Interleukin-2 receptor γ blocks the development of Leydig cells from stem/progenitor cells in male rats via JAK1-STAT3 pathway and GSDMD-mediated pyroptosis

  • J Steroid Biochem Mol Biol. 2026 May:259:106953. doi: 10.1016/j.jsbmb.2026.106953.
Jingyi Zheng  1 ,  Qingyuan Wang  1 ,  Huiqian Zhang  1 ,  Yubin Xu  1 ,  Feilu Wang  1 ,  Yiyan Wang  1 ,  Xiaoheng Li  2 ,  Ren-Shan Ge  3
Affiliations
  • 1. Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Precision Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Enviroment and Male Reproductive Medicine of Wenzhou, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
  • 2. Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Precision Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Enviroment and Male Reproductive Medicine of Wenzhou, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China. Electronic address: [email protected].
  • 3. Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Precision Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Enviroment and Male Reproductive Medicine of Wenzhou, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China. Electronic address: [email protected].
PMID: 41662993 DOI: 10.1016/j.jsbmb.2026.106953
Abstract

Interleukin-2 (IL-2) receptor γ (IL2RG) is present in the Leydig cell lineage, but its functional role remains elusive. To investigate how IL2RG impacts Leydig cell development from stem cells and elucidate the underlying mechanisms, we used a rat model of ethane dimethanesulfonate (EDS)-induced cell depletion in Wild-type (WT) and Il2rg knockout (KO) mice. WT and KO male rats received intratesticular IL-2 injections (1 and 10 ng/testis) from day 7 to day 21 post-EDS. Stem Leydig cells around tubules and isolated progenitor Leydig cells were cultured with IL-2 (1 and 10 ng/mL) with/without STAT3 Inhibitor. Hormone levels, cell counts, gene/protein expression, and signaling pathways were analyzed. The results revealed that IL-2 significantly reduced serum testosterone levels in WT rats but had no effects in KO rats, without altering luteinizing hormone and follicle-stimulating hormone levels. Furthermore, IL-2 lowered Leydig cell numbers and the labeling index of PCNA in CYP11A1+ Leydig cells at 10 ng/testis, and downregulated the expression of SCARB1, HSD3B1, CYP17A1, SRD5A1, and NR5A1, as well as their corresponding mRNA levels in WT rats with no effect observed in KO rats. IL-2 also inhibited the incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into stem Leydig cells in WT rats and [3H] thymidine incorporation into progenitor Leydig cells, as well as their differentiation. Importantly, the effects of IL-2 were reversed by the STAT3 Inhibitor. Signaling pathway analysis showed that IL-2 exerted effects via increasing JAK1, STAT5, and STAT3 phosphorylation. This study provides insights into the inhibitory effects of IL2RG on Leydig cell development and highlights the involvement of the JAK-STAT pathway, offering potential targets for further exploration in the context of Leydig Cell Biology and male reproductive health.

Keywords
GSDMD; IL2RG; JAK1-STAT3; Pyroptosis; Stem Leydig cells.
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