HIV-1-infected and/or immune-activated macrophages regulate astrocyte CXCL8 production through IL-1β and TNF-α: Involvement of mitogen-activated protein kinases and protein kinase R

Jialin C Zheng, Yunlong Huang, Kang Tang, Min Cui, Douglas F Niemann, Alicia Lopez, Susan Morgello, Shengdi Chen

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Monocyte infiltration is an important pathogenic event in human immunodeficiency virus type one (HIV-1) associated dementia (HAD). CXCL8 (Interleukin 8, IL-8), a CXC chemokine that elicits chemotaxis of neutrophils, has recently been found to recruit monocytes or synergistically enhance CCL2-mediated monocyte migration. In this report, we demonstrate CXCL8 levels in the cerebrospinal fluid of HAD patients are higher than HIV-1 seropositive patients without neurological impairment. The underlying mechanisms regulating CXCL8 production during disease are not completely understood. We investigated the role of HIV-1-infected and immune-competent macrophages, the principal target cell and mediator of neuronal injury in HAD, in regulating astrocyte CXCL8 production. Immune-activated and HIV-1-infected human monocyte-derived-macrophages (MDM) conditioned media (MCM) induced production of CXCL8 by human astrocytes. This CXCL8 production was dependent on MDM IL-1β and TNF-α production following viral and immune activation. CXCL8 production was reduced by inhibitors for mitogen-activated protein kinases (MAPKs), including p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK1/2). Moreover, prolonged IL-1β or TNF-α treatment activated double-stranded RNA-activated protein kinase (PKR). Inhibition of PKR prevented elevated CXCL8 production in astrocytes. We conclude that IL-1β and TNF-α, produced from HIV-1-infected and immune-competent macrophages, are critical in astrocyte CXCL8 production. Multiple protein kinases, including p38, JNK, ERK1/2, and PKR, participate in the inflammatory response of astrocytes. These observations will help to identify effective therapeutic strategies to reduce high-levels of CXCL8-mediated CNS inflammation during HAD.

Original languageEnglish (US)
Pages (from-to)100-110
Number of pages11
JournalJournal of Neuroimmunology
Volume200
Issue number1-2
DOIs
StatePublished - Aug 30 2008

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Keywords

  • Astrocyte
  • CXCL8
  • HIV-1 associated dementia
  • Inflammation
  • Macrophage

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Neurology
  • Clinical Neurology

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