Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Accumulation of Fingolimod (FTY720) in Lymphoid Tissues Contributes to Prolonged Efficacy

Sven-Christian Sensken, Constantin Bode and Markus H. Gräler
Journal of Pharmacology and Experimental Therapeutics March 2009, 328 (3) 963-969; DOI: https://doi.org/10.1124/jpet.108.148163
Sven-Christian Sensken
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Constantin Bode
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Markus H. Gräler
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

The immunomodulator fingolimod (FTY720) induces lymphopenia by inhibiting lymphocyte egress from thymus and secondary lymphoid organs (SLOs). It is phosphorylated mainly by sphingosine kinase (SK) 2 in vivo. FTY720-phosphate (FTY-P) activated and rapidly internalized S1P1, which is the major sphingosine 1-phosphate (S1P) receptor for mediating lymphocyte egress. Although FTY-P is thought to be the active metabolite for triggering the onset of lymphopenia, nonphosphorylated FTY720 was much more potent in inhibiting cellular calcium flux and splenocyte chemotaxis via S1P1 than FTY-P after preincubation. Determination of both compounds by liquid chromatography coupled to mass spectrometry revealed efficient uptake and accumulation of FTY720 but not FTY-P by splenocytes. Coculture experiments of B and T cells with and without FTY720 pretreatment led to rapid cellular transfer and phosphorylation by mouse lymphocytes. The presence of FTY720 in lymphoid tissues of FTY720-treated SK2-deficient mice without onset of lymphopenia excluded a potential role of the nonphosphorylated compound for lymphocyte egress. Local concentrations of both phosphorylated and nonphosphorylated FTY720 were much higher in lymphoid tissues than in blood. Therefore, we conclude that cellular accumulation of FTY720 generates a reservoir in thymus and SLOs, leading to sustained FTY-P production and activation of S1P1 within tissues.

Footnotes

  • This work was supported by the Emmy Noether Program and priority program 1267 of the German Research Foundation [Grants GR-1943/1-4, GR-1943/2-1].

  • doi:10.1124/jpet.108.148163.

  • ABBREVIATIONS: FTY720, fingolimod, 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol; SK, sphingosine kinase; SLO, secondary lymphoid organ; S1P, sphingosine 1-phosphate; FTY-P, FTY720-phosphate; 2-MEE, 2-(2-methoxyethoxy)ethanol; DMS, N,N-dimethylsphingosine; Sph, sphingosine; AAL(R/S), 2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol; AFD(R/S), phosphate ester of AAL(R/S); C17-Sph, 1,3-dihydroxy-2-amino-4-heptadecene; FCS, fetal calf serum; HA, hemagglutinin; FACS, fluorescence-activated cell sorter; PBS, phosphate-buffered saline; LC/MS/MS, liquid chromatography-mass spectrometry; ESI, electrospray ionization.

    • Received October 31, 2008.
    • Accepted December 11, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 377 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 2
1 May 2021
  • Table of Contents
  • About the Cover
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Accumulation of Fingolimod (FTY720) in Lymphoid Tissues Contributes to Prolonged Efficacy
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Accumulation of Fingolimod (FTY720) in Lymphoid Tissues Contributes to Prolonged Efficacy

Sven-Christian Sensken, Constantin Bode and Markus H. Gräler
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 963-969; DOI: https://doi.org/10.1124/jpet.108.148163

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Accumulation of Fingolimod (FTY720) in Lymphoid Tissues Contributes to Prolonged Efficacy

Sven-Christian Sensken, Constantin Bode and Markus H. Gräler
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 963-969; DOI: https://doi.org/10.1124/jpet.108.148163
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • CBD ENHANCES TREG CELLS AND REDUCES GVHD BY CB2 ACTIVATION
  • ONO-4641 Alleviates Mouse Immune-Mediated Aplastic Anemia
  • PP2A Is a Novel Therapeutic Target in Gout.
Show more Inflammation, Immunopharmacology, and Asthma

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics