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

Anna K. Wójtowicz, Agnieszka Sadowska, Kamil Myszczyński, Tomasz Molcan, Monika M. Kaczmarek, Anna Szóstek-Mioduchowska
In: Cell and Tissue Research · 2026 · vol. 403(2) · doi:10.1007/s00441-026-04049-6 · PMID:41729313 · W7131124559
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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. Interleukin-4 (IL-4) modulates the transcriptome, extracellular matrix (ECM)–associated components, and functional characteristics of mare endometrial fibroblasts derived from healthy and fibrotic uteri. IL-4 treatment induces distinct transcriptomic and proteomic changes, alters cell proliferation, migration, collagen contractility, and MMP activity, and elicits differential responses between non-fibrotic and fibrotic cells, highlighting fibrosis-dependent effects of IL-4 on endometrial remodeling.

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