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The Journal of Neuroscience, March 3, 2004, 24(9):2226-2235; doi:10.1523/JNEUROSCI.4922-03.2004

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

Lixia Zhao and Roberta D. Brinton

Department of Molecular Pharmacology and Toxicology, University of Southern California, Pharmaceutical Sciences Center, Los Angeles, California 90089-9121

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 V_1a 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-1 (IL-1) and tumor necrosis factor- (TNF-), 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-1 and TNF- 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-1 and TNF-, we demonstrated that decreased IL-1 and TNF- 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.

Key words: vasopressin; V_1a vasopressin receptor; fever; stress; calcium signaling; cortical astrocytes; cytokines; interleukin-1; IL-1; tumor necrosis factor-; TNF-; cyclic-AMP response element-binding protein; CREB; CREB antisense; gene array; neuroprotection

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Received Nov 3, 2003; revised December 12, 2003; accepted December 15, 2003.

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