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Background <p>Glucose homeostasis is essential for cellular function in the testis and deviations in glucose levels are triggering profound physiological and pathological changes. Sertoli cells, critical somatic cells for spermatogenesis, are particularly sensitive to metabolic stress, including fluctuations in extracellular glucose levels.</p> Aims <p>The present study explores the consequences of high and low extracellular glucose concentrations on miRNA (miR) expression, inflammatory responses, and cellular viability in TM4 Sertoli cells.</p> Methods <p>TM4 cells were cultured under control (5.5 mM glucose), high (115 mM glucose) and low (&lt; 0.505 mM glucose) conditions and analyzed for miR (miR-155, miR-155-5p, miR-124, and miR-132) expression, anti-and pro-inflammatory cytokine production (IL-1β, IL-6, TNF-α, TGF-β, and IL-10), and cell viability.</p> Results <p>Quantitative real-time polymerase chain reaction (qRT-PCR) revealed significant upregulation of miR-155 and miR-155-5p in high- and low-glucose conditions respectively, while low glucose elevated miR-155-5p but suppressed miR-124 expression. Both glucose conditions upregulated miR-132 without significant differences between the two treatments. Pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α were significantly elevated at the mRNA and protein levels and TGF-β at mRNA level in response to glucose stress. Low glucose induced more robust TNF-α and IL-6 responses compared to high glucose, whereas anti-inflammatory IL-10 expression significantly decreased only under low-glucose conditions. Cell viability was reduced under both glucose treatments, with a more pronounced effect in low glucose.</p> Conclusions <p>These findings highlight a glucose-dependent regulatory mechanism in TM4 Sertoli cells, where miRNA expression correlates with inflammatory cytokine profiles. Low glucose amplified pro-inflammatory responses, potentially driven by suppressed miR-124, while high glucose elicited a compensatory anti-inflammatory response with stable IL-10 expression. This study provides insights into the metabolic and inflammatory dynamics of Sertoli cells, emphasizing the role of miRNAs in modulating cellular responses to glucose stress, with implications for understanding diabetic testicular pathophysiology.</p> Graphical Abstract <p></p>

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Divergent glucose stress responses in TM4 Sertoli cells: a miRNA-driven regulatory landscape of inflammation and cytokine expression

  • 期刊论文

  • 发表日期：

    2025年8月11日

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  • Khder H. Rasul,
  • Esra O. Hameed,
  • Karim J. Karim,
  • Sana Moshari,
  • Amir Nahali

摘要

Background

Glucose homeostasis is essential for cellular function in the testis and deviations in glucose levels are triggering profound physiological and pathological changes. Sertoli cells, critical somatic cells for spermatogenesis, are particularly sensitive to metabolic stress, including fluctuations in extracellular glucose levels.

Aims

The present study explores the consequences of high and low extracellular glucose concentrations on miRNA (miR) expression, inflammatory responses, and cellular viability in TM4 Sertoli cells.

Methods

TM4 cells were cultured under control (5.5 mM glucose), high (115 mM glucose) and low (< 0.505 mM glucose) conditions and analyzed for miR (miR-155, miR-155-5p, miR-124, and miR-132) expression, anti-and pro-inflammatory cytokine production (IL-1β, IL-6, TNF-α, TGF-β, and IL-10), and cell viability.

Results

Quantitative real-time polymerase chain reaction (qRT-PCR) revealed significant upregulation of miR-155 and miR-155-5p in high- and low-glucose conditions respectively, while low glucose elevated miR-155-5p but suppressed miR-124 expression. Both glucose conditions upregulated miR-132 without significant differences between the two treatments. Pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α were significantly elevated at the mRNA and protein levels and TGF-β at mRNA level in response to glucose stress. Low glucose induced more robust TNF-α and IL-6 responses compared to high glucose, whereas anti-inflammatory IL-10 expression significantly decreased only under low-glucose conditions. Cell viability was reduced under both glucose treatments, with a more pronounced effect in low glucose.

Conclusions

These findings highlight a glucose-dependent regulatory mechanism in TM4 Sertoli cells, where miRNA expression correlates with inflammatory cytokine profiles. Low glucose amplified pro-inflammatory responses, potentially driven by suppressed miR-124, while high glucose elicited a compensatory anti-inflammatory response with stable IL-10 expression. This study provides insights into the metabolic and inflammatory dynamics of Sertoli cells, emphasizing the role of miRNAs in modulating cellular responses to glucose stress, with implications for understanding diabetic testicular pathophysiology.

Graphical Abstract