Document Detail

Activation of p38 MAPK is required in monocytic and neuronal cells for HIV glycoprotein 120-induced neurotoxicity.
MedLine Citation:
PMID:  20855878     Owner:  NLM     Status:  MEDLINE    
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.
Kathryn E Medders; Natalia E Sejbuk; Ricky Maung; Maya K Desai; Marcus Kaul
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-09-20
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  185     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-06     Completed Date:  2010-11-04     Revised Date:  2013-12-19    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4883-95     Citation Subset:  AIM; IM    
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MeSH Terms
Cells, Cultured
Enzyme Activation / physiology
Fluorescent Antibody Technique
HIV Envelope Protein gp120 / metabolism*
Monocytes / metabolism*
Neurons / metabolism*
Neurotoxins / biosynthesis*
Rats, Sprague-Dawley
Signal Transduction / physiology
p38 Mitogen-Activated Protein Kinases / metabolism*
Grant Support
Reg. No./Substance:
0/HIV Envelope Protein gp120; 0/Neurotoxins; 0/gp120 protein, Human immunodeficiency virus 1; EC Mitogen-Activated Protein Kinases

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