Proinflammatory cytokines and HIV-1 synergistically enhance CXCL10 expression in human astrocytes.
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 HAD/HIVE 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-gamma inducible peptide-10 (CXCL10), a neurotoxin and a chemoattractant, implicated in the pathophysiology of HAD. Additionally, the proinflammatory cytokines, IFN-gamma and TNF-alpha, 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-kappaB 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.
Williams
Rachel
R
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Dhillon
Navneet K
NK
Hegde
Sonia T
ST
Yao
Honghong
H
Peng
Fuwang
F
Callen
Shannon
S
Chebloune
Yahia
Y
Davis
Randall L
RL
Buch
Shilpa J
SJ
D001253:Astrocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D015153:Blotting, Western; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma