Despite advances in cytokine-based therapeutics, such as neutralizing antibodies, new therapies, based on naturally occurring anti-inflammatory cytokines, have the potential to be effective. Interleukin-37 (IL-37), a member of the IL-1 family, has been a neglected cytokine without clear function. It has now become clear that IL-37 broadly suppresses innate inflammation and acquired immunity. The present application focuses on this cytokine and proposes to advance to potential therapeutic forms to treat human disease. Two of four aims of this proposal address outstanding issues related to the mechanism of action of IL-37. IL-37 being a dual function cytokine, similar to IL-1? and IL-33, translocatesto the nucleus but also binds to an extracellular receptor. Both exert anti-inflammatory properties. Therefore, we will generate a new strain of transgenic mice that lack the ability for IL-37 nuclear function and compare the responses to mice transgenic for the native form of human IL-37. IL-37 binds to the naturally occurring IL-18 binding protein (IL-18BP) and IL-18BP is in several clinical trials to treat auto-inflammatory diseases. We will assess the in vivo consequence of IL-18BP on the therapeutic benefit of recombinant IL-37 by using a newly developed strain of mice deficient in IL-18BP. IL-37 will be tested for its anti-inflammatory properties in IL-18BP deficien mice. Transgenic mice expressing human IL-37 will be treated with increasing doses of recombinant IL-18BP and determine how the concentrations of exogenous IL-18BP affect outcomes to inflammatory challenges.
The third Aim directly addresses the question, what is the optimal form of IL-37 to develop as a therapeutic? Lacking a signal peptide, we will generate different N- and C-terminal forms of recombinant human IL-37 based on computerized molecular modeling, receptor binding assays and, most importantly, their anti-inflammatory and immunosuppressive properties using newly developed in vitro and in vivo assays. Once we have selected the sequence(s) of IL-37 for optimal anti-inflammatory properties, we will perform in vivo dosing studies in mice. In addition, we plan to produce a novel recombinant human IL-37 linked to the Fc domain of mouse IgG1 (IL-37:Fc) in order to increase in vivo efficacy of IL-37 in murine models of innate inflammation and immune-mediated diseases.
The fourth Aim addresses polymorphisms in the IL-37 gene and how these affect the function of the cytokine. Using the novel technique of Molecular Internal Probe, we will be able to link common and rare mutations in the IL-37 gene to in vitro production in 850 subjects. Data from this Aim will contribute to the identification of persons who may benefit from IL-37 therapy. The overall goal of these studies is to advance the field of cytokine-based therapeutics, particularly of naturally occurring anti-inflammatory cytokines such as IL-37. The objectives of this proposal are to investigate how best to accomplish this goal.

Public Health Relevance

Interleukin-37 is a small protein made by the body in response to inflammation or an infection. The major property of Interleukin-37 is to reduce inflammation and also to limit damage from infections. The project will result in a better understanding of the role of Interleukin-37 in human diseases and also develop methods to use Interleukin-37 as a therapeutic to treat various inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI015614-36
Application #
9201590
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dong, Gang
Project Start
1986-12-01
Project End
2017-01-31
Budget Start
2016-02-10
Budget End
2017-01-31
Support Year
36
Fiscal Year
2016
Total Cost
$311,000
Indirect Cost
$111,000
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Brinkmann, Christel Rothe; Højen, Jesper Falkesgaard; Rasmussen, Thomas Aagaard et al. (2018) Treatment of HIV-Infected Individuals with the Histone Deacetylase Inhibitor Panobinostat Results in Increased Numbers of Regulatory T Cells and Limits Ex Vivo Lipopolysaccharide-Induced Inflammatory Responses. mSphere 3:
Dinarello, Charles A (2018) Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 281:8-27
Dinarello, Charles Anthony; Kaplanski, Gilles (2018) Indeed, IL-18 is more than an inducer of IFN-?. J Leukoc Biol 104:237-238
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Dinarello, Charles Anthony (2018) An Interleukin-1 Signature in Breast Cancer Treated with Interleukin-1 Receptor Blockade: Implications for Treating Cytokine Release Syndrome of Checkpoint Inhibitors. Cancer Res 78:5200-5202
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Marchetti, Carlo; Swartzwelter, Benjamin; Gamboni, Fabia et al. (2018) OLT1177, a ?-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci U S A 115:E1530-E1539
Cavalli, Giulio; Justice, Jamie N; Boyle, Kristen E et al. (2017) Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance. Proc Natl Acad Sci U S A 114:2313-2318
Davis, Christopher J; Zielinski, Mark R; Dunbrasky, Danielle et al. (2017) Interleukin 37 expression in mice alters sleep responses to inflammatory agents and influenza virus infection. Neurobiol Sleep Circadian Rhythms 3:1-9

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