CD40-CD40 ligand interactions in human microglia induce CXCL8 (interleukin-8) secretion by a mechanism dependent on activation of ERK1/2 and nuclear translocation of nuclear factor-κB (NFκB) and activator protein-1 (AP-1)

Teresa G. D'Aversa, Eliseo A. Eugenin, Joan W. Berman

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

CXCL8 is a CXC chemokine that recruits leukocytes to sites of inflammation. Expression of CXCL8 in the CNS has been demonstrated in neuroinflammatory diseases, including human immunodeficiency virus (HIV-1) encephalitis, but the mechanism of secretion of this chemokine is not fully understood. CD40 is a 50-kDa protein on the surface of microglia, and we have previously shown that it is increased in expression in HIV-1-infected brain tissue as well as by interferon-γ (IFNγ) in tissue culture. We examined the expression and regulation of CXCL8 in cultured human fetal microglia after ligation of CD40 with soluble trimeric CD40 ligand (sCD40L) as well as the expression of CXCL8 on microglia in HIV encephalitic brain tissue sections. Treatment of cultured microglia with IFN7 + sCD40L resulted in significant induction of CXCL8. This expression was mediated by activation of the ERK1/2 MAPK pathway, as demonstrated by ELISA and Western blot using a specific inhibitor (U0126). Gel shift analyses demonstrated that NFKB and AP-1, but not C/EBPβ mediate microglial CXCL8 production. We also found increased colocalization of CXCL8 with CD68/CD40-positive cells in HIV encephalitic brain tissue compared with HIV-infected nonencephalitic and normal tissue. Thus, CD40-CD40L interactions facilitate chemokine expression, leading to the influx of inflammatory cells into the CNS. These events can lead to the pathology that is associated with neuroinflammatory diseases.

Original languageEnglish (US)
Pages (from-to)630-639
Number of pages10
JournalJournal of Neuroscience Research
Volume86
Issue number3
DOIs
StatePublished - Feb 15 2008

Keywords

  • Chemokines
  • HIV dementia
  • Microglia
  • Neuro-AIDS

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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