropic, M-tropic), and 89.6 (dual tropic). High levels of glutamate were produced by MDM infected with M-tropic viruses. AZT, an inhibitor of HIV-1 replication, inhibited glutamate generation, demonstrating a linkage between HIV-1 infection and enhanced glutamate production. In our culture system, glutamate production was dependent upon the presence of glutamine and was inhibited by 6-diazo-5-oxo-L-norleucine, a glutaminase inhibitor. Supernatants collected from HIV-1-infected MP generated more glutamate following glutamine addition than supernatants isolated from uninfected MP. These findings implicate the involvement of a glutamate-generating enzyme, such as phosphate-activated mitochondrial glutaminase (PMG) in MP-mediated glutamate production.

AIDS Dementia Complex↗

PubMed2004

Up-regulation of soluble tumor necrosis factor receptor two in plasma of HIV-seropositive individuals who use opiates.

Previously, we reported an increase in soluble tumor necrosis factor-alpha receptor two (sTNF-R2) and soluble CD14 (sCD14) in the plasma of HIV-seropositive individuals with neurocognitive dysfunction compared to their cognitively intact counterparts. As intravenous drug use is not only a risk factor for HIV but also an immunomodulator, we sought to examine the effects of drug use on soluble markers of immune activation. These relationships were investigated in 25 patients with late stage HIV-1 disease. TNF-alpha, sTNF-R1, sTNFR2, and sCD14 were measured in patient plasma. These values were correlated with drug use and neurocognitive function. sTNF-R2 was significantly up-regulated in those patients who used opiates compared to those who did not. There was no difference in TNF-alpha, sTNF-R1, or sCD14 between the groups. Further, there was no connection between opiate use and neurocognitive dysfunction.

Adolescent↗

PubMed2004

Classification of HIV-1-mediated neuronal dendritic and synaptic damage using multiple criteria linear programming.

The ability to identify neuronal damage in the dendritic arbor during HIV-1-associated dementia (HAD) is crucial for designing specific therapies for the treatment of HAD. To study this process, we utilized a computer-based image analysis method to quantitatively assess HIV-1 viral protein gp120 and glutamate-mediated individual neuronal damage in cultured cortical neurons. Changes in the number of neurites, arbors, branch nodes, cell body area, and average arbor lengths were determined and a database was formed (http://dm.ist.unomaha. edu/database.htm). We further proposed a two-class model of multiple criteria linear programming (MCLP) to classify such HIV-1-mediated neuronal dendritic and synaptic damages. Given certain classes, including treatments with brain-derived neurotrophic factor (BDNF), glutamate, gp120 or non-treatment controls from our in vitro experimental systems, we used the two-class MCLP model to determine the data patterns between classes in order to gain insight about neuronal dendritic damages. This knowledge can be applied in principle to the design and study of specific therapies for the prevention or reversal of neuronal damage associated with HAD. Finally, the MCLP method was compared with a well-known artificial neural network algorithm to test for the relative potential of different data mining applications in HAD research.

Animals↗

PubMed2003

Inhibition of long-term potentiation by interleukin-8: implications for human immunodeficiency virus-1-associated dementia.

Human immunodeficiency virus type 1 (HIV-1)-infected mononuclear phagocytes (MP; brain macrophages and microglia) secrete a number of toxic factors that affect the pathogenesis of HIV-1-associated dementia (HAD). The identification and relative role of each MP toxin for neuronal dysfunction during HAD are not well understood. Interleukin-8 (IL-8), a CXC chemokine involved in leukocyte activation and chemotaxis, is constitutively produced by MP, and elevated levels of IL-8 mRNA were detected in the brains of patients with HIV-1 encephalitis (HIVE) by both ribonuclease protection assays and real-time PCR. To determine the role that IL-8 might play in the neuronal dysfunction in HAD, we studied its effect on synaptic transmission and plasticity in the CA1 region of hippocampus, the seat of learning and memory. Bath application of IL-8 (50 ng/ml) to rat hippocampal slices had no effect on basal synaptic transmission. However, IL-8 was shown to inhibit long-term potentiation (LTP) in a concentration-dependent manner. In control and IL-8-treated slices, the LTP magnitudes were 167.8% +/- 11.9% (mean +/- SE; n = 17) and 122.2% +/- 16.2% of basal levels (n = 13), respectively. These differences were statistically significant (P < 0.05). Preincubation of hippocampal slices with a monoclonal CXCR2 antibody (2 microg/ml) but not control IgG (2 microg/ml) blocked IL-8-induced inhibition of LTP. The expression of CXCR2 receptors in the CA1 region was shown by Western blot assays. The induction of IL-8 in HAD, its inhibition of LTP, and the expression of its receptor, CXCR2, in the hippocampus all suggest that it plays a role in the cognitive dysfunction associated with HAD.

