Inhibition of telomerase activity alters tight junction protein expression and induces transendothelial migration of HIV-1-infected cells.
Telomerase, via its catalytic component telomerase reverse transcriptase (TERT), extends telomeres of eukaryotic chromosomes. The importance of this reaction is related to the fact that telomere shortening is a rate-limiting mechanism for human life span that induces cell senescence and contributes to the development of age-related pathologies. The aim of the present study was to evaluate whether the modulation of telomerase activity can influence human immunodeficiency virus type 1 (HIV-1)-mediated dysfunction of human brain endothelial cells (hCMEC/D3 cells) and transendothelial migration of HIV-1-infected cells. Telomerase activity was modulated in hCMEC/D3 cells via small interfering RNA-targeting human TERT (hTERT) or by using a specific pharmacological inhibitor of telomerase, TAG-6. The inhibition of hTERT resulted in the upregulation of HIV-1-induced overexpression of intercellular adhesion molecule-1 via the nuclear factor-kappaB-regulated mechanism and induced the transendothelial migration of HIV-1-infected monocytic U937 cells. In addition, the blocking of hTERT activity potentiated a HIV-induced downregulation of the expression of tight junction proteins. These results were confirmed in TERT-deficient mice injected with HIV-1-specific protein Tat into the cerebral vasculature. Further studies revealed that the upregulation of matrix metalloproteinase-9 is the underlying mechanisms of disruption of tight junction proteins in hCMEC/D3 cells with inhibited TERT and exposed to HIV-1. These results indicate that the senescence of brain endothelial cells may predispose to the HIV-induced upregulation of inflammatory mediators and the disruption of the barrier function at the level of the brain endothelium.
Dept. of Neurosurgery, Univ. of Kentucky, Lexington, 40536, USA.
Wen
W
Huang
Geun Bae
GB
Rha
Lei
L
Chen
Melissa J
MJ
Seelbach
Bei
B
Zhang
Ibolya E
IE
András
Dennis
D
Bruemmer
Bernhard
B
Hennig
Michal
M
Toborek
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D062507:Claudin-5; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D005260:Female; D020868:Gene Silencing; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000302:isolation & purification*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism*; D020298:U937 Cells; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology
C107466:CLDN5 protein, human; D062507:Claudin-5; D008565:Membrane Proteins; D016328:NF-kappa B; D054322:tat Gene Products, Human Immunodeficiency Virus; D018799:Intercellular Adhesion Molecule-1; D019098:Telomerase; D020780:Matrix Metalloproteinase 9