Suppression of Proinflammatory Cytokines Interleukin-1β and Tumor Necrosis Factor-α in Astrocytes by a V1 Vasopressin Receptor Agonist: A cAMP Response Element-Binding Protein-Dependent Mechanism

Lixia Zhao, Roberta D. Brinton

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Previous research from our laboratory has demonstrated that V1 vasopressin receptor agonist (V1 agonist) induces a complex intracellular Ca2+-signaling cascade in cortical astrocytes that is initiated by G-protein-coupled V1a vasopressin receptor-mediated cytoplasmic and nuclear Ca2+ rise and converges during activation of the nuclear transcription factor cAMP response element-binding protein (CREB). In the current study, we pursued the downstream functional consequences of V1 agonist-induced Ca2+-signaling cascade for gene expression. Because astrocytes can exert immune effects analogous to immune cells in the periphery, we investigated V1 agonist regulation of cytokine gene expression in astrocytes. Results from gene array studies indicated that V1 agonist dramatically decreased the mRNA level of five cytokines. Two prominent proinflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were selected for detailed analysis, and their expression was also confirmed with reverse transcriptase-PCR. Furthermore, ELISA analyses demonstrated that the peptide level of IL-1β and TNF-α in the astrocyte medium was also decreased in response to V1 agonist. Using CREB antisense to determine the causal relationship between V1 agonist-induced CREB activation and suppression of IL-1β and TNF-α, we demonstrated that decreased IL-1β and TNF-α gene expression was dependent on upstream CREB activation. V1 agonist-induced decrease of cytokine release from cortical astrocytes was also shown to be neuroprotective in cortical neurons. To our knowledge, this is the first documentation of V1 agonist modulation of cytokine gene expression in any cell type. Implications for vasopressin as an antipyretic agent and the role of vasopressin in neurodegeneration, autoimmune diseases, stress, and neuropsychiatric behaviors are discussed.

Original languageEnglish (US)
Pages (from-to)2226-2235
Number of pages10
JournalJournal of Neuroscience
Volume24
Issue number9
DOIs
StatePublished - Mar 3 2004
Externally publishedYes

Keywords

  • CREB
  • CREB antisense
  • Calcium signaling
  • Cortical astrocytes
  • Cyclic-AMP response element-binding protein
  • Cytokines
  • Fever
  • IL-1β
  • Interleukin-1β
  • Stress
  • TNF-α
  • Tumor necrosis factor-α
  • V vasopressin receptor
  • Vasopressin

ASJC Scopus subject areas

  • Neuroscience(all)

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