TY - JOUR T1 - Interleukin-6 Attenuates Serotonin 2A Receptor Signaling by Activating the JAK-STAT Pathway JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.096289 SP - mol.114.096289 AU - Jennifer J Donegan AU - Michael S Patton AU - Teresa S Chavera AU - Kelly A. Berg AU - David Morilak AU - Milena Girotti Y1 - 2014/01/01 UR - http://molpharm.aspetjournals.org/content/early/2014/12/30/mol.114.096289.abstract N2 - The serotonin 2A (5-HT2A) receptor and the pro-inflammatory cytokine, interleukin-6 (IL-6), have both been implicated in psychiatric disorders. Previously, we demonstrated that these molecules both facilitate cognitive flexibility, a prefrontal cortex-mediated executive function impaired in multiple mental illnesses. In this study, we tested the hypothesis that IL-6 influences 5-HT2A receptor signaling, providing a potential mechanism by which this cytokine may influence behavior. We first demonstrated that 5-HT2A receptors and IL-6-mediated STAT3 phosphorylation co-localize in cells of the prefrontal cortex, providing the neuroanatomical substrate for a potential interaction. In the neuronally derived A1A1 cell line, which expresses both IL-6 and 5-HT2A receptors, we found that IL-6 attenuates inositol phosphate (IP) accumulation in response to the 5-HT2 agonist, DOI, suggesting that IL-6 can regulate 5-HT2A receptor function. To identify the signaling pathway(s) that mediate this effect, we measured DOI-mediated IP accumulation in the presence of IL-6 and either the JAK-STAT inhibitor, JSI-124, or the ERK inhibitor, PD-98059. The IL-6 effect was blocked by JSI-124, but not PD-98059. Further, siRNA knockdown of either JAK or STAT blocked the IL-6 effect, suggesting that IL-6-induced JAK-STAT activation can regulate 5-HT2A receptor signaling. Finally, to determine if IL-6 specifically regulates the 5-HT2A receptor system, we measured IP production mediated by another Gq-coupled receptor, bradykinin B2. IL-6 had no effect on bradykinin-mediated IP accumulation, suggesting that regulation may occur at the 5-HT2A receptor. These results may provide clues to the pathological mechanisms underlying certain psychiatric disorders and may suggest novel therapeutic strategies for their treatment. ER -