# Pathogenesis of Fever in Man

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $388,750

## Abstract

Project Summary/Abstract
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-1α 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 α−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.

## Key facts

- **NIH application ID:** 9829996
- **Project number:** 5R01AI015614-38
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Charles anthony Dinarello
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 1986-12-01 → 2021-09-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829996

## Citation

> US National Institutes of Health, RePORTER application 9829996, Pathogenesis of Fever in Man (5R01AI015614-38). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9829996. Licensed CC0.

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