Ibudilast, a pharmacologic phosphodiesterase inhibitor, prevents human immunodeficiency virus-1 Tat-mediated activation of microglial cells

PLoS One. 2011 Apr 8;6(4):e18633. doi: 10.1371/journal.pone.0018633.

Abstract

Human Immunodeficiency Virus-1 (HIV-1)-associated neurocognitive disorders (HAND) occur, in part, due to the inflammatory response to viral proteins, such as the HIV-1 transactivator of transcription (Tat), in the central nervous system (CNS). Given the need for novel adjunctive therapies for HAND, we hypothesized that ibudilast would inhibit Tat-induced excess production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα) in microglial cells. Ibudilast is a non-selective cyclic AMP phosphodiesterase inhibitor that has recently shown promise as a treatment for neuropathic pain via its ability to attenuate glial cell activation. Accordingly, here we demonstrate that pre-treatment of both human and mouse microglial cells with increasing doses of ibudilast inhibited Tat-induced synthesis of TNFα by microglial cells in a manner dependent on serine/threonine protein phosphatase activity. Ibudilast had no effect on Tat-induced p38 MAP kinase activation, and blockade of adenosine A(2A) receptor activation did not reverse ibudilast's inhibition of Tat-induced TNFα production. Interestingly, ibudilast reduced Tat-mediated transcription of TNFα, via modulation of nuclear factor-kappa B (NF-κB) signaling, as shown by transcriptional activity of NF-κB and analysis of inhibitor of kappa B alpha (IκBα) stability. Together, our findings shed light on the mechanism of ibudilast's inhibition of Tat-induced TNFα production in microglial cells and may implicate ibudilast as a potential novel adjunctive therapy for the management of HAND.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Enzyme Activation / drug effects
  • HIV-1 / drug effects*
  • HIV-1 / metabolism*
  • Humans
  • Inflammation Mediators / metabolism
  • Mice
  • Microglia / drug effects*
  • Microglia / enzymology
  • Microglia / metabolism*
  • NF-kappa B / metabolism
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoprotein Phosphatases / metabolism
  • Pyridines / pharmacology*
  • Receptor, Adenosine A2A / metabolism
  • Signal Transduction / drug effects
  • Transcription, Genetic / drug effects
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • tat Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • Inflammation Mediators
  • NF-kappa B
  • Phosphodiesterase Inhibitors
  • Pyridines
  • Receptor, Adenosine A2A
  • Tumor Necrosis Factor-alpha
  • tat Gene Products, Human Immunodeficiency Virus
  • p38 Mitogen-Activated Protein Kinases
  • Phosphoprotein Phosphatases
  • ibudilast