Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.
A critical role of nitric oxide in human immunodeficiency virus type 1-induced hyperresponsiveness of cultured monocytes.
Mol Med. 1996 Jul;2(4):460-8. Unique Identifier : AIDSLINE MED/96425273 Bukrinsky M; Schmidtmayerova H; Zybarth G; Dubrovsky L; Sherry B; Enikolopov G; Picower Institute for Medical Research, Manhasset, New York.
Abstract:
BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infection leads to a general exhaustion of the immune system. Prior to this widespread decline of immune functions, however, there is an evident hyperactivation of the monocyte/macrophage arm. Increased levels of cytokines and other biologically active molecules produced by activated monocytes may contribute to the pathogenesis of HIV disease both by activating expression of HIV-1 provirus and by direct effects on cytokine-sensitive tissues, such as lung or brain. In this article, we investigate mechanisms of hyperresponsiveness of HIV-infected monocytes. MATERIALS AND METHODS: The study was performed on monocyte cultures infected in vitro with a monocytetropic strain HIV-1ADA. Cytokine production was induced by stimulation of cultures with lipopolysaccharides (LPS) and measured by ELISA. To study involvement of nitric oxide (NO) in the regulation of cytokine expression, inhibitors of nitric oxide synthase (NOS) or chemical donors of NO were used. RESULTS: We demonstrate that infection with HIV-1 in vitro primes human monocytes for subsequent activation with LPS, resulting in increased production of pro-inflammatory cytokines tumor necrosis factor (TNF) and interleukin 6 (IL-6). This priming effect can be blocked by Ca(2+)-chelating agents and by the NOS inhibitor L-NMMA, but not by hemoglobin. It could be reproduced on uninfected monocyte cultures by using donors of NO, but not cGMP, together with LPS. CONCLUSIONS: NO, which is expressed in HIV-1-infected monocyte cultures, induces hyperresponsiveness of monocytes by synergizing with calcium signals activated in response to LPS stimulation. This activation is cGMP independent. Our findings demonstrate the critical role of NO in HIV-1-specific hyperactivation of monocytes.
Keywords: omega-N-Methylarginine/PHARMACOLOGY Calcium/METABOLISM Chelating Agents/PHARMACOLOGY Cyclic GMP/METABOLISM Egtazic Acid/ANALOGS & DERIVATIVES/PHARMACOLOGY Enzyme Inhibitors/PHARMACOLOGY Enzyme-Linked Immunosorbent Assay Human *HIV-1 Interleukin-6/METABOLISM Lipopolysaccharides/PHARMACOLOGY Monocytes/*VIROLOGY Nitric Oxide/*ANALYSIS Nitric-Oxide Synthase/ANTAGONISTS & INHIB Support, Non-U.S. Gov't Tumor Necrosis Factor/METABOLISM JOURNAL ARTICLE 970228
M9721917
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Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.
