Adenosine receptors control HIV-1 Tat-induced inflammatory responses through protein phosphatase

J. Fotheringham, M. Mayne, C. Holden, A. Nath, J. D. Geiger

Research output: Contribution to journalArticlepeer-review

Abstract

Recently, adenosine has been proposed to be a "metabolic" switch that may sense and direct immune and inflammatory responses. Inflammation and pro-inflammatory cytokine production are important in development of HIV-1 associated dementia, a devastating consequence of HIV-1 infection of the CNS. The HIV-1 protein Tat induces cell death in the CNS and activates local inflammatory responses partially by inducing calcium release from the endoplasmic reticulum. Because activation of adenosine receptors decreases production of the pro-inflammatory cytokine TNF-α in several experimental paradigms both in vitro and in vivo, we hypothesized that adenosine receptor activation would control both increased intracellular calcium and TNF-α production induced by Tat. Treatment of primary monocytes with Tat significantly increased the levels of intracellular calcium released from IP 3 stores. Activation of adenosine receptors with CGS 21680 inhibited Tat-induced increases of intracellular calcium by 90 ± 8% and was dependent on protein phosphatase activity because okadaic acid blocked the actions of CGS 21680. Tat-induced TNF-α production was inhibited 90 ± 6% by CGS 21680 and concurrent treatment with okadaic acid blocked the inhibitory actions of CGS 21680. Using a model monocytic cell line, CGS 21680 treatment increased cytosolic serine/threonine phosphatase. Together, these data indicate that A 2A receptor activation increases protein phosphatase activity, which blocks IP 3 receptor-regulated calcium release and reduction of intracellular calcium inhibits TNF-α production in monocytes.

Original languageEnglish (US)
Pages (from-to)186-195
Number of pages10
JournalVirology
Volume327
Issue number2
DOIs
StatePublished - Oct 1 2004

Keywords

  • Cellular activation
  • Cytokines
  • Immunodeficiency diseases
  • Monocytes/macrophages
  • Signal transduction

ASJC Scopus subject areas

  • Virology

Fingerprint Dive into the research topics of 'Adenosine receptors control HIV-1 Tat-induced inflammatory responses through protein phosphatase'. Together they form a unique fingerprint.

Cite this