Inhibition of p38 MAPK activity in mononuclear phagocytes abrogates HIV gp120-induced neurotoxicity while triggering expression of numerous anti-viral and cytoprotective factors. (105.42)

• Published in: The Journal of immunology (1950) Vol. 186; no. 1_Supplement; pp. 105 - 105.42
• Main Authors: Kaul, Marcus, Sejbuk, Natalia, Maung, Ricky, Medders, Kathryn
• Format: Journal Article
• Language: English
• Published: 01.04.2011
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.186.Supp.105.42

Macrophages produce neurotoxins upon infection with HIV-1 or exposure to its envelope protein gp120. Both stimuli lead to activation of p38 mitogen-activated protein kinase (MAPK). In order to study the basis for the neurotoxic phenotype of monocytic cells that is initiated by HIV/gp120 and prevented by inhibition of p38 MAPK, we performed a genome-wide gene expression analysis. We treated monocytic THP-1 cells for 4 h or 24 hr with HIV gp120 (1 nM) in the presence or absence of the p38 MAPK inhibitor (SB203580; 10 μM) and subsequently isolated RNA. Microarray analysis indicated that HIVgp120 moderately affected gene expression in comparison to the p38 MAPK inhibitor. Blocking p38 MAPK suppressed some cytokines but, surprisingly, also significantly increased others, such as CCL3, CCL4 and CCL5, all of which have anti-HIV activity and protect against gp120 neurotoxicity. Using a multiplex protein array, we confirmed expression changes for thirteen cytokines. Thus, p38 MAPK signaling is critical for the neurotoxicity of HIVgp120-exposed monocytic cells but only moderately alters gene expression. In contrast, inhibition of p38 MAPK substantially changes gene and protein expression, including increases in potentially neuroprotective chemokines. Thus, inhibition of p38 MAPK may not only protect from HIVgp120-induced neurotoxicity of mononuclear phagocytes by interrupting toxic signaling pathways but also by inducing an array of potentially cytoprotective factors.