Limited role of COX-2 in HIV Tat-induced alterations of tight junction protein expression and disruption of the blood-brain barrier.
Tat protein released from HIV-infected blood-borne leukocytes can contribute to the breakdown of the blood-brain barrier (BBB) and induction of inflammatory responses and can provide entry for HIV into the brain. To mimic this pathology, Tat was injected into the tail vein of C57BL/6 mice. Treatment with Tat markedly upregulated expression of cyclooxygenase-2 (COX-2) and decreased expression of tight junction proteins, occludin and zonula occludens-1 (ZO-1). These alterations were associated with the disruption of the BBB integrity as quantified by extravasation of Evans blue dye into the brain tissue. In addition, direct treatment of brain microvessels with prostaglandin E(2), a product of COX-2 activity, resulted in decreased expression of both occludin and ZO-1. To determine if upregulation of COX-2 is involved in the disruption of tight junction proteins and BBB integrity, mice were pretreated with rofecoxib, a specific inhibitor of COX-2, prior to Tat treatment. COX-2 inhibition attenuated Tat-induced alterations of occludin expression. However, rofecoxib was ineffective in preventing downregulation of ZO-1 expression and increased BBB permeability. These results suggest only a limited role of COX-2 overexpression in the loss of tight junction integrity and the BBB breakdown in HIV-related brain diseases.
Pu
Hong
H
Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky, Lexington, KY 40536, USA.
Hayashi
Kentaro
K
Andras
Ibolya E
IE
Eum
Sung Yong
SY
Hennig
Bernhard
B
Toborek
Michal
M
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007783:Lactones / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D062793:Occludin; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D062826:Zonula Occludens-1 Protein; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007783:Lactones; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D013450:Sulfones; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D054322:tat Gene Products, Human Immunodeficiency Virus; C470431:tat peptide (1-72), Human immunodeficiency virus 1; C116926:rofecoxib; D051546:Cyclooxygenase 2; D015232:Dinoprostone