title: U50,488 inhibits HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2) production by human astrocytes.
abstract: Kappa-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 kappaB (NF-kappaB) 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-kappaB activation, it potently suppressed Tat-induced NF-kappaB 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.
authors.affiliation: Neuroimmunology Laboratory, Minneapolis Medical Research Foundation, 914 South 8th Street, Minneapolis, MN 55404, USA. wsheng@cbs.umn.edu
authors.forename: Wen S
authors.initials: WS
authors.lastname: Sheng
authors.forename: Shuxian
authors.initials: S
authors.lastname: Hu
authors.forename: James R
authors.initials: JR
authors.lastname: Lokensgard
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Peterson
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D004347:Drug Interactions; D015696:Gene Products, tat / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D018712:Analgesics, Non-Narcotic; D018932:Chemokine CCL2; D015696:Gene Products, tat; D016328:NF-kappa B; D009292:Narcotic Antagonists; D054322:tat Gene Products, Human Immunodeficiency Virus; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer