The acid sphingomyelinase inhibitors block interferon-α-induced serotonin uptake via a COX-2/Akt/ERK/STAT-dependent pathway in T cells

Hui Chen Su, Ching Ting Ma, Chiou Feng Lin, Hung Tsung Wu, Yeu Hui Chuang, Li Jen Chen, Chiung Wen Tsao

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1823-1831
Number of pages9
JournalInternational Immunopharmacology
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 2011
Externally publishedYes

Keywords

  • Akt
  • Cyclooxygenase-2
  • Interferon-α
  • Serotonin uptake
  • Sphingomyelinases

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Pharmacology

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