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Serotonin via 5‐HT 7 receptors activates p38 mitogen‐activated protein kinase and protein kinase C ɛ resulting in interleukin‐6 synthesis in human U373 MG astrocytoma cells
Author(s) -
Lieb Klaus,
Biersack Lisa,
Waschbisch Anne,
Orlikowski Sonja,
Akundi Ravi Shankar,
CandelarioJalil Eduardo,
Hüll Michael,
Fiebich Bernd L.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03079.x
Subject(s) - 5 ht receptor , receptor , agonist , receptor antagonist , protein kinase c , biology , microbiology and biotechnology , 5 ht7 receptor , serotonin , p38 mitogen activated protein kinases , signal transduction , mapk/erk pathway , pharmacology , biochemistry , antagonist
Abstract Serotonin [5‐hydroxytryptamine (5‐HT)] is a widely distributed neurotransmitter which is involved in neuroimmunomodulatory processes. Previously, it has been demonstrated that 5‐HT may induce interleukin (IL)‐6 expression in primary rat hippocampal astrocytes. The present study was undertaken to investigate the molecular pathways underlying this induction of IL‐6 synthesis. As a model system, we used the human astrocytoma cell line U373 MG, which synthesizes IL‐6 upon stimulation with various inducers. 5‐HT dose‐ and time‐dependently induced IL‐6 protein synthesis. We identified several 5‐HT receptors to be expressed on U373 MG cells, including the 5‐HT 1D , 5‐HT 2A , 5‐HT 3 and 5‐HT 7 receptors. In this report, we show that the 5‐HT‐induced IL‐6 release is mediated by the 5‐HT 7 receptor based on several agonist/antagonists that were used. 5‐HT‐induced IL‐6 synthesis is inhibited by the partially selective 5‐HT 7 receptor antagonist, pimozide, and the selective antagonist SB269970. Furthermore, IL‐6 synthesis was induced by the 5‐HT 7 receptor agonist carboxamidotryptamin. In addition, we found p38 MAPKs and protein kinase C (PKC) ɛ to be involved in 5‐HT‐induced IL‐6 synthesis as specific inhibitors of these enzymes (SB202190 and RO‐31‐8425, respectively) blocked 5‐HT‐induced IL‐6 synthesis. Furthermore, 5‐HT mediated the phosphorylation of both p38 MAPK as well as the PKC ɛ isoform. The p42/44 MAPKs, however, were not involved in 5‐HT‐induced IL‐6 synthesis. This study shows, for the first time, a central role of 5‐HT 7 receptor linked to p38 MAPK and PKC ɛ for the induction of cytokine synthesis in astrocytic cells.