Cooperative induction of CXCL10 involves NADPH oxidase: Implications for HIV dementia.
With the increasing prevalence of HIV-associated neurocognititve disorders (HAND), understanding the mechanisms by which HIV-1 induces neuro-inflammation and subsequent neuronal damage is important. The hallmark features of HIV-encephalitis, the pathological correlate of HIV-associated Dementia (HAD), are gliosis, oxidative stress, chemokine dysregulation, and neuronal damage/death. Since neurons are not infected by HIV-1, the current thinking is that these cells are damaged indirectly by pro-inflammatory chemokines released by activated glial cells. CXCL10 is a neurotoxic chemokine that is upregulated in astroglia activated by HIV-1 Tat, IFN-gamma, and TNF-alpha. In this study we have demonstrated that HIV-1 Tat increases CXCL10 expression in IFN-gamma and TNF-alpha stimulated human astrocytes via NADPH oxidase. We have shown that the treatment of astrocytes with a mixture of Tat and cytokines leads to a respiratory burst that is abrogated by apocynin, an NADPH oxidase inhibitor. Pretreatment of Tat, IFN-gamma, and TNF-alpha stimulated astrocytes with apocynin also resulted in concomitant inhibition of CXCL10 expression. Additionally, apocynin was also able to reduce Tat and cytokine-mediated activation of the corresponding signaling molecules Erk1/2, Jnk, and Akt with a decrease in activation and nuclear translocation of NF-kappaB, important regulators of CXCL10 induction. Understanding the mechanisms involved in reducing both oxidative stress and the release of pro-inflammatory agents could lead to the development of therapeutics aimed at decreasing neuro-inflammation in patients suffering from HAD.
Williams
Rachel
R
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Yao
Honghong
H
Peng
Fuwang
F
Yang
Yanjing
Y
Bethel-Brown
Crystal
C
Buch
Shilpa
S
D000098:Acetophenones / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002461:Cell Line, Transformed; D054357:Chemokine CXCL10 / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
D000098:Acetophenones; D054357:Chemokine CXCL10; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma; C056165:acetovanillone; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases