U50,488 inhibits HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2) production by human astrocytes

Wen Sheng, Shuxian Hu, James R Lokensgard, Phillip K. Peterson

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

κ-Opioid receptor (KOR) ligands have been reported to alter many cell functions and to exert an immunomodulatory role in the CNS. Astrocytes, the predominant brain cell type, have been implicated in the neuropathogenesis of human immunodeficiency virus type 1 (HIV-1). HIV-1 nuclear protein Tat has been reported to induce production of the chemokine monocyte chemoattractant protein-1 (MCP-1 or CCL2) and to activate nuclear factor κB (NF-κB) in human astrocytes. In the present study, we investigated whether the synthetic KOR ligand trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl]benzeneacetamide methanesulfonate (U50,488) would down-regulate MCP-1 production in primary human astrocytes stimulated by Tat. Treatment of astrocytes with U50,488 inhibited Tat-induced MCP-1 production in a concentration-dependent manner. The KOR-selective antagonist nor-binaltrophimine (nor-BNI) completely blocked the inhibitory effect of U50,488, indicating involvement of KOR. While U50,488 alone had a partial inhibitory effect on constituent NF-κB activation, it potently suppressed Tat-induced NF-κB activation. These findings suggest that KOR ligands could have an anti-inflammatory effect in the CNS and thereby be beneficial in the treatment of HIV-1-associated brain disease.

Original languageEnglish (US)
Pages (from-to)9-14
Number of pages6
JournalBiochemical Pharmacology
Volume65
Issue number1
DOIs
StatePublished - Jan 1 2003

Bibliographical note

Funding Information:
This study was supported by U.S. Public Health Service Grant DA09924.

Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.

Keywords

  • Astrocytes
  • MCP-1
  • Tat
  • U50,488
  • κ-Opioid receptor

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