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 #
5R01AI015614-37
Application #
9594138
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Liu, Qian
Project Start
1986-12-01
Project End
2020-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
37
Fiscal Year
2019
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
Dinarello, Charles Anthony; Kaplanski, Gilles (2018) Indeed, IL-18 is more than an inducer of IFN-?. J Leukoc Biol 104:237-238
Cavalli, Giulio; Dinarello, Charles A (2018) Suppression of inflammation and acquired immunity by IL-37. Immunol Rev 281:179-190
Jeong, Mark Y; Lin, Ying H; Wennersten, Sara A et al. (2018) Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Sci Transl Med 10:
Dinarello, Charles A (2018) Introduction to the interleukin-1 family of cytokines and receptors: Drivers of innate inflammation and acquired immunity. Immunol Rev 281:5-7
Cavalli, Giulio; Dinarello, Charles A (2018) Anakinra Therapy for Non-cancer Inflammatory Diseases. Front Pharmacol 9:1157
Wade, Morgan F; Collins, Morgan K; Richards, Denay et al. (2018) TLR9 and IL-1R1 Promote Mobilization of Pulmonary Dendritic Cells during Beryllium Sensitization. J Immunol 201:2232-2243
Marchetti, Carlo; Swartzwelter, Benjamin; Koenders, Marije I et al. (2018) NLRP3 inflammasome inhibitor OLT1177 suppresses joint inflammation in murine models of acute arthritis. Arthritis Res Ther 20:169
Kuipers, Eline N; van Dam, Andrea D; Ballak, Dov B et al. (2018) IL-37 Expression Reduces Lean Body Mass in Mice by Reducing Food Intake. Int J Mol Sci 19:
Tengesdal, Isak W; Kitzenberg, David; Li, Suzhao et al. (2018) The selective ROCK2 inhibitor KD025 reduces IL-17 secretion in human peripheral blood mononuclear cells independent of IL-1 and IL-6. Eur J Immunol 48:1679-1686
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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