Human immunodeficiency virus type 1 Tat and methamphetamine affect the release and activation of matrix-degrading proteinases.
Human immunodeficiency virus (HIV) dementia (HIVD) is associated with an increase in the number of activated monocytes within the central nervous system (CNS), a pathological feature that may be more remarkable in the setting of superimposed substance abuse. Monocytes may transport HIV to the brain, and, moreover, activated and/or infected monocytes have been shown to release a number of potent neurotoxins. Although the mechanisms responsible for the increase in the CNS ingress of monocytes are multiple, blood-brain barrier (BBB)-degrading matrix metalloproteinases (MMPs) are likely to play an important role. The current study investigates the effects of the HIV-1-encoded protein Tat, and the drug of abuse methamphetamine, on MMP release from brain derived cells. The release of urokinase plasminogen activator (uPA), an activator of MMPs, was also investigated. Mixed human neuron/astrocyte cultures were stimulated with Tat or methamphetamine, and supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA) and/or gelatin substrate zymography. Results showed that Tat and methamphetamine increased the release of MMP-1 from these cultures. Tat also increased supernatant levels of active MMP-2. In addition, both Tat and methamphetamine stimulated the release of the MMP activator uPA, and in a manner that was sensitive to inhibition with pertussis toxin. Together, these results suggest that in HIVD, Tat and methamphetamine may contribute to CNS inflammation by stimulating increased release and/or activation of matrix-degrading proteinases through mechanisms that include Gi/Go-coupled signaling. These results also suggest a potential mechanism for acceleration of HIVD with methamphetamine use.
Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA. kconant@mail.jhmi.edu
Katherine
K
Conant
Coryse
C
St Hillaire
Caroline
C
Anderson
David
D
Galey
Jessica
J
Wang
Avindra
A
Nath
D015526:AIDS Dementia Complex / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D015696:Gene Products, tat / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020782:Matrix Metalloproteinases / Q000187:drug effects* / Q000378:metabolism; D008694:Methamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000187:drug effects / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D000697:Central Nervous System Stimulants; D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus; D008694:Methamphetamine; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases