HIV-1 gp120 induces cytokine expression, leukocyte adhesion, and transmigration across the blood-brain barrier: modulatory effects of STAT1 signaling.
How neuroinflammatory activities affect signaling pathways leading to blood-brain barrier (BBB) injury during HIV/AIDS are currently unknown. Our previous work demonstrated that HIV-1 exposure activates pro-inflammatory genes in human brain microvascular endothelial cells (HBMEC) and showed that these genes are linked to the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Here, we report that HIV-1 gp120 protein activated STAT1 and induced interleukin (IL)-6 and IL-8 secretion in HBMEC. IL-6, IL-8, and gp120 increased monocyte adhesion and migration across in vitro BBB models. The STAT1 inhibitor, fludarabine, prevented gp120-induced IL-6 and IL-8 secretion. Inhibitors of STAT1, mitogen activated protein kinase kinase (MEK) (PD98059), and phosphatidyl inositol 3 kinase (PI3K) (LY294002), blocked gp120-induced STAT1 activation and significantly diminished IL-8-, IL-6-, and gp120-induced monocyte adhesion and migration across in vitro BBB models. These data support the notion that STAT1 plays an important role in gp120-induced inflammation and BBB dysfunction associated with viral infection. Results also suggest crosstalk between STAT1, MEK, and PI3K pathways in gp120-induced BBB dysfunction. Inhibition of STAT1 activation could provide a unique therapeutic strategy to decrease neuroinflammation and BBB dysfunction in HIV/AIDS.
Yang
Bo
B
University of Nebraska Medical Center, Department of Pharmacology and Experimental Neuroscience, Center for Neurovirology and Neurodegenerative Disorders, 985215 Nebraska Medical Center, Omaha, Nebraska 68198-5215, USA.
Akhter
Sidra
S
Chaudhuri
Anathbandhu
A
Kanmogne
Georgette D
GD
D015526:AIDS Dementia Complex / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000098:blood supply; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology / Q000821:virology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D055806:Microvessels / Q000473:pathology / Q000821:virology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D008959:Models, Neurological; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
C508606:CXCL8 protein, human; D002867:Chromones; D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D015699:HIV Envelope Protein gp120; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C514793:gp120 protein, Human immunodeficiency virus 1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D020929:Mitogen-Activated Protein Kinase Kinases; D014740:Vidarabine; C024352:fludarabine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one