2. Academic Validation
  3. Expression of IL-33 in rodent testes and its role in Leydig cell steroidogenesis and aging

Expression of IL-33 in rodent testes and its role in Leydig cell steroidogenesis and aging

  • Andrology. 2025 Jun 16. doi: 10.1111/andr.70078.
Hu Wang 1 2 3,  Yun Hu 1 3,  Zhenni Li 1 4,  Enhui Wu 1 2,  Qichao Yuan 1,  Xinyu Niu 1,  Jingwen Liu 3,  Hanmin Cai 2,  Mengjie Qin 4,  Jingfeng Xu 2,  Jiexia Wang 3,  Xiaoju Guan 1,  Haolin Chen 1 2 3 4,  Congde Chen 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Children Genitourinary Diseases of Wenzhou City, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Department of Pediatric Urology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2 Key Laboratory of Pediatric Anesthesiology of Ministry of Education, Key Laboratory of Anesthesiology of Zhejiang Province, Department of Anesthesiology and Perioperative Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3 Department of Gynecology and Obstetrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4 Department of Pharmacology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
PMID: 40521800 DOI: 10.1111/andr.70078
Abstract

Background: Serum testosterone (T) concentration declines with aging in men, potentially affecting reproduction, mental and physical well-beings. A role of immune factors in Leydig cell (LC) function is well-known, but the specific factors involved, especially these playing roles in LC aging, are still unclear. This study investigated effects of interleukin 33 (IL-33) on LC function and its expression during testicular aging.

Methods: Immunohistochemistry and Western blotting were used to determine IL-33 and its receptor IL1RL1 expressions in testes of young (3-month-old) and old (19-24-month-old) Wistar rats. In vitro, the effects of IL-33 on sex steroid hormone productions were evaluated in primary and MLTC-1 LCs over 2-24 h. Different steroidogenic stimulators or signaling molecules (luteinizing hormone [LH], 8-Br-cAMP, Forskolin, pertussis toxin, and MAPK activators) were compared with elucidate mechanisms. Steroidogenic pathway proteins and potential signaling molecules were explored by Western blotting.

Results: IL-33 is expressed by mesenchymal cells, with the number increasing significantly with aging. IL1RL1, its receptor, is expressed by LCs and remains unchanged. In vitro, IL-33 acutely inhibited LC steroidogenesis in a dose-dependent manner (1-100 ng/mL) within 2-24 h. The effect was LH-dependent; replacing LH with either 8-Br-cAMP or Forskolin abolished the inhibition. IL-33 mainly affected STAR in the steroidogenic pathway. Signaling molecules involving STAR regulation (Akt and MAPK) were down-regulated while PKA phosphorylation was increased. p38 MAPK involvement was confirmed as increased Tyr182 phosphorylation of P38 by SB203580 partly reversed the IL-33-induced steroidogenesis inhibition.

Conclusion: Testicular mesenchymal cells can synthesize IL-33, and LCs express the receptor IL1RL1. IL-33 inhibits LC steroidogenesis in vitro, partially via inhibiting p38 MAPK phosphorylation. As IL-33-expressing cell numbers rise significantly with aging, its role in age-related LC T production decline warrants further study.

Keywords

IL‐33; Leydig cells; aging; mesenchymal cells; steroidogenesis.

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