HIV-1 gp120-Induced Apoptosis in the Rat Neocortex Involves Enhanced Expression of Cyclo-oxygenase Type 2 (COX-2)

doi:10.1006/bbrc.1998.8321

Biochemical and Biophysical Research Communications

Volume 244, Issue 3, 27 March 1998, Pages 819-824

https://doi.org/10.1006/bbrc.1998.8321 Get rights and content

Abstract

The effect of subchronic intracerebroventricular (i.c.v.) injection of the human immunodeficiency virus type 1 (HIV-1) recombinant protein gp120 (100 ng, given daily for up to 7 consecutive days) on cyclo-oxygenase type 2 (COX-2) expression was studied by immunohistochemistry in the brain of adult rats. In comparison to control, bovine serum albumin (100 ng, given i.c.v. for up to 7 days) treated animals (n=6), a single daily injection of the viral protein for 7 consecutive days enhanced the number of COX-2 immunoreactive cells in the brain cortex of rats (n=6 per group) and this was accompanied by a 50% increase over control PGE₂content in whole brain tissue homogenates (n=6). In another series of experiments, pretreatment of rats (n=6) with indomethacin (6.0 mg/kg given i.p. 1 h before gp120 injection), an inhibitor COX activity, prevented apoptotic death typically produced by gp120 in the neocortex of rat suggesting that enhancement of COX-2 expression may be involved in the mechanisms of apoptosis yielded by the HIV-1 coat protein.

