Molecular mechanism(s) involved in the synergistic induction of CXCL10 by human immunodeficiency virus type 1 Tat and interferon-γ in macrophages

Navneet Dhillon, Xuhui Zhu, Fuwang Peng, Honghong Yao, Rachel Williams, Shannon Callen, Amy O.Brien Ladner, Shilpa J. Buch, Jianming Qiu

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Synergistic interactions between viral proteins and soluble host factors released from infected mononuclear phagocytes play a critical role in the pathogenesis of human immunodeficiency virus (HIV)-associated dementia (HAD). The chemokine CXCL10 has been found to be closely associated with the progression of HIV-1-related central nervous system (CNS) disease and its related neuropsychiatric impairment. In this report the authors demonstrate that the HIV-1 protein Tat can interact with the proinflammatory cytokine interferon (IFN)-γ to dramatically induce the expression of CXCL10 in macrophages. Synergistic induction of CXCL10 by both Tat and IFN-γ was susceptible to inhibition by the MEK1/2 inhibitor U0126 and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. In addition, JAK/STAT pathway plays a major role in Tat/γ-mediated CXCL10 induction in macrophages because pretreatment of stimulated macrophages with JAK inhibitor completely abrogated the synergistic induction of the chemokine. Functionality of the synergistically induced CXCL10 was further demonstrated by its chemotactic activity for peripheral blood lymphocytes. Taken together, these findings demonstrate that the cooperative interaction of Tat and IFN-γ results in enhanced chemokine expression, which in turn can amplify the inflammatory responses within the CNS of HAD patients by recruiting more lymphocytes in the brain.

Original languageEnglish (US)
Pages (from-to)196-204
Number of pages9
JournalJournal of neurovirology
Volume14
Issue number3
DOIs
StatePublished - May 2008

Keywords

  • HIV
  • JAK
  • MAP kinase
  • STAT

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Virology

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