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 ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

A Selective Small Molecule IκB Kinase β Inhibitor Blocks Nuclear Factor κB-Mediated Inflammatory Responses in Human Fibroblast-Like Synoviocytes, Chondrocytes, and Mast Cells

Danyi Wen, Yuhua Nong, Jennifer G. Morgan, Pranoti Gangurde, Andrew Bielecki, Jennifer DaSilva, Marie Keaveney, Hong Cheng, Chris Fraser, Lisa Schopf, Michael Hepperle, Geraldine Harriman, Bruce D. Jaffee, Timothy D. Ocain and Yajun Xu
Journal of Pharmacology and Experimental Therapeutics June 2006, 317 (3) 989-1001; DOI: https://doi.org/10.1124/jpet.105.097584
Danyi Wen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuhua Nong
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jennifer G. Morgan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pranoti Gangurde
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew Bielecki
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jennifer DaSilva
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marie Keaveney
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hong Cheng
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chris Fraser
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa Schopf
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael Hepperle
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Geraldine Harriman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bruce D. Jaffee
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy D. Ocain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yajun Xu
  • 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

IκB kinase (IKK) β is essential for inflammatory cytokine-induced activation of nuclear factor κB (NF-κB). NF-κB plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA). Here, we report the mechanism and the effect of the IKKβ inhibitor N-(6-chloro-7-methoxy-9H-β-carbolin-8-yl)-2-methylnicotinamide (ML120B), a β-carboline derivative, on NF-κB signaling and gene activation in RA-relevant cell systems. ML120B is a potent, selective, reversible, and ATP-competitive inhibitor of IKKβ with an IC50 of 60 nM when evaluated in an IκBα kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentration-dependently inhibits tumor necrosis factor α (TNFα)-stimulated NF-κB signaling via inhibition of IκBα phosphorylation, degradation, and NF-κB translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast-like synoviocytes, TNFα- or interleukin (IL)-1β-induced monocyte chemoattractant protein-1 regulated on activation, normal T cell expressed and secreted and production is IKKβ-dependent. In addition, for the first time, we have demonstrated that lipopolysaccharide- or peptidoglycan-induced cytokine production in human cord blood-derived mast cells is IKKβ-dependent. In addition, in human chondrocytes, ML120B inhibited IL-1β-induced matrix metalloproteinase production with an IC50 of approximately 1 μM. ML120B also blocked IL-1β-induced prostaglandin E2 production. In summary, ML120B blocked numerous NF-κB-regulated cell responses that are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKKβ inhibitors as anti-inflammatory agents for the treatment of RA.

Footnotes

  • This work was presented as a poster in Keystone Symposia NF-κB: Biology and Pathology. UT, 2004 [Wen D, Gangurde P, Morgan JG, Nong Y, Savinainen A, Kujawa J, Schopf L, Hepperle M, Harriman G, Jaffee B, et al. (2004) NF-κB regulation by IKKβ in rheumatoid arthritis Poster 365.].

  • ML120B was covered in the published Parent Cooperation Treaty patent application WO 2004092167: Hepperle ME, Liu JF, Soucy F, Ye Y, Murray RS, Prakash R, Little JD, Castro A, Mazdiyasni H, Fleming PE, et al. (2004) inventors, Millennium Pharmaceuticals, Inc., assignee. Preparation of substituted β-carboline IκB kinase 2 (IKK-2) inhibitors as potential anti-inflammatory, immunomodulatory, or anticancer agents.

  • doi:10.1124/jpet.105.097584.

  • ABBREVIATIONS: NF-κB, nuclear factor κB; RA, rheumatoid arthritis; TNF, tumor necrosis factor; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; RANTES, regulated on activation, normal T cell expressed and secreted; MMP, matrix metalloproteinase; IKK, IκB kinase; ML120B, N-(6-chloro-7-methoxy-9H-β-carbolin-8-yl)-2-methylnicotinamide; LPS, lipopolysaccharide; PBMC, peripheral blood mononuclear cell; HFLS, human fibroblast-like synoviocyte(s); MC, mast cell; PGE, prostaglandin E; BSA, bovine serum albumin; PS1145, N-(6-chloro-9H-β-carbolin-8-yl) nicotinamide; DMSO, dimethyl sulfoxide; PMA, phorbol myristate acetate; PGN, peptidoglycan; GST, glutathione S-transferase; AP-1, activator protein-1; MEKK, mitogen-activated protein kinase kinase kinase; PKC, protein kinase C; FBS, fetal bovine serum; DMEM, Dulbecco's modified Eagle's medium; ELISA, enzyme-linked immunosorbent assay; FACS, fluorescence-activated cell sorting; PE, phosphatidylethanolamine; TLR, toll-like receptor; wt, wild type; DN, dominant-negative; SR, super-repressor; GFP, green fluorescent protein; ELAM, endothelial cell leukocyte adhesion molecule (E-selectin); LDH, lactate dehydrogenase; MAP, mitogen-activated protein; COX, cyclooxygenase; m.o.i., multiplicity of infection.

    • Received October 25, 2005.
    • Accepted March 6, 2006.
  • 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: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
  • 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.
A Selective Small Molecule IκB Kinase β Inhibitor Blocks Nuclear Factor κB-Mediated Inflammatory Responses in Human Fibroblast-Like Synoviocytes, Chondrocytes, and Mast Cells
(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

A Selective Small Molecule IκB Kinase β Inhibitor Blocks Nuclear Factor κB-Mediated Inflammatory Responses in Human Fibroblast-Like Synoviocytes, Chondrocytes, and Mast Cells

Danyi Wen, Yuhua Nong, Jennifer G. Morgan, Pranoti Gangurde, Andrew Bielecki, Jennifer DaSilva, Marie Keaveney, Hong Cheng, Chris Fraser, Lisa Schopf, Michael Hepperle, Geraldine Harriman, Bruce D. Jaffee, Timothy D. Ocain and Yajun Xu
Journal of Pharmacology and Experimental Therapeutics June 1, 2006, 317 (3) 989-1001; DOI: https://doi.org/10.1124/jpet.105.097584

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

A Selective Small Molecule IκB Kinase β Inhibitor Blocks Nuclear Factor κB-Mediated Inflammatory Responses in Human Fibroblast-Like Synoviocytes, Chondrocytes, and Mast Cells

Danyi Wen, Yuhua Nong, Jennifer G. Morgan, Pranoti Gangurde, Andrew Bielecki, Jennifer DaSilva, Marie Keaveney, Hong Cheng, Chris Fraser, Lisa Schopf, Michael Hepperle, Geraldine Harriman, Bruce D. Jaffee, Timothy D. Ocain and Yajun Xu
Journal of Pharmacology and Experimental Therapeutics June 1, 2006, 317 (3) 989-1001; DOI: https://doi.org/10.1124/jpet.105.097584
Reddit logo Twitter logo Facebook 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

  • PK/PD of Dexamethasone in LPS-Challenged Rats
  • Expression of PAR2 in iKera to Model Atopic Dermatitis
  • Cholesterol Esterification and Acute Lung Injury
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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics