Genomes and Genes
Role of a novel IKK-related kinase in inflammation
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
- Antiviral gene expression in rheumatoid arthritis: role of IKKepsilon and interferon regulatory factor 3Susan 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)...
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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...
- Hematopoietic stem cell transplant for systemic lupus erythematosus: Interferon regulatory factor 7 activation correlates with the IFN signature and recurrent diseaseS 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...
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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...
- Role of interferon regulatory factor 7 in serum-transfer arthritis: regulation of interferon-β productionSusan 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...