Cross-talk between STAT1 and PI3K/AKT signaling in HIV-1-induced blood-brain barrier dysfunction: role of CCR5 and implications for viral neuropathogenesis.
How neuroinflammation affects signaling pathways leading to human blood-brain barrier (BBB) dysfunction during HIV-1 infection is incompletely understood. We previously demonstrated that signal transducers and activators of transcription-1 (STAT1) signaling is involved in HIV-1 induced BBB damage and is relevant to viral neuropathogenesis. The objective of this study was to delineate the signaling pathways upstream and downstream of STAT1 involved in HIV-1-induced endothelial dysfunction. We show that HIV-1 activation of STAT1 and STAT3 in human brain microvascular endothelial cells (HBMEC) is associated with induction of promoter activity of the interferon-stimulated response element (ISRE)/interferon-γ-activated sequence (GAS). The STAT1 inhibitor fludarabine diminished HIV-1-induced ISRE/GAS promoter activity. CCR5 neutralizing antibodies and the phosphoinositide-3-kinase (PI3K) inhibitor LY-294002 diminished HIV-1-induced phosphorylation of STAT1 and STAT3, significantly diminished HIV-1-induced ISRE/GAS promoter activity, and diminished virus-induced monocyte adhesion and transendothelial migration. HIV-1 infection did not phosphorylate janus kinases but induced activation of the phosphoinositide-dependent kinase-1 (PDK1) and the serine-threonine protein kinase AKT, both downstream effectors of PI3K. CCR5 antibodies also diminished virus-induced phosphorylation ofPDK1 and AKT. These results suggest that the chemokine receptor CCR5 is partially involved in HIV-1 binding to HBMEC and show cross-talk between STAT1 and PI3K pathways in HIV-1-induced BBB dysfunction.
Yang
Bo
B
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nerbraska, USA.
Singh
Sangya
S
Bressani
Rafael
R
Kanmogne
Georgette D
GD
D015526:AIDS Dementia Complex / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000503:physiopathology / Q000821:virology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D020239:Receptor Cross-Talk / Q000502:physiology; D019713:Receptors, CCR5 / Q000502:physiology*; D020218:Response Elements / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D019713:Receptors, CCR5; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt