ACR Meeting Abstracts

ACR Meeting Abstracts

  • Meetings
    • ACR Convergence 2024
    • ACR Convergence 2023
    • 2023 ACR/ARP PRSYM
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • ACR Meetings

Abstract Number: 736

Inhibition of Interleukin-17 Signaling Via De-Ubiquitinatio

Sarah L. Gaffen1 and Abhishek Garg2, 1Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, 2Rheumatology/Clinical Immun, University of Pittsburgh, Pittsburgh, PA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Interleukins (IL) and signal transduction

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print
Session Information

Title: Cytokines, Mediators, and Gene Regulation I

Session Type: Abstract Submissions (ACR)

Background/Purpose: IL-17A (IL-17) is a proinflammatory cytokine that contributes to the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA), multiple sclerosis (MS) and psoriasis. Despite limited homology with the toll-like receptors, IL-17 receptor subunits (IL-17RA and IL-17RC) do not recruit TLR-associated adaptors such as MyD88, but instead associate with the adaptor protein Act1/CIKS. Upon recruitment, Act1 activates pro-inflammatory signaling pathways including TRAF6/NF-kappaB, MAPK and CCAAT Enhancer Binding Proteins (C/EBP) Despite advances in identifying molecular events downstream of IL-17 signal transduction, mechanisms by which IL-17 signaling is constrained remain poorly understood. Ubiquitination is a central post-translational signaling mechanism involved in activation of inflammation, particularly the NF-kappaB pathway. Notably, both Act1 and Traf6 exhibit E3 ubiquitin ligase activity. Genome analysis has identified over 100 deubiquitinases (DUBs) in humans but their role in IL-17 signaling is unknown. Polymorphisms in the gene encoding the DUB A20 (Tnfaip3) are associated with autoimmune diseases including RA and psoriasis. A20 was originally defined as an inhibitor of the TNF signaling pathway. Here, we show that A20 also participates in downregulating the IL-17 signaling pathway.

Methods: IL-17 signaling was assessed in the stromal cell line ST2. Regulation of IL-17-induced genes was assessed by combinations of siRNA silencing, quantitative real-time RT-PCR (qPCR), immunoblotting and luciferase analyses. Association of receptor-associated proteins was determined by co-immunoprecipitation.

Results: IL-17 induced A20 expression, and transient knockdown of A20 resulted in increased IL-17-dependent proinflammatory target gene expression. Consistently, overexpression of A20 inhibits IL-17 target gene expression, which was associated with reduced NF-κB activity. Interestingly, A20 associated with IL-17RA at a motif that was previously linked to negative regulation of the IL-17 signaling pathway.

Conclusion: We show for the first time that A20 is an inhibitor of the IL-17 signaling pathway. This provides a new mechanistic explanation for the role of A20 in regulating autoimmune disease. Moreover, regulation of A20 could serve as a potential target for pharmacologic manipulation of inflammatory signaling in autoimmunity.


Disclosure:

S. L. Gaffen,
None;

A. Garg,
None.

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print

« Back to 2012 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-interleukin-17-signaling-via-de-ubiquitinatio/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

All abstracts accepted to ACR Convergence are under media embargo once the ACR has notified presenters of their abstract’s acceptance. They may be presented at other meetings or published as manuscripts after this time but should not be discussed in non-scholarly venues or outlets. The following embargo policies are strictly enforced by the ACR.

Accepted abstracts are made available to the public online in advance of the meeting and are published in a special online supplement of our scientific journal, Arthritis & Rheumatology. Information contained in those abstracts may not be released until the abstracts appear online. In an exception to the media embargo, academic institutions, private organizations, and companies with products whose value may be influenced by information contained in an abstract may issue a press release to coincide with the availability of an ACR abstract on the ACR website. However, the ACR continues to require that information that goes beyond that contained in the abstract (e.g., discussion of the abstract done as part of editorial news coverage) is under media embargo until 10:00 AM ET on November 14, 2024. Journalists with access to embargoed information cannot release articles or editorial news coverage before this time. Editorial news coverage is considered original articles/videos developed by employed journalists to report facts, commentary, and subject matter expert quotes in a narrative form using a variety of sources (e.g., research, announcements, press releases, events, etc.).

Violation of this policy may result in the abstract being withdrawn from the meeting and other measures deemed appropriate. Authors are responsible for notifying colleagues, institutions, communications firms, and all other stakeholders related to the development or promotion of the abstract about this policy. If you have questions about the ACR abstract embargo policy, please contact ACR abstracts staff at [email protected].

Wiley

  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences

© Copyright 2025 American College of Rheumatology