# Taming IL-33 to Control Inflammation and Fibrosis

> **NIH NIH R56** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $339,900

## Abstract

Inflammation and fibrosis often co-occur and contribute to a remarkably broad variety of diseases of every
organ and tissue. The overall role of interleukin (IL)-33 in inflammation and fibrosis has already been
established, but the mechanisms of such regulation are not fully understood. Limited attention has been paid
to the IL-33 precursor—full-length IL-33 (FLIL33)—which is basally and inducibly expressed, resides mostly
in the cell nucleus, and is thought to regulate inflammatory responses, wound healing, and transcriptional
regulation independently of the mature IL-33 (MIL33) cytokine. The understudied FLIL33 requires more
attention, because it is both the immediate source of the MIL33 cytokine and an independently active factor.
These IL-33 forms become pathophysiologically engaged under stress, but IL-33-null mice have no noticeable
basal phenotype, suggesting that IL-33 depletion is a safe therapeutic approach. Our objective is to form the
basis for therapeutic manipulation of IL-33 in inflammatory fibrotic diseases through integrated understanding
of proteolytic maturation and extracellular release of MIL33, intracellular signaling and functioning of FLIL33,
and proteolytic stability of the FLIL33 protein pool. We amassed new data related to the molecular control of
IL-33 subcellular localization, functional maturation, and extracellular release through a previously unknown
region within the FLIL33 molecule, which spans substantially more of the N-terminus than the currently known
“sensor domain.” We hypothesize that this segment may be targeted to control IL-33 activation and
extracellular release. We also discovered that the intracellular function of FLIL33 is centered on Smad3
phosphorylation in a TGF-beta-independent fashion. We hypothesize that this process is mediated by the
adaptor-related protein complex 2 and that targeting this mechanism allows for abrogation of the functional
effects of intracellular FLIL33. We also recently reported that importin 5 (IPO5) protects FLIL33 from
proteolytic degradation, driving the hypothesis that IPO5-binding, cell-permeable decoy peptide(s) will induce
the loss of IPO5-mediated protection of FLIL33 from proteasomal degradation. This prospective therapy will
deplete the FLIL33 protein pool, thus exhausting the source of MIL33 and simultaneously attenuating the
intracellular effects ofFLIL33. The Specific Aims of this project are to: 1) Precisely map the segments in the
N-terminal region of FLIL33 that are responsible for its nuclear-versus-cytoplasmic localization, functional
maturation, extracellular release, and selective binding of intracellular molecular partners; 2) Define the
molecular mechanism responsible for FLIL33-induced, TGF-βligand-independent phosphorylation of Smad3;
and 3) Develop a cell-permeable decoy peptide-based approach to deplete intracellular FLIL33, thereby
exhausting the source of MIL33 and simultaneously attenuating the independent effects of FLIL33. Evaluate
the in vi...

## Key facts

- **NIH application ID:** 10242333
- **Project number:** 1R56AR077562-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Irina G. Luzina
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,900
- **Award type:** 1
- **Project period:** 2020-09-03 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242333

## Citation

> US National Institutes of Health, RePORTER application 10242333, Taming IL-33 to Control Inflammation and Fibrosis (1R56AR077562-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242333. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*