Project

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T1/ST2 receptor dependent and independent functions of IL-33 in arthritis

Applicant Palmer Gaby
Number 134691
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 01.05.2011 - 31.10.2014
Approved amount 375'000.00
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Keywords (4)

inflammation; autoimmunity; interleukin; immune response

Lay Summary (English)

Lead
Lay summary

Aimof the project: To define therole of the cytokine interleukin (IL)-33 in arthritis.

Context: Cytokines are signaling proteins,which allow communication between cells and are important mediators of theimmune response. Rheumatoid arthritis (RA) is an autoimmune diseasecharacterized by chronic inflammation of the synovial tissue in multiplejoints, which leads to joint destruction. In RA, there is an excessiveactivity of pro-inflammatory cytokines and this observation led to thedevelopment of new therapies based on anti-cytokine treatments. In thisproject, we propose to study the role of a recently discovered cytokinebelonging to the IL-1 family, IL-33, in the disease process leading toarthritis.

Hypothesisand expected results:Studies performed over the last years have suggested that IL-33 haspro-inflammatory effects in joint inflammation in human and mouse. IL-33 is aninteresting molecule, which possesses both extracellular effects mediated byits binding to the cell surface receptor T1/ST2, and intracellular effects as anuclear protein. However, while the extracellular effects of IL-33 are beingwidely explored, only scarce information is available about its nuclear, T1/ST2independent activity. We are particularly interested in defining T1/ST2dependent and independent effects of IL-33 in the context of jointinflammation.   

Significanceas well as on the therapeutic potential of this new target in the treatment ofinflammatory arthritis.in vivo,: The results of these studies will provideimportant information concerning T1/ST2 receptor dependent and independentfunctions of IL-33 in modulating immune responses and inflammation

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The interleukin (IL)-1 cytokine family – Balance between agonists and antagonists in inflammatory diseases
Palomo Jennifer, Dietrich Damien, Martin Praxedis, Palmer Gaby, Gabay Cem (2015), The interleukin (IL)-1 cytokine family – Balance between agonists and antagonists in inflammatory diseases, in Cytokine, 76(1), 25-37.
Atherosclerosis severity is not affected by a deficiency in IL-33/ST2 signalingDeficiency in IL-33 signaling does not affect atherosclerosis severity
Martin Praxedis, Palmer Gaby, Rodriguez Emiliana, Woldt Estelle, Mean Isabelle, James Richard W., Smith Dirk E., Kwak Brenda R., Gabay Cem (2015), Atherosclerosis severity is not affected by a deficiency in IL-33/ST2 signalingDeficiency in IL-33 signaling does not affect atherosclerosis severity, in Immunity, Inflammation and Disease, 3(3), 239-246.
Immune-mediated experimental arthritis in IL-33 deficient mice.
Talabot-Ayer Dominique, Martin Praxedis, Seemayer Christian Alexander, Vigne Solenne, Lamacchia Céline, Finckh Axel, Saiji Essia, Gabay Cem, Palmer Gaby (2014), Immune-mediated experimental arthritis in IL-33 deficient mice., in Cytokine, 69(1), 68-74.
Severe neutrophil-dominated inflammation and enhanced myelopoiesis in IL-33-overexpressing CMV/IL33 mice
Talabot-Ayer Dominique, Martin Praxedis G., Vesin Christian, Seemayer Christian Alexander, Vigne Solenne, Gabay Cem E M, Palmer Gaby William (2014), Severe neutrophil-dominated inflammation and enhanced myelopoiesis in IL-33-overexpressing CMV/IL33 mice, in Journal of Immunology, 194(2), 750-760.
Disease severity in K/BxN serum transfer-induced arthritis is not affected by IL-33 deficiency.
Martin Praxedis, Talabot-Ayer Dominique, Seemayer Christian Alexander, Vigne Solenne, Lamacchia Céline, Rodriguez Emiliana, Finckh Axel, Smith Dirk E, Gabay Cem, Palmer Gaby (2013), Disease severity in K/BxN serum transfer-induced arthritis is not affected by IL-33 deficiency., in Arthritis research & therapy, 15(1), 13-13.
Reply to Xie et al. about the article "Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis".
Talabot-Ayer Dominique, Gabay Cem, Palmer Gaby (2013), Reply to Xie et al. about the article "Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis"., in Joint, bone, spine : revue du rhumatisme, 80(1), 117-8.
The mouse interleukin (Il)33 gene is expressed in a cell type- and stimulus-dependent manner from two alternative promoters.
Talabot-Ayer Dominique, Calo Nicolas, Vigne Solenne, Lamacchia Céline, Gabay Cem, Palmer Gaby (2011), The mouse interleukin (Il)33 gene is expressed in a cell type- and stimulus-dependent manner from two alternative promoters., in Journal of leukocyte biology, 91(1), 119-125.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
10th Joint Meeting of the International Society for Interferon and Cytokine Research and the International Cytokine Society Talk given at a conference IL-33 and ST2 KO mice display different phenotypes in K/BxN serum transfer-induced arthritis 11.09.2012 Geneva, Switzerland, Switzerland Palmer Gaby;
9th Joint Meeting of the International Society for Interferon and Cytokine Research and the International Cytokine Society Poster The mouse interleukin-33 gene is expressed in cell type and stimulus dependent manner from two alternative promoters 09.10.2011 Florence, Italy Palmer Gaby;


Associated projects

Number Title Start Funding scheme
120319 Expression and function of the novel IL-1 family cytokine IL-33 in arthritis 01.05.2008 Project funding

Abstract

Background: Interleukin (IL)-33 (or IL-1F11) is the most recently discovered member of the IL-1 cytokine family, which was identified as a ligand for the T1/ST2 receptor. IL-33 is constitutively expressed in the nucleus of endothelial and epithelial cells. In addition, IL-33 expression is induced in both resident and infiltrated cells in inflamed tissues. Consistent with expression of the T1/ST2 receptor on many cells involved in Th2 type immunity, IL-33 injection induces or amplifies Th2 type responses in various mouse models. However, IL-33 also displays pro-inflammatory effects in models which are independent of Th2 type immunity, including experimental models of arthritis. Over the last year, it has become clear that IL-33 is not, as initially thought, a caspase-1 dependent cytokine, but this interesting molecule rather emerged as a dual function protein, similar to IL-1a, displaying both nuclear and extracellular effects. However, while the extracellular, T1/ST2 dependent effects of IL-33 are being widely explored, only scarce information is available about its nuclear, T1/ST2 independent functions.Working hypothesis: Our working hypothesis is that the new IL-1 family cytokine IL-33 is involved in the inflammatory process in arthritis. In this context, we are particularly interested in defining both extracellular, T1/ST2 dependent, as well as potential nuclear functions of IL-33. Specific aims and experimental design: The purpose of our studies is to explore the respective roles of IL-33 and T1/ST2 in mouse models of arthritis in vivo. In addition, we plan to investigate nuclear effects of IL-33 in vitro in cultured myeloid cells and to analyze the regulation of IL-33 transcription. Accordingly, this proposal includes the following 3 specific aims:1. To examine the effect of IL-33 deficiency, as compared to that of T1/ST2deficiency, in three complementary models of arthritis in mice2. To investigate the nuclear functions, protein-protein and protein-DNA interactions of IL-333. To study the regulation of IL-33 mRNA expression Expected value of the proposed project: Our understanding of the role of cytokines, such as TNF-a or IL-6, in the pathogenesis of rheumatoid arthritis, has led to the development of efficacious treatments. However, a proportion of patients does not respond to treatments based on blockade of these molecules, indicating that additional mediators are involved in the pathophysiology of this disease. Recently, IL-33 emerged as an interesting dual function cytokine with both extracellular and nuclear effects. The results of the experiments described in this proposal will provide important information concerning T1/ST2 receptor dependent and independent functions of IL-33 in modulating immune responses and inflammation in vivo, as well as on the therapeutic potential of this new target in the treatment of inflammatory arthritis. Focusing on receptor-independent effects of IL-33, we will complete this work by in vitro analysis of the nuclear functions of IL-33 in activated innate immune cells. Finally, we will study the regulation of IL-33 mRNA expression.
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