title: Nox2-based NADPH oxidase mediates HIV-1 Tat-induced up-regulation of VCAM-1/ICAM-1 and subsequent monocyte adhesion in human astrocytes.
abstract: Up-regulation of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by the HIV-1 transactivator of transcription (Tat) in activated microglia and astrocytes may play a pivotal role during the development of AIDS-related encephalitis and dementia. Previous studies demonstrated that HIV-1 Tat-induced up-regulation of adhesion molecules was mediated by reactive oxygen species (ROS), although the mechanisms underlying HIV-1 Tat-induced ROS generation are unknown. In this study, we examined the possible role of NADPH oxidase in HIV-1 Tat-induced up-regulation of adhesion molecules in astroglioma cell lines. HIV-1 Tat-induced up-regulation of VCAM-1/ICAM-1 and subsequent increased adhesion of monocytes to astrocytes were blocked by a general NADPH oxidase inhibitor, diphenylene iodonium, and a specific inhibitor of NADPH oxidase assembly, 9R3A-gp91ds. Nox2 knockdown using small interfering RNA (siRNA) inhibited HIV-1 Tat-induced up-regulation of adhesion molecules and subsequent increased adhesion of monocytes to astrocytes. Nox2 siRNA blocked HIV-1 Tat-induced ROS production, increase in NADPH oxidase activity, and Rac1 activation. Furthermore, Nox2 siRNA decreased HIV-1 Tat-induced NF-κB activation as well as activation of MAP kinases including ERK, JNK, and p38. These data indicate that Nox2-based NADPH oxidase is responsible for HIV-1 Tat-induced generation of ROS and plays an important role in the up-regulation of adhesion molecules such as VCAM-1/ICAM-1 and subsequent increased adhesion of monocytes to astrocytes and serves as a novel target for HIV-1 Tat-mediated neurological diseases.
authors.affiliation: Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Ha Yong
authors.initials: HY
authors.lastname: Song
authors.forename: Sung Mi
authors.initials: SM
authors.lastname: Ju
authors.forename: Won Yong
authors.initials: WY
authors.lastname: Seo
authors.forename: Ah Ra
authors.initials: AR
authors.lastname: Goh
authors.forename: Jin-Koo
authors.initials: JK
authors.lastname: Lee
authors.forename: Yong Soo
authors.initials: YS
authors.lastname: Bae
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Jinseu
authors.initials: J
authors.lastname: Park
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000502:physiology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009000:Monocytes / Q000276:immunology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009861:Onium Compounds / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D009861:Onium Compounds; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D054322:tat Gene Products, Human Immunodeficiency Virus; D018799:Intercellular Adhesion Molecule-1; C007517:diphenyleneiodonium; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases