Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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
  • Submit
  • 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
    • Special Sections
    • 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
  • Submit
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleDrug Discovery and Translational Medicine

Differential Anti-inflammatory Activity of HDAC Inhibitors in Human Macrophages and Rat Arthritis

Rink-Jan Lohman, Abishek Iyer, Thomas J. Fairlie, Adam Cotterell, Praveer Gupta, Robert C. Reid, David A. Vesey, Matthew J. Sweet and David P. Fairlie
Journal of Pharmacology and Experimental Therapeutics February 2016, 356 (2) 387-396; DOI: https://doi.org/10.1124/jpet.115.229328
Rink-Jan Lohman
Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Abishek Iyer
Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas J. Fairlie
Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adam Cotterell
Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Praveer Gupta
Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert C. Reid
Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David A. Vesey
Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew J. Sweet
Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David P. Fairlie
Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
  • 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

Vorinostat and other inhibitors of different histone deacetylase (HDAC) enzymes are currently being sought to modulate a variety of human conditions, including chronic inflammatory diseases. Some HDAC inhibitors are anti-inflammatory in rodent models of arthritis and colitis, usually at cytotoxic doses that may cause side effects. Here, we investigate the dose-dependent pro- and anti-inflammatory efficacy of two known inhibitors of multiple HDACs, vorinostat and BML281, in human macrophages and in a rat model of collagen-induced arthritis by monitoring effects on disease progression, histopathology, and immunohistochemistry. Both HDAC inhibitors differentially modulated lipopolysaccharide (LPS)-induced cytokine release from human macrophages, suppressing release of some inflammatory mediators (IL12p40, IL6) at low concentrations (<3 µM) but amplifying production of others (TNF, IL1β) at higher concentration (>3 μΜ). This trend translated in vivo to rat arthritis, with anti-inflammatory activity inversely correlating with dose. Both compounds were efficacious only at a low dose (1 mg⋅kg−1⋅day−1 s.c.), whereas a higher dose (5 mg⋅kg−1⋅day−1 s.c.) showed no positive effects on reducing pathology, even showing signs of exacerbating disease. These striking effects suggest a smaller therapeutic window than previously reported for HDAC inhibition in experimental arthritis. The findings support new investigations into repurposing HDAC inhibitors for anti-inflammatory therapeutic applications. However, HDAC inhibitors should be reinvestigated at lower, rather than higher, doses for enhanced efficacy in chronic diseases that require long-term treatment, with careful management of efficacy and long-term safety.

Footnotes

    • Received September 14, 2015.
    • Accepted December 7, 2015.
  • R.J.L. and A.I. contributed equally to this work.

  • Funding for this work was provided by the National Health and Medical Research Council of Australia for a Senior Principal Research Fellowship to D.F. [1027369], a Senior Research Fellowship to M.J.S. [APP1003470], and grant funding [Grants APP1047921, APP1030169, APP1074016]; the Australian Research Council for funding of a Centre of Excellence in Advanced Molecular Imaging [Grant CE140100011]; and the University of Queensland for a UQ Postdoctoral Fellowship to A.I. and a UQ Early Career Grant to R.J.L. and A.I.

  • dx.doi.org/10.1124/jpet.115.229328.

  • Copyright © 2016 by 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.
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 356 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 356, Issue 2
1 Feb 2016
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
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.
Differential Anti-inflammatory Activity of HDAC Inhibitors in Human Macrophages and Rat Arthritis
(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 ArticleDrug Discovery and Translational Medicine

HDAC Inhibition in Human Macrophages and Rat Arthritis

Rink-Jan Lohman, Abishek Iyer, Thomas J. Fairlie, Adam Cotterell, Praveer Gupta, Robert C. Reid, David A. Vesey, Matthew J. Sweet and David P. Fairlie
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 387-396; DOI: https://doi.org/10.1124/jpet.115.229328

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleDrug Discovery and Translational Medicine

HDAC Inhibition in Human Macrophages and Rat Arthritis

Rink-Jan Lohman, Abishek Iyer, Thomas J. Fairlie, Adam Cotterell, Praveer Gupta, Robert C. Reid, David A. Vesey, Matthew J. Sweet and David P. Fairlie
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 387-396; DOI: https://doi.org/10.1124/jpet.115.229328
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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

Related Articles

Cited By...

More in this TOC Section

  • Preclinical pharmacology of vadadustat (AKB-6548)
  • Direct AMPK Activation for X-Linked Adrenoleukodystrophy
  • Sulindac Derivative Protects against Oxidative Damage
Show more Drug Discovery and Translational Medicine

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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics