Proinflammatory cytokines and HIV-1 synergistically enhance CXCL10 expression in human astrocytes

Rachel Williams, Navneet K. Dhillon, Sonia T. Hegde, Hong Hong Yao, Fuwang Peng, Shannon Callen, Yahia Chebloune, Randall L. Davis, Shilpa J. Buch

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

HIV encephalitis (HIVE), the pathologic correlate of HIV-associated dementia (HAD) is characterized by astrogliosis, cytokine/chemokine dysregulation, and neuronal degeneration. Increasing evidence suggests that inflammation is actively involved in the pathogenesis of HAD. In fact, the severity of HADMIVE correlates more closely with the presence of activated glial cells than with the presence and amount of HIV-infected cells in the brain. Astrocytes, the most numerous cell type within the brain, provide an important reservoir for the generation of inflammatory mediators, including interferon-γ inducible peptide-10 (CXCL10), a neurotoxin and a chemoattractant, implicated in the pathophysiology of HAD. Additionally, the proinflammatory cytokines, IFN-γ and TNF-α, are also markedly increased in CNS tissues during HIV-1 infection. In this study, we hypothesized that the interplay of host cytokines and HIV-1 could lead to enhanced expression of the toxic chemokine, CXCL10. Our findings demonstrate a synergistic induction of CXCL10 mRNA and protein in human astrocytes exposed to HIV-1 and the proinflammatory cytokines. Signaling molecules, including JAK, STATs, MAPK (via activation of Erk1/ 2, AKT, and p38), and NF-κB were identified as instrumental in the synergistic induction of CXCL10. Understanding the mechanisms involved in HIV-1 and cytokine-mediated up-regulation of CXCL10 could aid in the development of therapeutic modalities for HAD.

Original languageEnglish
Pages (from-to)734-743
Number of pages10
JournalGLIA
Volume57
Issue number7
DOIs
StatePublished - 8 Jun 2009

Fingerprint

AIDS Dementia Complex
Astrocytes
HIV-1
Cytokines
HIV
Chemokine CXCL10
Poisons
Chemotactic Factors
Neurotoxins
Brain
Encephalitis
Chemokines
Neuroglia
Interferons
HIV Infections
Up-Regulation
Inflammation
Messenger RNA
Peptides
Proteins

Keywords

  • Astrocytes
  • CXCL10
  • HIV-associated dementia

Cite this

Williams, R., Dhillon, N. K., Hegde, S. T., Yao, H. H., Peng, F., Callen, S., ... Buch, S. J. (2009). Proinflammatory cytokines and HIV-1 synergistically enhance CXCL10 expression in human astrocytes. GLIA, 57(7), 734-743. https://doi.org/10.1002/glia.20801
Williams, Rachel ; Dhillon, Navneet K. ; Hegde, Sonia T. ; Yao, Hong Hong ; Peng, Fuwang ; Callen, Shannon ; Chebloune, Yahia ; Davis, Randall L. ; Buch, Shilpa J. / Proinflammatory cytokines and HIV-1 synergistically enhance CXCL10 expression in human astrocytes. In: GLIA. 2009 ; Vol. 57, No. 7. pp. 734-743.
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Williams, R, Dhillon, NK, Hegde, ST, Yao, HH, Peng, F, Callen, S, Chebloune, Y, Davis, RL & Buch, SJ 2009, 'Proinflammatory cytokines and HIV-1 synergistically enhance CXCL10 expression in human astrocytes', GLIA, vol. 57, no. 7, pp. 734-743. https://doi.org/10.1002/glia.20801

Proinflammatory cytokines and HIV-1 synergistically enhance CXCL10 expression in human astrocytes. / Williams, Rachel; Dhillon, Navneet K.; Hegde, Sonia T.; Yao, Hong Hong; Peng, Fuwang; Callen, Shannon; Chebloune, Yahia; Davis, Randall L.; Buch, Shilpa J.

In: GLIA, Vol. 57, No. 7, 08.06.2009, p. 734-743.

Research output: Contribution to journalArticle

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AU - Williams, Rachel

AU - Dhillon, Navneet K.

AU - Hegde, Sonia T.

AU - Yao, Hong Hong

AU - Peng, Fuwang

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AU - Buch, Shilpa J.

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AB - HIV encephalitis (HIVE), the pathologic correlate of HIV-associated dementia (HAD) is characterized by astrogliosis, cytokine/chemokine dysregulation, and neuronal degeneration. Increasing evidence suggests that inflammation is actively involved in the pathogenesis of HAD. In fact, the severity of HADMIVE correlates more closely with the presence of activated glial cells than with the presence and amount of HIV-infected cells in the brain. Astrocytes, the most numerous cell type within the brain, provide an important reservoir for the generation of inflammatory mediators, including interferon-γ inducible peptide-10 (CXCL10), a neurotoxin and a chemoattractant, implicated in the pathophysiology of HAD. Additionally, the proinflammatory cytokines, IFN-γ and TNF-α, are also markedly increased in CNS tissues during HIV-1 infection. In this study, we hypothesized that the interplay of host cytokines and HIV-1 could lead to enhanced expression of the toxic chemokine, CXCL10. Our findings demonstrate a synergistic induction of CXCL10 mRNA and protein in human astrocytes exposed to HIV-1 and the proinflammatory cytokines. Signaling molecules, including JAK, STATs, MAPK (via activation of Erk1/ 2, AKT, and p38), and NF-κB were identified as instrumental in the synergistic induction of CXCL10. Understanding the mechanisms involved in HIV-1 and cytokine-mediated up-regulation of CXCL10 could aid in the development of therapeutic modalities for HAD.

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Williams R, Dhillon NK, Hegde ST, Yao HH, Peng F, Callen S et al. Proinflammatory cytokines and HIV-1 synergistically enhance CXCL10 expression in human astrocytes. GLIA. 2009 Jun 8;57(7):734-743. https://doi.org/10.1002/glia.20801