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Insulin‐like growth factor‐I–forkhead box O transcription factor 3a counteracts high glucose/tumor necrosis factor‐α‐mediated neuronal damage: Implications for human immunodeficiency virus encephalitis
Author(s) -
Wilk Anna,
Urbanska Katarzyna,
Yang Shuo,
Ying Wang Jin,
Amini Shohreh,
Del Valle Luis,
Peruzzi Francesca,
Meggs Leonard,
Reiss Krzysztof
Publication year - 2011
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22542
Subject(s) - biology , transcription factor , tumor necrosis factor alpha , foxo1 , apoptosis , insulin resistance , cancer research , endocrinology , insulin like growth factor , growth factor , microbiology and biotechnology , medicine , insulin , receptor , gene , biochemistry
In HIV patients, antiretroviral medications trigger metabolic abnormalities, including insulin resistance. In addition, the inflammatory cytokine tumor necrosis factor‐α (TNFα), which is elevated in human immunodeficiency virus encephalitis (HIVE), also induces insulin resistance and inflicts neuronal damage in vitro. In differentiated PC12 cells and rat cortical neurons, high glucose (HG; 25 mM) triggers reactive oxygen species (ROS) accumulation, contributing to the retraction of neuronal processes, with only a minimal involvement of neuronal apoptosis. In the presence of TNFα, HG‐treated neurons undergo massive apoptosis. Because mammalian homolog of the Forkhead family of transcription factors, Forkhead box O transcription factor 3a (FOXO3a), controls ROS metabolism, we asked whether FOXO3a could affect the fate of differentiated neurons in the paradigm of HIVE. We observed FOXO3a nuclear translocation in HG‐treated neuronal cultures, accompanied by partial loss of mitochondrial potential and gradual retraction of neuronal processes. Addition of TNFα to HG‐treated neurons increased expression of the FOXO‐dependent proapoptotic gene Bim, which resulted in extensive apoptotic death. Insulin‐like growth factor‐I (IGF‐I) significantly lowered intracellular ROS, which was accompanied by IGF‐I‐mediated FOXO3a nuclear export and decrease in its transcriptional activity. The clinical relevance of these findings is supported by detection of nuclear FOXO3a in TUNEL‐positive cortical neurons from HIVE, especially in brain areas characterized by elevated TNFα. © 2010 Wiley‐Liss, Inc.