Role of a novel IKK-related kinase in inflammation

Summary

Principal Investigator: SUSAN ELAINE SWEENEY
Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes symmetric polyarthritis and joint destruction. Considerable work in the pathogenesis of RA has implicated multiple signaling pathways that regulate the production of pro-inflammatory mediators. NF-kB, in particular, plays a key role, and IkB kinase- 2 (IKK2) is an attractive therapeutic target. However, blockade of this kinase poses major safety concerns. As a result, we have focused on a recently described alternate pathway that activates innate immune responses and NF-kB. The IKK-related kinases, inducible IKK (IKKi) and TANK-binding kinase 1 (TBK1) were as originally identified as NF-kB activating kinases that phosphorylated IkB. It is now clear, however, that this represents only one of several substrates for IKKi. For instance, IKKi phosphorylates interferon regulatory factor 3 (IRF) and coordinates its activation with NF-kB after Toll-like receptor (TLR) ligation. IKKi might also serve to link the NF-kB and CCAAT enhancer binding protein (C/EBP) pathways in LPS stimulated cells. Our preliminary data indicate that IKKi can activate c-Jun and enhance MMP expression in cultured synoviocytes. We hypothesize that IKKi activates both innate and adaptive immunity in RA and represents a novel approach to blocking pathogenic transcription factor activation implicated in synovial inflammation. We propose to assess the role of IKKi in synovial inflammation by first determining the signal transduction pathways activated by IKKi in synoviocytes. We will then determine the function and regulation of IKKi in synovial tissue and synoviocytes from RA patients. Finally, we will determine the role of IKKi in animal models by studying a passive K/BxN model of arthritis in IKKi knockout and wild type mice as well as a collagen-induced arthritis model in IKKi knockout mice crossbred on the DBA/1 background. These experiments will allow an assessment of the potential of IKKi as a therapeutic target in RA. Rheumatoid arthritis (RA) causes joint destruction and significant disability in many patients, affecting up to 1% of the adult population worldwide. Studies of the intracellular pathways activated in RA might lead to prevention and development of novel therapies for this chronic, debilitating disease.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Antiviral gene expression in rheumatoid arthritis: role of IKKepsilon and interferon regulatory factor 3
    Susan E Sweeney
    University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
    Arthritis Rheum 56:743-52. 2007
  2. pmc Synoviocyte innate immune responses: II. Pivotal role of IFN regulatory factor 3
    Susan E Sweeney
    Division of Rheumatology, Allergy, and Immunology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA
    J Immunol 184:7162-8. 2010
  3. ncbi Hematopoietic stem cell transplant for systemic lupus erythematosus: Interferon regulatory factor 7 activation correlates with the IFN signature and recurrent disease
    S E Sweeney
    Division of Rheumatology, Allergy, and Immunology, University of California San Diego, La Jolla, CA, USA
    Lupus 20:975-80. 2011
  4. pmc Targeting interferon regulatory factors to inhibit activation of the type I IFN response: implications for treatment of autoimmune disorders
    Susan E Sweeney
    Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, La Jolla, CA 92093, United States
    Cell Immunol 271:342-9. 2011
  5. pmc Role of interferon regulatory factor 7 in serum-transfer arthritis: regulation of interferon-β production
    Susan E Sweeney
    University of California San Diego, La Jolla, CA 92093 0663, USA
    Arthritis Rheum 64:1046-56. 2012

Scientific Experts

Detail Information

Publications5

  1. ncbi Antiviral gene expression in rheumatoid arthritis: role of IKKepsilon and interferon regulatory factor 3
    Susan E Sweeney
    University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
    Arthritis Rheum 56:743-52. 2007
    ..This study was designed to investigate the role of the IKK-related kinase IKKepsilon and IFN regulatory factor 3 (IRF-3) in the activation of antiviral genes in rheumatoid arthritis (RA)...
  2. pmc Synoviocyte innate immune responses: II. Pivotal role of IFN regulatory factor 3
    Susan E Sweeney
    Division of Rheumatology, Allergy, and Immunology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA
    J Immunol 184:7162-8. 2010
    ..Targeting synoviocyte IRF3 represents a potential approach to suppress diverse mediators while limiting suppression of IRF7-mediated immune responses...
  3. ncbi Hematopoietic stem cell transplant for systemic lupus erythematosus: Interferon regulatory factor 7 activation correlates with the IFN signature and recurrent disease
    S E Sweeney
    Division of Rheumatology, Allergy, and Immunology, University of California San Diego, La Jolla, CA, USA
    Lupus 20:975-80. 2011
    ..This unique trend in regulation of IRF warrants further mechanistic investigation and confirmation with increased numbers of SLE patients...
  4. pmc Targeting interferon regulatory factors to inhibit activation of the type I IFN response: implications for treatment of autoimmune disorders
    Susan E Sweeney
    Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, La Jolla, CA 92093, United States
    Cell Immunol 271:342-9. 2011
    ..IRF regulation of inflammation and induction of the IFN signature might contribute to the pathogenesis of autoimmune diseases and therefore represent novel therapeutic targets...
  5. pmc Role of interferon regulatory factor 7 in serum-transfer arthritis: regulation of interferon-β production
    Susan E Sweeney
    University of California San Diego, La Jolla, CA 92093 0663, USA
    Arthritis Rheum 64:1046-56. 2012
    ..The purpose of this study was to examine the effect of genetic deficiency of IRF-7 in a passive K/BxN serum-transfer model of arthritis...