Abstract
Octamer-binding transcription factor 4 (OCT4) and cancerous inhibitor of protein phosphatase 2A (CIP2A) are upregulated in testicular cancer and cell lines. However, its contribution to orchitis (testicular inflammation) is unclear and was thus, investigated herein. Cell-based experiments on a lipopolysaccharide (LPS)-induced orchitis mouse model revealed robust inflammation, apoptotic cell death, and redox disorder in the Leydig (interstitial), Sertoli (supporting), and, germ cells. Meanwhile, real-time quantitative PCR revealed low OCT4 and CIP2A levels in testicular tissue and LPS-stimulated cells. A gain-of-function study showed that OCT4 overexpression not only increased CIP2A expression but also repressed LPS-induced inflammation, apoptosis, and redox disorder in the aforementioned cells. Furthermore, the re-inhibition of CIP2A expression by TD-19 in OCT4-overexpressing cells counteracted the effects of OCT4 overexpression on inflammation, apoptosis, and redox equilibrium. In addition, our results indicated that the Keap1-Nrf2-HO-1 signaling pathway was mediated by OCT4 and CIP2A. These findings provide insights into the potential mechanism underlying OCT4- and CIP2A-mediated testicular inflammation.
Highlights
In the process of mammalian sperm formation, many new antigens, including sperm agglutination antigen-1 (SAGA-1) and hyaluronidase (PH-20), are generated during reproductive cell development after the immune capacity of the organism is established (A et al, 2019)
To study whether Octamer-binding transcription factor 4 (OCT4) and cancerous inhibitor of protein phosphatase 2A (CIP2A) participated in orchitis, LPS was administered to induce an inflammatory response in mouse testes
We examined the levels of three proinflammatory factors; namely, IL-1β, IL-6, and tumor necrosis factorα (TNF-α), as well as monocyte chemoattractant protein-1 (MCP-1), IFN-α, and IFN-β in the interstitial Leydig, supporting Sertoli, and reproductive germ cells of LPS-treated mouse testes
Summary
In the process of mammalian sperm formation, many new antigens, including sperm agglutination antigen-1 (SAGA-1) and hyaluronidase (PH-20), are generated during reproductive cell development after the immune capacity of the organism is established (A et al, 2019). Under physiological conditions, such antigens usually do not trigger harmful immunological reactions in the testes owing to testicular immune privilege. Significance of OCT4 cell tumors, seminoma, and embryonal carcinoma (Jones et al, 2004) It aids in maintaining and regulating pluripotency and is involved in normal cell development by regulating the expression of multiple downstream target genes, such as UTF1 and REX1/ZFP42 (Saijoh et al, 1996). The involvement of OCT4 in testicular tumors and inflammation has been elucidated, further investigation its role in testicular inflammation, namely, orchitis, is warranted
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