κ-opioid potentiation of tumor necrosis factor-α-induced anti-HIV-1 activity in acutely infected human brain cell cultures

被引:13
作者
Chao, CC
Gekker, G
Hu, SX
Kravitz, F
Peterson, PK
机构
[1] Minneapolis Med Res Fdn Inc, Inst Brain & Immune Disorders, Minneapolis, MN 55404 USA
[2] Univ Minnesota, Sch Med, Minneapolis, MN 55404 USA
关键词
AIDS; HIV; cytokines; brain cell cultures; neuroimmunology; opioids;
D O I
10.1016/S0006-2952(98)00161-0
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Opioids have been postulated to play an immunomodulatory role in the pathogenesis of HIV-1. Synthetic kappa-opioid receptor (KOR) ligands have been found to inhibit HIV-1 expression in acutely infected microglial cell cultures. We recently found that interleukin(IL)-1 beta and tumor necrosis factor(TNF)-alpha have antiviral effects in acutely infected mixed glial/neuronal cell cultures. In the present study, we investigated whether selective KOR ligands would exert antiviral effects in acutely infected brain cell cultures. While the KOR Ligand trans-3,4-dichloro-N-methyl-N [2-( 1-pyrolidinyl)cyclohexyl]benzeneaceamide methanesulfonate (U50,488) alone had little anti-HIV-1 activity, this opioid potentiated in a concentration-dependent manner the antiviral activity of TNF-alpha, but not of IL-1 beta. The potentiating effect: of U50,488 was detected after a 6-hr pretreatment and peaked at 24 hr. The KOR antagonist nor-binaltorphimine completely blocked the potentiating effect of U50,488, suggesting the involvement of a KOR-mediated mechanism. Antibodies to TNF-alpha completely blocked the potentiating effect of U50,488, suggesting a critical role for TNF-alpha. Antibodies to IL-1 beta blocked the potentiating effect of U50,488, suggesting that IL-1 beta was released following U50,488 treatment, which might contribute to the potentiating effect of U50,488. These in vitro findings support the notion that synthetic kappa-opioids could be considered as potential adjunctive therapeutic agents in HIV-l-related brain disease. BIOCHEM PHARMACOL 56;3:397-404, 1998. (C) 1998 Elsevier Science Inc.
引用
收藏
页码:397 / 404
页数:8
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