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Journal of Virology, October 2000, p. 9214-9221, Vol. 74, No. 19
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Induction of the Chemokines Interleukin-8 and IP-10 by Human Immunodeficiency Virus Type 1 Tat in Astrocytes

O. Kutsch,1 J.-W. Oh,1 A. Nath,2 and E. N. Benveniste1,*

Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, Alabama,1 and Department of Neurology, University of Kentucky, Lexington, Kentucky2

Received 9 May 2000/Accepted 14 July 2000

A finding commonly observed in human immunodeficiency virus type 1 (HIV-1)-infected patients is invasion of the brain by activated T cells and infected macrophages, eventually leading to the development of neurological disorders and HIV-1-associated dementia. The recruitment of T cells and macrophages into the brain is likely the result of chemokine expression. Indeed, earlier studies revealed that levels of different chemokines were increased in the cerebrospinal fluid of HIV-1-infected patients whereas possible triggers and cellular sources for chemokine expression in the brain remain widely undefined. As previous studies indicated that HIV-1 Tat, the retroviral transactivator, is capable of inducing a variety of cellular genes, we investigated its capacity to induce production of chemokines in astrocytes. Herein, we demonstrate that HIV-1 Tat72aa is a potent inducer of MCP-1, interleukin-8 (IL-8), and IP-10 expression in astrocytes. Levels of induced IP-10 protein were sufficiently high to induce chemotaxis of peripheral blood lymphocytes. In addition, Tat72aa induced IL-8 expression in astrocytes. IL-8 mRNA induction was seen less then 1 h after Tat72aa stimulation, and levels remained elevated for up to 24 h, leading to IL-8 protein production. Tat72aa-mediated MCP-1 and IL-8 mRNA induction was susceptible to inhibition by the MEK1/2 inhibitor UO126 but was only modestly decreased by the inclusion of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190. In contrast, Tat-mediated IP-10 mRNA induction was suppressed by SB202190 but not by the MEK1/2 inhibitor UO126. These findings indicate that MAPKs play a major role in Tat72aa-mediated chemokine induction in astrocytes.

* Corresponding author. Mailing address: Department of Cell Biology, 350 MCLM, The University of Alabama at Birmingham, 1918 University Blvd., Birmingham, AL 35294-0005. Phone: (205) 934-7667. Fax: (205) 975-6748. E-mail: tika{at}uab.edu.

Journal of Virology, October 2000, p. 9214-9221, Vol. 74, No. 19
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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