# On- and Off-Axis Control of Fibrosis by IL-33 and ST2

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2024 · —

## Abstract

Interleukin (IL)-33 and its receptor, ST2, centrally control a remarkable variety of inflammatory and fibrotic
diseases. The IL-33 – ST2 axis relies mostly on the proteolytically mature form of IL-33 cytokine (MIL33), with
less attention usually devoted to the full-length precursor (FLIL33), which is a nuclear factor. The MIL33 – ST2
axis serves diverse functions, among which one of the most prominent is induction of the Th2 phenotype, with
an overt elevation of IL-4, IL-5, and IL-13, leading to eosinophilia, mucus production, and clinical manifestation
of allergy. It remains unclear how the MIL33 – ST2 pathway, while certainly contributing to inflammation and
fibrosis, mediates its proinflammatory and profibrotic effects without always eliciting the Th2 phenotype. Our
preliminary data strongly suggest that IL-33, particularly in its FLIL33 form, may promote inflammation and
fibrosis in an ST2-independent fashion, and reciprocally, ST2 may control inflammation and fibrosis without
requiring IL-33. Thus, we proposed, for the first time, that IL-33 and ST2 may contribute to inflammation and
fibrosis in an “off-axis” fashion. FLIL33 behaves distinctly from MIL33. Some earlier studies suggested that as
a basally and inducibly expressed nuclear factor, FLIL33 modulates inflammatory responses, wound healing,
chromatin stability, and transcriptional regulation in a non-Th2 and receptor-independent manner. Yet, the
pathophysiology of the understudied FLIL33 requires more attention in general and is nearly completely
unknown in fibrosis specifically. Our published and preliminary data suggest that: FLIL33 but not MIL33
potentiates fibrosis without inducing the Th2 phenotype; such distinct effect is partially mediated by ST2 and
also occurs in the absence of ST2; FLIL33 acts so at the levels of both transcriptional and post-transcriptional
regulation; ST2 by itself controls fibrosis; and such regulation involves IL-9.
Based on these findings, the Hypothesis of this study is that in addition to the commonly acknowledged role of
the MIL33 – ST2 axis, FLIL33 contributes to fibrosis both with and without engaging ST2, through both
transcriptional and post-transcriptional regulation, and that ST2 itself may regulate fibrosis through a
mechanism that in part involves IL-9. To challenge this hypothesis, the following Specific Aims will be pursued.
Aim 1 is to define ST2-independent, Th2-independent, post-transcriptional, mechanisms through which full-
length IL-33 potentiates fibrosis. Aim 2 is to define ST2-dependent, Th2-independent, transcriptional,
mechanisms through which full-length IL-33 potentiates fibrosis. Aim 3 is to determine the role of IL-9 in
controlling fibrosis in an ST2-dependent fashion and identify the mechanisms through which both full-length
and mature IL-33 forms attenuate IL-9. A successful completion of these studies will form the basis for better
therapeutic targeting of IL-33 and ST2 is inflammatory and fibrotic diseases. Inflammation a...

## Key facts

- **NIH application ID:** 10697478
- **Project number:** 1I01BX006173-01A1
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Irina G. Luzina
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10697478

## Citation

> US National Institutes of Health, RePORTER application 10697478, On- and Off-Axis Control of Fibrosis by IL-33 and ST2 (1I01BX006173-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10697478. Licensed CC0.

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