Inhibition of long-term potentiation by interleukin-8: implications for human immunodeficiency virus-1-associated dementia.
Human immunodeficiency virus type 1 (HIV-1)-infected mononuclear phagocytes (MP; brain macrophages and microglia) secrete a number of toxic factors that affect the pathogenesis of HIV-1-associated dementia (HAD). The identification and relative role of each MP toxin for neuronal dysfunction during HAD are not well understood. Interleukin-8 (IL-8), a CXC chemokine involved in leukocyte activation and chemotaxis, is constitutively produced by MP, and elevated levels of IL-8 mRNA were detected in the brains of patients with HIV-1 encephalitis (HIVE) by both ribonuclease protection assays and real-time PCR. To determine the role that IL-8 might play in the neuronal dysfunction in HAD, we studied its effect on synaptic transmission and plasticity in the CA1 region of hippocampus, the seat of learning and memory. Bath application of IL-8 (50 ng/ml) to rat hippocampal slices had no effect on basal synaptic transmission. However, IL-8 was shown to inhibit long-term potentiation (LTP) in a concentration-dependent manner. In control and IL-8-treated slices, the LTP magnitudes were 167.8% +/- 11.9% (mean +/- SE; n = 17) and 122.2% +/- 16.2% of basal levels (n = 13), respectively. These differences were statistically significant (P < 0.05). Preincubation of hippocampal slices with a monoclonal CXCR2 antibody (2 microg/ml) but not control IgG (2 microg/ml) blocked IL-8-induced inhibition of LTP. The expression of CXCR2 receptors in the CA1 region was shown by Western blot assays. The induction of IL-8 in HAD, its inhibition of LTP, and the expression of its receptor, CXCR2, in the hippocampus all suggest that it plays a role in the cognitive dysfunction associated with HAD.
Xiong
Huangui
H
The Laboratory of Neurophysiology, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5215, USA. hxiong@unmc.edu
Boyle
Jeffery
J
Winkelbauer
Matthew
M
Gorantla
Santhi
S
Zheng
Jialin
J
Ghorpade
Anuja
A
Persidsky
Yuri
Y
Carlson
Kimberly A
KA
Gendelman
Howard E
HE
D015526:AIDS Dementia Complex / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000096:biosynthesis / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D016209:Interleukin-8