title: The acid sphingomyelinase inhibitors block interferon-α-induced serotonin uptake via a COX-2/Akt/ERK/STAT-dependent pathway in T cells.
abstract: Sphingomyelinase (SMase) regulates an activation of the sphingomyelin cycle. Recent studies have shown that it is a novel modulator of monoamine receptor and transporter functions; however, its mechanisms are not fully understood. Our previous studies have found that interferon-alpha (IFN-α) up-regulates serotonin (5-HT) transporter expression and induces 5-HT uptake via an extracellular signal-regulated kinase (ERK)1/2-dependent pathway in T cells, which is blocked by a selective 5-HT transporter inhibitor fluoxetine. In the present study, we further investigated the roles of various SMase inhibitors in IFN-α-induced 5-HT uptake, including sphingolactone-24 (sph24) for neutral SMase or tricyclodecan-9-yl-xanthogenate (D609) for acid SMase. Pretreatments with Sph24 and D609 inhibited IFN-α-induced 5-HT uptake, and activation of ERK1/2 and signal transducer and transactivator (STAT) 1 and STAT3. The elevated protein levels of pro-inflammatory enzyme cycloxygenase (COX)-2 were observed upon IFN-α stimulation. The COX-2 inhibitor celecoxib blocked IFN-α-induced COX-2 expression, 5-HT uptake and activation of Akt, ERK and STAT. Moreover, a PI3K/Akt inhibitor Wortamannin blocked IFN-α-induced 5-HT uptake and activation of Akt and ERK. D609 also blocked IFN-α-induced COX-2 and Akt activation. Contrarily, sph24 did not result in these effects. Furthermore, fluoxetine as an acid SMase inhibitor lowered IFN-α-induced SMase activity as well as attenuated COX-2, Akt, ERK, and STAT activation. These results suggest that inhibiting SMase attenuates IFN-α-induced ERK and STAT activation to regulate 5-HT uptake. Moreover, inhibition of COX-2 induction and an Akt-dependent pathway are involved in IFN-α-induced 5-HT uptake by the blockade of acid SMase activity.
authors.affiliation: Department of Pharmacy, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Su
authors.forename: Ching-Ting
authors.initials: CT
authors.lastname: Ma
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
authors.forename: Hung-Tsung
authors.initials: HT
authors.lastname: Wu
authors.forename: Yeu-Hui
authors.initials: YH
authors.lastname: Chuang
authors.forename: Li-Jen
authors.initials: LJ
authors.lastname: Chen
authors.forename: Chiung-Wen
authors.initials: CW
authors.lastname: Tsao
mesh_terms: D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003863:Depression / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000494:pharmacology*; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D012701:Serotonin; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D013108:Sphingomyelin Phosphodiesterase