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Home / Equine Research Bank / Cell Tissue Res / Interleukin-4 changes the transcriptome, ECM-associated comp...
Cell and tissue research2026; 403(2); 25; doi: 10.1007/s00441-026-04049-6

Interleukin-4 changes the transcriptome, ECM-associated components and function of mare endometrial fibroblast: Insights from healthy and fibrotic cells.

Abstract: Fibrosis remains incompletely understood, particularly in terms of how immune mediators shape stromal programs. We used a spontaneous large‑animal model-endometrosis (equine endometrial fibrosis) to define how interleukin‑4 (IL‑4) reprograms fibroblasts from healthy and fibrotic endometrium. Primary fibroblasts were exposed to IL‑4 (10 ng/mL) for 48 or 96 h. At 48 h, bulk transcriptomes revealed 1307 differentially expressed genes (DEGs; 648 up, 659 down) and 1271 DEGs (645 up, 626 down) in fibroblasts derived from endometria without or with endometrosis, respectively. Enrichment analyses implicated cellular metabolism, extracellular matrix (ECM) organization and remodeling, and signaling pathways commonly linked to fibrogenesis. IL‑4 also affected the long non‑coding RNA (lncRNA) expression, with 143 and 135 differentially expressed lncRNAs in fibroblasts derived from healthy or fibrotic endometria, respectively; linking these lncRNAs to DEGs involved in inflammation, ECM organization, and cytokine signaling. Moreover, IL‑4 increased proliferation and viability in fibroblasts derived from healthy or fibrotic endometria, while selectively reducing migration in fibroblasts derived from endometria without fibrosis after 96 h. IL‑4 further altered mRNA expression, protein abundance, and gelatinolytic activity of matrix metalloproteinases in a manner contingent on the fibrosis status of the tissue of origin, indicating stage‑dependent control of ECM turnover. Collectively, these data identify IL‑4 as a potent modulator of fibroblast function in a spontaneous large‑animal fibrosis model, revealing fibrosis stage‑dependent responses.
© 2026. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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Publication Date: 2026-02-23 PubMed ID: 41729313PubMed Central: 3302189DOI: 10.1007/s00441-026-04049-6Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This study investigates how interleukin-4 (IL-4), an immune signaling molecule, influences the behavior and gene expression of fibroblasts in the mare’s endometrium, both in healthy tissue and in tissue affected by fibrosis (endometrosis).
  • The research reveals that IL-4 notably changes gene activity, extracellular matrix-related components, and the functional characteristics of these fibroblasts in a way that depends on whether the tissue is fibrotic or not.

Background and Objective

  • Fibrosis is a process where excessive connective tissue builds up, impairing normal tissue function; it remains poorly understood, especially how immune factors such as IL-4 influence stromal (connective) cells.
  • The mare endometrium provides a spontaneous large-animal model of fibrosis called endometrosis, allowing study in a relevant biological context.
  • The researchers aimed to clarify how IL-4 affects fibroblast gene expression (transcriptome), extracellular matrix (ECM) components, and cellular functions in healthy versus fibrotic endometrial fibroblasts.

Methodology

  • Primary fibroblasts were isolated from mare endometrial tissue, both from healthy samples and from those with fibrotic changes (endometrosis).
  • Cells were treated with IL-4 at a concentration of 10 ng/mL, for two durations: 48 hours and 96 hours.
  • Bulk RNA sequencing was performed at 48 hours to identify differentially expressed genes (DEGs) between treated and untreated cells.
  • Functional assays measured fibroblast proliferation, viability, and migration.
  • Protein analysis assessed matrix metalloproteinases (MMPs) abundance, and enzymatic activity assays focused on gelatinolytic activity, indicative of ECM remodeling capacity.