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Extracellular HIV Tat was found to induce COX-2 mRNA and protein expression, as well as PGE2 synthesis in astrocytoma cell lines and primary human astrocytes.112 COX-2 inhibitors attenuated HIV Tat-induced alterations in occluding expression at the blood–brain barrier,113 prevented the apoptotic death typically produced by HIV-1 gp120 in the neo-cortex,114 and reduced the level of PGE2, thereby reversing T cell anergy.115 Moreover, the expression of COX-2 mRNA and PGE2 are selectively increased in vulnerable regions during the symptomatic stages of TD encephalopathy in animal models.116
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Increased production of free radicals has been shown to involve and initiate several important intracellular cascades. The gp120, one of the components of the viral envelope coating has been shown to be neurotoxic and cause apoptotic cell death (Bagetta et al., 1998; Yeung et al., 1998). Earlier studies have shown that gp120 infection causes an elevation in the production of the reactive oxygen species in vivo as well as in vitro (Foga et al., 1997; Pocernich et al., 2000).
HIV infection affects the central nervous system resulting in HIV associated neurocognitive disorder (HAND), which is characterized by depression, behavioral and motor dysfunctions. The HIV-1 viral envelope protein gp120 is known to induce the release of neurotoxic factors which lead to apoptotic cell death. Although the exact mechanisms involved in HIV-1 gp120-induced neurotoxicity are not completely understood, oxidative stress is suggested to play a vital role in the neuropathogenesis of HAND. Astrocytes represent major population of the non-neuronal cell type in the brain and play a critical role in the neuropathogenesis of HAND. Increased oxidative stress is known to induce nuclear factor erythroid derived 2-related factor 2 (Nrf2), a basic leucine zipper transcription factor which is known to regulate the antioxidant defensive mechanism. However, the role of Nrf2 in HAND has not been elucidated. We report that gp120 significantly upregulates Nrf2 in human astrocytes and is associated with stimulation of key antioxidant defensive enzymes Hemoxygenase (HO-1) and NAD(P)H dehydrogenase quinone1 (Nqo1). Pretreatment of the astrocytes with antioxidants or a specific calcium chelator BAPTA-AM, significantly blocked the upregulation of Nrf2, HO-1 and Nqo1. These results suggest a possible role of the intracellular calcium and oxidative stress in Nrf2 mediated antioxidant defense mechanism, which may have protective role in promoting cell survival.
NS3 protein of hepatitis C virus regulates cyclooxygenase-2 expression through multiple signaling pathways
2008, Virology
Hepatitis C virus (HCV) causes chronic hepatitis, which often results in the development of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. In this study, we demonstrated that the non-structural protein NS3 of HCV enhances cyclooxygenase-2 (COX-2) gene promoter activity, COX-2 mRNA expression, COX-2 protein production, and prostaglandin E2 (PGE2) release in HepG2 cells in a concentration-dependent fashion. We also showed that transcription factor NF-κB is required for the activation of COX-2 regulated by NS3. In addition, multiple signaling pathways are involved cooperatively in the expression of COX-2 activated by the viral protein in a calcium-independent manner, which requires signaling components including JNK, ERK, and PKD2. A thorough investigation of mechanism involved in the activation of COX-2 regulated by HCV would provide insights into our understanding the processes of liver inflammatory response and hepatocellular carcinoma development caused by the viral infection and also into the development of novel therapeutics against HCV infection.
Transplacental Infection with Non-Cytopathic Bovine Viral Diarrhoea Virus Types 1b and 2: Viral Spread and Molecular Neuropathology
2008, Journal of Comparative Pathology
Citation Excerpt :
Both pathways could be envisaged to occur in the brain of PI fetuses. COX-2 expression has also been linked to virus-induced apoptosis of neurons and oligodendrocytes in other models (Bagetta et al., 1998; Carlson et al., 2006). However, in the present study COX-2 expression appeared limited to infiltrating macrophage-like cells, and direct induction by viral replication and involvement in apoptosis therefore seem unlikely.
Infection with bovine viral diarrhoea virus (BVDV) represents a reproducible natural animal model in which to study mechanisms of transplacental viral infection. In the present study, BVDV-seronegative heifers were challenged intranasally with non-cytopathic BVDV of genotype 1b or 2. Fetuses were retrieved by caesarean section 7–114 days post-challenge of the dam and subjected to virological, histopathological and immunohistochemistry(IHC) studies. Gross and histopathological changes were only seen in fetuses infected at gestational age 75–85 days and retrieved at gestational age 190 days. Viral antigen could be detected in most tissues from 14 days post-infection, but the primary target organs for histopathological changes were brain, liver and spleen. In the brain, microscopical changes included leucomalacia and macrophage infiltration of meninges and neuropil. Viral antigen was detected in neurons, oligodendrocyte precursors and infiltrating macrophages. IHC revealed normal to slightly increased expression of hypoxia-inducible factor-1α (HIF-1α) in the infected fetuses, with evidence of neuronal apoptosis and induction of inducible nitric oxide synthase (iNOS) and phospho-p38α mitogen-activated protein kinase (MAPK). These findings suggest that hypoxia may play only a limited role in the pathogenesis of the neural lesions. By contrast, virus-induced cytokine cascades, as part of the fetal innate immune response, and apoptosis of neurons and glial precursor cells may be central to the development of lesions.
Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein
2006, International Journal of Biochemistry and Cell Biology
SARS-associated coronavirus (SARS-CoV) causes inflammation and damage to the lungs resulting in severe acute respiratory syndrome. To evaluate the molecular mechanisms behind this event, we investigated the roles of SARS-CoV proteins in regulation of the proinflammatory factor, cyclooxygenase-2 (COX-2). Individual viral proteins were tested for their abilities to regulate COX-2 gene expression. Results showed that the COX-2 promoter was activated by the nucleocapsid (N) protein in a concentration-dependent manner. Western blot analysis indicated that N protein was sufficient to stimulate the production of COX-2 protein in mammalian cells. COX-2 promoter mutations suggested that activation of COX-2 transcription depended on two regulatory elements, a nuclear factor-kappa B (NF-κB) binding site, and a CCAAT/enhancer binding protein (C/EBP) binding site. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) demonstrated that SARS-CoV N protein bound directly to these regulatory sequences. Protein mutation analysis revealed that a Lys-rich motif of N protein acted as a nuclear localization signal and was essential for the activation of COX-2. In addition, a Leu-rich motif was found to be required for the N protein function. A sequence of 68 residuals was identified as a potential DNA-binding domain essential for activating COX-2 expression. We propose that SARS-CoV N protein causes inflammation of the lungs by activating COX-2 gene expression by binding directly to the promoter resulting in inflammation through multiple COX-2 signaling cascades.

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^☆: Moncada, S.Nisticò, G.Bagetta, G.Higgs, A. E.

¹: Corresponding author at Department of Pharmaco-Biology, University of Calabria at Cosenza, 87030 Arcavacata di Rende (CS). Fax: 39-984/493763. E-mail:[email protected].

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Regular ArticleHIV-1 gp120-Induced Apoptosis in the Rat Neocortex Involves Enhanced Expression of Cyclo-oxygenase Type 2 (COX-2)☆

Abstract

Biochem. Biophys. Res. Commun.

Trends Neurosci.

Immunol. Today

Neuron

Neurodegeneration

Proc. Natl. Acad. Sci. USA

NeuroReport

FASEB J.

J. Virol.

J. Exp. Med.

J. Immunol.

Regular Article
HIV-1 gp120-Induced Apoptosis in the Rat Neocortex Involves Enhanced Expression of Cyclo-oxygenase Type 2 (COX-2)☆