Tight junction regulation by morphine and HIV-1 tat modulates blood-brain barrier permeability.
Human immunodeficiency virus (HIV)-1 patients who abuse opiates are at a greater risk of developing neurological complications of AIDS. Alterations in blood-brain barrier (BBB) integrity are associated with cytoskeletal disorganization and disruption of tight junction (TJ) integrity. We hypothesize that opiates in combination with HIV-1 viral proteins can modulate TJ expression in primary brain microvascular endothelial cells (BMVEC), thereby compromising BBB integrity and exacerbating HIV-1 neuropathogenesis. We investigated the effect of morphine and/or tat on the expression of TJ proteins ZO-1, JAM-2, Occludin and P-glycoprotein and the functional effects of TJ modulation in BMVEC. Morphine and/or tat, via the activation of pro-inflammatory cytokines, intracellular Ca(2+) release, and activation of myosin light chain kinase, modulated TJ expression resulting in decreased transendothelial electric resistance and enhanced transendothelial migration across the BBB. These studies may lead to the development of novel anti-HIV-1 therapeutics that target specific TJ proteins, thus preventing TJ disruption in opiate using HIV-1 patients.
Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Buffalo General Hospital, 301 Multi Research Bldg, 100 High Street, Buffalo, NY 14203, USA.
Supriya D
SD
Mahajan
Ravikumar
R
Aalinkeel
Donald E
DE
Sykes
Jessica L
JL
Reynolds
B
B
Bindukumar
Stanley F
SF
Fernandez
Ramnik
R
Chawda
Thomas C
TC
Shanahan
Stanley A
SA
Schwartz
D015526:AIDS Dementia Complex / Q000097:blood / Q000473:pathology / Q000821:virology*; D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000821:virology*; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D018929:Cell Culture Techniques; D016207:Cytokines / Q000378:metabolism; D016257:Fura-2; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009020:Morphine / Q000097:blood / Q000494:pharmacology*; D019966:Substance-Related Disorders; D019108:Tight Junctions / Q000187:drug effects* / Q000473:pathology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000097:blood / Q000494:pharmacology*
D016207:Cytokines; D054322:tat Gene Products, Human Immunodeficiency Virus; D009020:Morphine; D016257:Fura-2