Project

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Expression and function of the novel IL-1 family cytokine IL-33 in arthritis

Applicant Palmer Gaby
Number 120319
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.05.2008 - 30.04.2011
Approved amount 279'000.00
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Keywords (4)

inflammation; autoimmunity; interleukin; immune response

Lay Summary (English)

Lead
Lay summary
Cytokines are signaling proteins, which allow communication between cells and are important mediators of the innate and adaptive immune responses. Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial tissue in multiple joints, which leads to joint destruction. In rheumatoid arthritis, there is an excessive activity of pro-inflammatory cytokines and this observation led to the development of new therapies based on anti-cytokine treatments. In this project, we propose to study the role of IL-33, a newly identified cytokine belonging to the interleukin (IL)-1 family, in the pathogenesis of arthritis. The interleukin (IL)-1 family includes IL-1?, IL-1?, and IL-18, which play an important role in inflammatory responses, as well as IL-1 receptor antagonist (IL-1Ra), a specific IL-1 inhibitor. In addition, seven novel family members, namely IL- 1F5 to IL-1F10 and IL-33 (or IL-1F11), have been cloned in the last years. The biologic function of these cytokines is still poorly characterized. The role of the four ‘classical’ IL-1 family members, IL-1?, IL-1?, IL-1Ra and IL-18 in the development of inflammatory autoimmune diseases such as RA is widely recognized. Interestingly, the cell surface receptor for IL-33, called T1/ST2, is highly expressed on mast cells, which are important mediators of the pathogenesis of arthritis. These observations suggest that, like other IL-1 family cytokines, IL-33 and T1/ST2 might be involved in the disease process in RA and other inflammatory conditions. The experiments included in this proposal aim at investigating the effects of IL-33 on mast cells, as well as on cells isolated from joint tissues such as cartilage and synovium in vitro. Furthermore, we plan to study expression of IL-33 in normal and inflamed mouse tissues and in the human joint. Finally, we will explore the role of the IL-33 - T1/ST2 pathway in mouse models of arthritis in vivo. The results of these experiments will provide important new information on the role of IL-33 in joint inflammation, hopefully leading to novel strategies in the treatment of inflammatory arthritis.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
134691 T1/ST2 receptor dependent and independent functions of IL-33 in arthritis 01.05.2011 Project funding

Abstract

Background: The interleukin (IL)-1 family includes IL-1alpha, IL-1beta, and IL-18, which play an important role in inflammatory responses, as well as IL-1 receptor antagonist (IL-1Ra), a specific IL-1 inhibitor. In addition, seven novel cytokines homologous to IL-1, namely IL-1F5 to IL-1F10 and IL-33 (or IL-1F11), have been cloned in the last years. The biologic function of these cytokines is still poorly characterized. IL-33 was recently identified as a ligand for the orphan IL-1 family receptor T1/ST2. A number of studies had established the T1/ST2 receptor as a selective marker of both murine and human T helper (Th)2 lymphocytes. In addition, T1/ST2 is also highly expressed on mast cells. Like other IL-1 family cytokines, IL-33 mediates its biological effects via T1/ST2 by activating NF-kB and MAP kinases. The role of the four ‘classical’ IL-1 family members, IL-1alpha, IL-1beta, IL-1Ra and IL-18 in the development of inflammatory autoimmune diseases such as rheumatoid arthritis (RA) is widely accepted. Interestingly, mast cells have also been recognized as important mediators of the pathogenesis of arthritis. Working hypothesis: These observations suggest that, like other members of the IL-1/IL-1R families, IL-33 and T1/ST2 might be involved in the disease process in RA and other inflammatory conditions.Specific aims and experimental design: The objective of the experiments included in this proposal is to investigate the expression and biological functions of the new IL-1 family member IL-33 and its receptor T1/ST2 in arthritis through the three following specific aims:1. To characterize the effects of IL-33 on mast cells, chondrocytes and synovial fibroblasts in vitro. 2. To study the expression pattern of IL-33 in normal and inflamed mouse tissues and in the human joint and to investigate the post-translational processing of the IL-33 protein.3. To explore the role of the IL-33 - T1/ST2 pathway in the mouse models of K/BxN serum transfer-induced arthritis and collagen-induced arthritis in vivo. Expected value of the proposed project: Recent findings on the role of cytokines such as IL-1, tumor necrosis factor (TNF)-alpha and IL-6 have led to significant improvement in our understanding of the pathogenesis and to the development of efficacious treatments for RA. However, some patients do not respond to treatments based on blockade of these cytokines, indicating that additional mediators are involved in the pathophysiology of the disease. Recently, novel members of the IL-1 family of cytokines and their receptors have been described, but their biological relevance remains unclear. The results of the experiments described in this proposal will provide important new information on the role of one of these cytokines, IL-33, and its receptor T1/ST2, in joint inflammation, hopefully leading to novel strategies in the treatment of inflammatory arthritis.
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