Protective effect of TNFAIP3 on testosterone production in Leydig cells under an aging inflammatory microenvironment.

Arch Gerontol Geriatr

Andrology Department of Integrative Medicine, Zhongda Hospital, Southeast University, 210009, Nanjing, Jiangsu, China. Electronic address:

Published: February 2024

AI Article Synopsis

  • The study explores how TNFAIP3, an anti-inflammatory factor, impacts testosterone production in Leydig cells within an aging inflammatory environment, linking its effects to decreased testosterone levels in males.
  • Researchers utilized bioinformatics, in vitro experiments, and transcriptomic analysis to demonstrate that TNFAIP3 expression increases with age and plays a protective role against inflammation-induced damage in Leydig cells.
  • Results indicate that TNFAIP3 reduces apoptosis and boosts testosterone synthesis by regulating the P38MAPK signaling pathway and enhancing the expression of CEBPB.

Article Abstract

Background: The aging inflammatory microenvironment surrounding Leydig cells is linked to reduced testosterone levels in males. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) acts as a critical anti-inflammatory factor in various aging-related diseases. This study aims to investigate the protective effect of TNFAIP3 on testosterone production in Leydig cells under an aging inflammatory microenvironment.

Methods: Bioinformatics analysis examined TNFAIP3 expression differences in aging rat testes and validated the findings in aging mouse testes. In vitro models of inflammation were established using two Leydig cell lines, with tumor necrosis factor alpha (TNF-α) as the inflammatory factor. Lentiviral transduction was utilized to manipulate TNFAIP3 expression in these cell lines. Transcriptomic sequencing identified differentially expressed genes in TNFAIP3-overexpressing cells.

Results: Bioinformatics analysis and validation experiments revealed increased inflammatory signaling and elevated TNFAIP3 expression in aging rat and mouse testes. TNFAIP3 knockdown worsened testosterone synthesis inhibition and apoptosis in cells, while TNFAIP3 overexpression reversed these effects. Transcriptome analysis identified alterations in the P38MAPK pathway following TNFAIP3 overexpression. TNFAIP3 knockdown enhanced TNF-induced P38MAPK signaling, whereas its overexpression attenuated this effect. TNFAIP3 was found to regulate testosterone synthesis by upregulating CEBPB expression.

Conclusions: TNFAIP3 exhibits inhibitory effects on apoptosis and promotes testosterone production in Leydig cells. The protective influence of TNFAIP3 on Leydig cells within an inflammatory microenvironment is likely mediated through by inhibiting the P38MAPK pathway and upregulating CEBPB expression.

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http://dx.doi.org/10.1016/j.archger.2023.105274DOI Listing

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