TY - JOUR
T1 - HIV-1 tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain
AU - Pu, Hong
AU - Tian, Jing
AU - Flora, Govinder
AU - Lee, Yong Woo
AU - Nath, Avindra
AU - Hennig, Bernhard
AU - Toborek, Michal
N1 - Funding Information:
This work was supported by NIH Grants NS39254, MH63022, and AA013843.
PY - 2003/9/1
Y1 - 2003/9/1
N2 - Impaired inflammatory functions may be critical factors in the mechanisms by which HIV-1 enters the CNS. Evidence indicates that a viral gene product, the protein Tat, can markedly contribute to these effects. In the present study we tested the hypothesis that Tat can upregulate the expression of inflammatory cytokines and adhesion molecules and facilitate the entry of monocytes into the brain. Expression of inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) was assessed in C57BL/6 mice injected with Tat1-72 into the right hippocampus. In the Tat1-72-injected groups, mRNA and protein levels of MCP-1, TNF-α, VCAM-1, and ICAM-1 were markedly elevated compared to those in control animals. The most pronounced changes were observed in and around the injected hippocampus. Double-labeling immunohistochemistry demonstrated that inflammatory proteins were primarily expressed in activated microglial cells and perivascular cells. In addition, astrocytes and endothelial cells were susceptible to Tat1-72-induced inflammatory responses. These changes were associated with a substantial infiltration of monocytes into the brain. These data demonstrate that intracerebral administration of Tat can induce profound proinflammatory effects in the brain, leading to monocyte infiltration.
AB - Impaired inflammatory functions may be critical factors in the mechanisms by which HIV-1 enters the CNS. Evidence indicates that a viral gene product, the protein Tat, can markedly contribute to these effects. In the present study we tested the hypothesis that Tat can upregulate the expression of inflammatory cytokines and adhesion molecules and facilitate the entry of monocytes into the brain. Expression of inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) was assessed in C57BL/6 mice injected with Tat1-72 into the right hippocampus. In the Tat1-72-injected groups, mRNA and protein levels of MCP-1, TNF-α, VCAM-1, and ICAM-1 were markedly elevated compared to those in control animals. The most pronounced changes were observed in and around the injected hippocampus. Double-labeling immunohistochemistry demonstrated that inflammatory proteins were primarily expressed in activated microglial cells and perivascular cells. In addition, astrocytes and endothelial cells were susceptible to Tat1-72-induced inflammatory responses. These changes were associated with a substantial infiltration of monocytes into the brain. These data demonstrate that intracerebral administration of Tat can induce profound proinflammatory effects in the brain, leading to monocyte infiltration.
KW - Blood-brain barrier
KW - Brain endothelium
KW - HIV
KW - Inflammatory responses
KW - NeuroAIDS
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U2 - 10.1016/S1044-7431(03)00171-4
DO - 10.1016/S1044-7431(03)00171-4
M3 - Article
C2 - 14550782
AN - SCOPUS:0141726832
SN - 1044-7431
VL - 24
SP - 224
EP - 237
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
IS - 1
ER -