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Cross‐talk between STAT1 and PI3K/AKT signaling in HIV‐1‐induced blood–brain barrier dysfunction: Role of CCR5 and implications for viral neuropathogenesis
Author(s) -
Yang Bo,
Singh Sangya,
Bressani Rafael,
Kanmogne Georgette D.
Publication year - 2010
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.22458
Subject(s) - protein kinase b , phosphorylation , stat1 , biology , pi3k/akt/mtor pathway , signal transduction , stat3 , microbiology and biotechnology , janus kinase , kinase , cancer research
Abstract 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. © 2010 Wiley‐Liss, Inc.