Activation of p38 MAPK Is Required in Monocytic and Neuronal Cells for HIV Glycoprotein 120-Induced Neurotoxicity
| Autor: | Ricky Maung, Marcus Kaul, Maya K. Desai, Natalia E. Sejbuk, Kathryn E. Medders |
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| Rok vydání: | 2010 |
| Předmět: |
Cell type
p38 mitogen-activated protein kinases Immunoblotting Neurotoxins Immunology Fluorescent Antibody Technique HIV Envelope Protein gp120 Biology p38 Mitogen-Activated Protein Kinases Monocytes Article Rats Sprague-Dawley medicine Animals Humans Immunology and Allergy Neurotoxin Cells Cultured Neurons Microglia Kinase Neurotoxicity virus diseases medicine.disease Rats Cell biology Enzyme Activation medicine.anatomical_structure nervous system Cell culture Signal transduction Signal Transduction |
| Zdroj: | The Journal of Immunology. 185:4883-4895 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.0902535 |
| Popis: | HIV-1 envelope protein gp120 has been implicated in neurotoxin production by monocytic cells (i.e., macrophages and microglia), as well as in the pathogenesis of HIV-1–associated neurocognitive disorders. We previously showed in cerebrocortical cell cultures from rodents containing microglia, astrocytes, and neurons that overall inhibition of p38 MAPK signaling abrogated the neurotoxic effect of HIV-1 gp120. However, the time course of p38 MAPK activation and the contribution of this kinase in the various cell types remained unknown. In this study, we found that active p38 MAPK is required in monocytic lineage cells (i.e., macrophages and microglia) and neuronal cells for HIV gp120-induced neurotoxicity to occur. In cerebrocortical cell cultures, HIV-1 gp120 stimulated a time-dependent overall increase in active p38 MAPK, and the activated kinase was primarily detected in microglia and neurons. Interestingly, increased activation of p38 MAPK and neuronal death in response to gp120 were prevented by prior depletion of microglia or the presence of CCR5 ligand CCL4 or p38 MAPK inhibitors. In human monocytic THP-1 cells and primary monocyte-derived macrophages, HIV gp120-stimulated production of neurotoxins was abrogated by prior introduction into the cells of a dominant-negative p38 MAPK mutant or p38 MAPK small interfering RNA. In addition, the neurotoxic effects of cell-free supernatants from gp120-stimulated monocytic THP-1 cells were prevented in microglia-depleted cerebrocortical cells pretreated with a pharmacological inhibitor of p38 MAPK. Thus, p38 MAPK signaling was critical, upon exposure to HIV gp120, for the neurotoxic phenotype of monocytic cells and subsequent toxin-initiated neuronal apoptosis. |
| Databáze: | OpenAIRE |
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