Interleukin-37 (IL-37), a member of the IL-1 family, has been a neglected cytokine mostly because there is no mouse homologue for IL-37. However, we expressed human IL-37 in mice, which revealed that IL-37 broadly suppresses innate inflammation and acquire immunity and that recombinant human IL-37 accomplishes the same in wild type mice. Similar to IL-1? and IL-33, IL-37 is a dual function cytokine in that IL-37 translocates to the nucleus but also binds its cell surface receptor complex. The present application focuses on the mechanism for these properties. The translocation of IL-37 to the nucleus depends on caspase-1 cleavage followed by the carboxyl domain binding to chromatin. To determine to what extent nuclear IL-37 contributes to suppression of innate and acquire immunity, we have generated a new strain of mice that lacks the ability for IL-37 to translocate to the nucleus by to mutating the caspase-1 recognition site on IL-37 without altering the activity of caspase-1 in the same cell. In order to establish an independent role for nuclear IL-37, the cell surface receptors for IL-37 (IL-18 Receptor ??chain) will be prevented using a blocking antibody in short-term models. In both short and long-term models, we will use mice deficient in IL-1R8, the IL-37 co-receptor.
The second Aim of this proposal directly addresses the binding of IL-37 to the IL-18 Binding Protein (IL-18BP) and investigates whether administration of IL-18BP reduces the protection afforded by endogenous IL-37. We have generated a transgenic mouse expressing human IL-18BP to determine whether administration of recombinant human IL-37 is less effective in mice expressing human IL-18BP. Since recombinant human IL-37 possesses several properties to suppress innate and acquired immunity, the translational component of the proposal is the development of IL-37 as a therapeutic. As with several members of the IL-1 family, the N- and C-terminal for optimal biologic activity is unknown. We have produced a recombinant form of IL-37 fused to the Fc domain of human IgG1 (IL-37Fc fusion protein) and demonstrated its efficacy. We will now determine the N- and C-termini of IL-37 for an optimal form of recombinant IL-37 to limit of innate inflammation. Once this has been established, an improved IL-37Fc fusion protein will also be produced and tested in preclinical models. The overall goal of these studies is to advance the biology and clinical significance of IL-37 as well as to exploit its anti- inflammatory properties as a therapeutic.

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. The project also will make Interleukin-37 a therapeutic to treat various inflammatory diseases in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI015614-36A1
Application #
9448601
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Singleton, Kentner L
Project Start
1986-12-01
Project End
2020-10-31
Budget Start
2017-11-03
Budget End
2018-10-31
Support Year
36
Fiscal Year
2018
Total Cost
Indirect Cost
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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Cri?an, Tania O; Cleophas, Maartje C P; Novakovic, Boris et al. (2017) Uric acid priming in human monocytes is driven by the AKT-PRAS40 autophagy pathway. Proc Natl Acad Sci U S A 114:5485-5490
Zeng, Qingchun; Song, Rui; Fullerton, David A et al. (2017) Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice. Proc Natl Acad Sci U S A 114:1631-1636
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
Dinarello, Charles A; Nold-Petry, Claudia; Nold, Marcel et al. (2016) Suppression of innate inflammation and immunity by interleukin-37. Eur J Immunol 46:1067-81
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Dinarello, Charles A; Joosten, Leo A B (2016) Inflammation in rheumatology in 2015: New tools to tackle inflammatory arthritis. Nat Rev Rheumatol 12:78-80
Tzanetakou, Vassiliki; Kanni, Theodora; Giatrakou, Sophia et al. (2016) Safety and Efficacy of Anakinra in Severe Hidradenitis Suppurativa: A Randomized Clinical Trial. JAMA Dermatol 152:52-59
Coll-MirĂ³, Marina; Francos-Quijorna, Isaac; Santos-Nogueira, Eva et al. (2016) Beneficial effects of IL-37 after spinal cord injury in mice. Proc Natl Acad Sci U S A 113:1411-6

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