Key Findings: Transcriptomic Changes

  • At 48 hours, IL-4 treatment induced large-scale gene expression changes:
    • In fibroblasts from healthy endometrium: 1307 DEGs (648 upregulated, 659 downregulated).
    • In fibroblasts from fibrotic tissue: 1271 DEGs (645 upregulated, 626 downregulated).
  • Gene enrichment analysis showed affected pathways related to:
    • Cellular metabolism.
    • Extracellular matrix organization and remodeling.
    • Fibrosis-associated signaling pathways.
  • Long non-coding RNAs (lncRNAs), which regulate gene expression, were also altered by IL-4:
    • 143 lncRNAs differentially expressed in healthy fibroblasts.
    • 135 in fibrotic fibroblasts.
    • Many of these lncRNAs linked to genes involved in inflammation, ECM organization, and cytokine signaling.

Functional Effects of IL-4 on Fibroblasts

  • IL-4 increased both proliferation (cell growth) and viability in fibroblasts from healthy and fibrotic tissues.
  • Migration behavior was selectively reduced by IL-4 in fibroblasts from healthy endometrium after 96 hours, but not in fibrotic fibroblasts.

Regulation of ECM Remodeling and MMP Activity

  • Matrix metalloproteinases (MMPs) are enzymes that degrade ECM components, playing a key role in ECM turnover and fibrosis.
  • IL-4 modified:
    • MMP mRNA expression levels.
    • Protein abundance of MMPs.
    • Gelatinolytic enzymatic activity of MMPs.
  • These changes were dependent on whether the fibroblasts originated from healthy or fibrotic tissues, indicating IL-4’s role is stage-dependent in controlling ECM dynamics during fibrosis progression.

Conclusions and Implications

  • IL-4 acts as a strong modulator of fibroblast behavior and gene expression in the mare endometrium.
  • The cytokine’s effects vary depending on whether the fibroblasts come from healthy or fibrotic tissue, highlighting different cellular states or stages of fibrosis.
  • This study provides novel insights into immune regulation of fibrosis in a relevant large-animal model, which may help develop strategies to manage or treat fibrosis by targeting IL-4 pathways.

Cite This Article

APA
Wójtowicz A, Sadowska A, Myszczyński K, Molcan T, Kaczmarek MM, Szóstek-Mioduchowska A. (2026). Interleukin-4 changes the transcriptome, ECM-associated components and function of mare endometrial fibroblast: Insights from healthy and fibrotic cells. Cell Tissue Res, 403(2), 25. https://doi.org/10.1007/s00441-026-04049-6

Publication

Cell and tissue research
ISSN: 1432-0878
NlmUniqueID: 0417625
Country: Germany
Language: English
Volume: 403
Issue: 2
PII: 25

Researcher Affiliations

Wójtowicz, Anna
  • Team of Molecular Basis of Equine Reproduction, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
Sadowska, Agnieszka
  • Team of Molecular Basis of Equine Reproduction, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
Myszczyński, Kamil
  • Molecular Biology Laboratory, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
  • Computational Biology Laboratory, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
Molcan, Tomasz
  • Molecular Biology Laboratory, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
  • Computational Biology Laboratory, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
Kaczmarek, Monika M
  • Team of Programming of Fertility and Development, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
Szóstek-Mioduchowska, Anna
  • Team of Molecular Basis of Equine Reproduction, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland. a.szostek-mioduchowska@pan.olsztyn.pl.

MeSH Terms

  • Animals
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibroblasts / drug effects
  • Endometrium / pathology
  • Endometrium / metabolism
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / drug effects
  • Transcriptome / drug effects
  • Transcriptome / genetics
  • Fibrosis
  • Interleukin-4 / pharmacology
  • Horses
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • Cell Proliferation / drug effects
  • Cell Movement / drug effects
  • Gene Expression Profiling

Conflict of Interest Statement

Declarations. Ethics approval: This study used mare endometrial tissue obtained post-mortem from mares at a commercial slaughterhouse, where the animals were processed solely for meat production. As the samples were collected after death from non-experimental animals, no ethical approval was required. Competing interests: The authors declare no competing interests.

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