Neuronal apoptosis by HIV-1 Vpr: contribution of proinflammatory molecular networks from infected target cells
| Autor: | Debjani Guha, Carrie J. Redinger, Pruthvi Nagilla, Alagarsamy Srinivasan, Gerald Schatten, Velpandi Ayyavoo |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
viruses
p38 mitogen-activated protein kinases Immunology Apoptosis HIV Infections lcsh:RC346-429 Proinflammatory cytokine 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine HIV-1Vpr medicine Humans Gene Regulatory Networks Interleukin 8 Protein kinase A lcsh:Neurology. Diseases of the nervous system Cells Cultured Caspase 030304 developmental biology Neurons Proinflammatory cytokines 0303 health sciences Microglia biology Research Macrophages General Neuroscience Interleukin-8 virus diseases vpr Gene Products Human Immunodeficiency Virus 3. Good health Cell biology HEK293 Cells medicine.anatomical_structure Neurology biology.protein Virus Inactivation Neuropathogenesis Tumor necrosis factor alpha Inflammation Mediators 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neuroinflammation Journal of Neuroinflammation, Vol 9, Iss 1, p 138 (2012) |
| ISSN: | 1742-2094 |
| DOI: | 10.1186/1742-2094-9-138 |
| Popis: | Background Human immunodeficiency virus type 1 (HIV-1) induces neuronal dysfunction through host cellular factors and viral proteins including viral protein R (Vpr) released from infected macrophages/microglia. Vpr is important for infection of terminally differentiated cells such as macrophages. The objective of this study was to assess the effect of Vpr in the context of infectious virus particles on neuronal death through proinflammatory cytokines released from macrophages. Methods Monocyte-derived macrophages (MDM) were infected with either HIV-1 wild type (HIV-1wt), Vpr deleted mutant (HIV-1∆Vpr) or mock. Cell lysates and culture supernatants from MDMs were analyzed for the expression and release of proinflammatory cytokines by quantitative reverse transcription-PCR and enzyme-linked immunosorbent assay respectively. Mitogen-activated protein kinases (MAPK) were analyzed in activated MDMs by western blots. Further, the effect of Vpr on neuronal apoptosis was examined using primary neurons exposed to culture supernatants from HIV-1wt, HIV-1∆Vpr or mock-infected MDMs by Annexin-V staining, MTT and Caspase - Glo® 3/7 assays. The role of interleukin (IL)-1β, IL-8 and tumor necrosis factor (TNF)-α on neuronal apoptosis was also evaluated in the presence or absence of neutralizing antibodies against these cytokines. Results HIV-1∆Vpr-infected MDMs exhibited reduced infection over time and specifically a significant downregulation of IL-1β, IL-8 and TNF-α at the transcriptional and/or protein levels compared to HIV-1wt-infected cultures. This downregulation was due to impaired activation of p38 and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) in HIV-1∆Vpr-infected MDMs. The association of SAPK/JNK and p38 to IL-1β and IL-8 production was confirmed by blocking MAPKs that prevented the elevation of IL-1β and IL-8 in HIV-1wt more than in HIV-1∆Vpr-infected cultures. Supernatants from HIV-1∆Vpr-infected MDMs containing lower concentrations of IL-1β, IL-8 and TNF-α as well as viral proteins showed a reduced neurotoxicity compared to HIV-1wt-infected MDM supernatants. Reduction of neuronal death in the presence of anti-IL-1β and anti-IL-8 antibodies only in HIV-1wt-infected culture implies that the effect of Vpr on neuronal death is in part mediated through released proinflammatory factors. Conclusion Collectively, these results demonstrate the ability of HIV-1∆Vpr to restrict neuronal apoptosis through dysregulation of multiple proinflammatory cytokines in the infected target cells either directly or indirectly by suppressing viral replication. |
| Databáze: | OpenAIRE |
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