Pro-inflammatory and pro-oxidant properties of the HIV protein Tat in a microglial cell line: attenuation by 17 beta-estradiol.
Microglia are activated in humans following infection with human immunodeficiency virus (HIV), and brain inflammation is thought to be involved in neuronal injury and dysfunction during HIV infection. Numerous studies indicate a role for the HIV regulatory protein Tat in HIV-related inflammatory and neurodegenerative processes, although the specific effects of Tat on microglial activation, and the signal transduction mechanisms thereof, have not been elucidated. In the present study, we document the effects of Tat on microglial activation and characterize the signal transduction pathways responsible for Tat's pro-inflammatory effects. Application of Tat to N9 microglial cells increased multiple parameters of microglial activation, including superoxide production, phagocytosis, nitric oxide release and TNF alpha release. Tat also caused activation of both p42/p44 mitogen activated protein kinase (MAPK) and NF kappa B pathways. Inhibitor studies revealed that Tat-induced NF kappa B activation was responsible for increased nitrite release, while MAPK activation mediated superoxide release, TNF alpha release, and phagocytosis. Lastly, pre-treatment of microglial cells with physiological concentrations of 17 beta-estradiol suppressed Tat-mediated microglial activation by interfering with Tat-induced MAPK activation. Together, these data elucidate specific components of the microglial response to Tat and suggest that Tat could contribute to the neuropathology associated with HIV infection through microglial promulgation of oxidative stress.
Bruce-Keller
A J
AJ
Department of Anatomy, University of Kentucky, Lexington, Kentucky, USA. abruce@pop.uky.edu
Barger
S W
SW
Moss
N I
NI
Pham
J T
JT
Keller
J N
JN
Nath
A
A
D000818:Animals; D002460:Cell Line; D004958:Estradiol / Q000494:pharmacology*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D016877:Oxidants / Q000494:pharmacology*; D015398:Signal Transduction
D015696:Gene Products, tat; D018836:Inflammation Mediators; D016328:NF-kappa B; D016877:Oxidants; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases