Morphine exacerbates HIV-1 Tat-induced cytokine production in astrocytes through convergent effects on [Ca(2+)](i), NF-kappaB trafficking and transcription

PLoS One. 2008;3(12):e4093. doi: 10.1371/journal.pone.0004093. Epub 2008 Dec 31.


Astroglia are key cellular sites where opiate drug signals converge with the proinflammatory effects of HIV-1 Tat signals to exacerbate HIV encephalitis. Despite this understanding, the molecular sites of convergence driving opiate-accelerated neuropathogenesis have not been deciphered. We therefore explored potential points of interaction between the signaling pathways initiated by HIV-1 Tat and opioids in striatal astrocytes. Profiling studies screening 152 transcription factors indicated that the nuclear factor-kappa B (NF-kappaB) subunit, c-Rel, was a likely candidate for Tat or Tat plus opiate-induced increases in cytokine and chemokine production by astrocytes. Pretreatment with the NF-kappaB inhibitor parthenolide provided evidence that Tat+/-morphine-induced release of MCP-1, IL-6 and TNF-alpha by astrocytes is NF-kappaB dependent. The nuclear export inhibitor, leptomycin B, blocked the nucleocytoplasmic shuttling of NF-kappaB; causing p65 (RelA) accumulation in the nucleus, and significantly attenuated cytokine production in Tat+/-morphine exposed astrocytes. Similarly, chelating intracellular calcium ([Ca(2+)](i)) blocked Tat+/-morphine-evoked MCP-1 and IL-6 release, while artificially increasing the concentration of extracellular Ca(2+) reversed this effect. Taken together, these results demonstrate that: 1) exposure to Tat+/-morphine is sufficient to activate NF-kappaB and cytokine production, 2) the release of MCP-1 and IL-6 by Tat+/-morphine are highly Ca(2+)-dependent, while TNF-alpha appears to be less affected by the changes in [Ca(2+)](i), and 3) in the presence of Tat, exposure to opiates augments Tat-induced NF-kappaB activation and cytokine release through a Ca(2+)-dependent pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / immunology*
  • Calcium / metabolism*
  • Cell Nucleus / metabolism
  • Cytokines / biosynthesis*
  • Cytoplasm / metabolism
  • Genes, rel
  • HIV-1*
  • Mice
  • Mice, Inbred ICR
  • Models, Biological
  • Morphine / pharmacology*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Signal Transduction
  • Transcription, Genetic*
  • Tumor Necrosis Factor-alpha / metabolism
  • tat Gene Products, Human Immunodeficiency Virus / genetics
  • tat Gene Products, Human Immunodeficiency Virus / metabolism*


  • Analgesics, Opioid
  • Cytokines
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • tat Gene Products, Human Immunodeficiency Virus
  • Morphine
  • Calcium