AIDS Dementia Complex↗

PubMed2003

C1q-calreticulin induced oxidative neurotoxicity: relevance for the neuropathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) remains one of the most challenging brain disorders facing modern medicine. Neuronal loss underlies the pathogenesis of AD and can occur, in part, by oxidative stress, by beta-amyloid peptide (Abeta), and by excitotoxins. The complement cascade, especially C1q, may affect reactive oxygen species (ROS) and mediate neuronal injury during AD. We demonstrate that incubation of neurons with purified C1q results in increased ROS, which can be partially blocked by low concentrations of Abeta. C1q-binding sites on neurons were demonstrated by 125I-C1q-binding and immunofluorescence tests performed on primary neurons. The blocking of neuronal calreticulin by its antibody abrogated ROS by C1q. We suggest that the C1q may be an important factor contributing to neuronal oxidative stress and neuronal demise during AD.

Alzheimer Disease↗

PubMed2003

Neuronal injury regulates fractalkine: relevance for HIV-1 associated dementia.

Fractalkine (FKN), a chemokine highly expressed in the central nervous system, participates in inflammatory responses operative in many brain disorders including HIV-1 associated dementia (HAD). In this report, HIV-1 progeny virions and pro-inflammatory products led to FKN production associated with neuronal injury and apoptosis. FKN was produced by neurons and astrocytes; but differentially produced by the two cell types. Laboratory tests paralleled those in infected people where cerebrospinal fluid FKN levels in HIV-1 infected cognitively impaired (n=16) patients were found to be increased when compared to infected patients without cognitive impairment (n=8, P=0.0345). These results demonstrate a possible role of FKN in HAD pathogenesis.

AIDS Dementia Complex↗

PubMed2003

Amyloid precursor protein-processing products affect mononuclear phagocyte activation: pathways for sAPP- and Abeta-mediated neurotoxicity.

Increasing evidence strongly supports the role of glial immunity in the pathogenesis of Alzheimer's disease (AD). To investigate such events we have developed cell systems mimicking the interactions between beta-amyloid precursor protein (APP)-expressing neurons and brain mononuclear phagocytes (MP; macrophages and microglia). MP were co-cultured with neuronal cells expressing wild type APP or familial AD-linked APP mutants. The latter was derived from recombinant adenoviral constructs. Neuronal APP processing products induced MP activation, reactive oxygen species, and neurotoxic activities. These occurred without the addition of pro-inflammatory cytokines and were reversed by depletion of amyloid beta-peptide (Abeta) and secreted APP (sAPP). Neurotoxic activities were diminished by superoxide dismutase mimetics and NMDA receptor inhibitors. Microglial glutamate secretion was suppressed by the cystine-glutamate antiporter inhibitor and its levels paralleled the depletion of sAPP and Abeta from conditioned media prepared from APP-expressing neurons. The excitotoxins from activated MP were potent enough to evoke recombinant NMDA receptor-mediated inward currents expressed in vitro in the Xenopus oocytes. These results demonstrate that neuronal APP-processing products can induce oxidative neurotoxicity through microglial activation.

Amino Acid Transport System y+↗

PubMed2002

Macrophages, chemokines and neuronal injury in HIV-1-associated dementia.

Human immunodeficiency virus type-one (HIV- 1)-associated dementia (HAD) is manifested as a spectrum of behavioral, motor and cognitive dysfunctions. The disorder commonly occurs during late stage HIV disease and remains an important complication despite highly active antiretroviral therapies. A metabolic encephalopathy, fueled by neurotoxic secretions from brain mononuclear phagocytes (MP) (macrophages and microglia) underlies HIV- I neuropathogenesis. One pivotal question, however, is how brain MP evolve from neurotrophic to neurotoxic cells. The interplay between the virus, the macrophage and the neuron has just recently begun to be unraveled. Along with a multitude of other MP secretory products, chemokines effect neuronal function by engaging neuronal receptors then activating pathways that alter synaptic transmission, cell growth, injury and protection. Both neurons and glia secrete chemokines. Interestingly, HIV-1 and its gene products can mimic chemokine neuronal signaling by binding to neuronal chemokine receptors or by other non-specific mechanisms. The elucidation of mechanisms involved in chemokine-mediated neural compromise will likely provide unique insights into the pathogenesis and treatment, not only of HAD, but of a wide range of neurodegenerative disorders.

AIDS Dementia Complex↗