TNF‐α inhibits GDNF levels in Sertoli cells, through a NF‐κB‐dependent, HES1‐dependent mechanism

Abstract

Background Glial cell line‐derived neurotrophic factor (GDNF) is a soluble molecule crucial for the regulation of the spermatogonial stem cells (SSC) of the testis. The effects of GDNF on target cells have been extensively described, but mechanisms underlying GDNF regulation are currently under investigation. In the nervous system, GDNF expression is regulated by pro‐inflammatory cytokines including lipopolysaccharide (LPS), interleukin 1 beta (IL‐1β), and tumor necrosis factor alpha (TNF‐α) but the effect of these cytokines on GDNF expression in the testis is unclear. Objectives The aim of the present study was to investigate the impact of TNF‐α on GDNF expression levels using primary murine Sertoli cells as experimental model. Material and methods The expression of TNF‐α‐regulated genes including Gdnf in different culture conditions was determined by real‐time PCR. GDNF protein levels were determined by ELISA. The activation of the NF‐κb pathway and HES1 levels were assessed by Western Blot analysis and immunofluorescence. HES1 expression was downregulated by RNAi. Results In primary Sertoli cells, TNF‐α downregulates GDNF levels through a nuclear factor‐κB (NF‐κB)‐dependent mechanism. Mechanistically, TNF‐α induces the transcriptional repressor HES1 by a NF‐Κb‐dependent mechanism, which in turn downregulates GDNF. Discussion Under physiological conditions, TNF‐α is secreted by germ cells suggesting that this cytokine plays a role in the paracrine control of SSC niche by modulating GDNF levels. HES1, a well‐known target of the Notch pathway, is implicated in the regulation of GDNF expression. In Sertoli cells, TNF‐α and Notch signaling may converge at molecular level, to regulate the expression of HES1 and HES1‐ target genes, including GDNF. Conclusions Because of the importance of GDNF for spermatogonial stem cell self‐renewal and proliferation, this data may give important insights on how cytokine signals in the testis modulate the expression of niche‐derived factors.

Chicoric acid prevents neurodegeneration via microbiota-gut-brain axis in a mouse Parkinson’s disease model

“…Rajkumar Verma et al found that the decline in BDNF expression showed possible correlation to the higher degree of TNF-α and IL-1β(Verma et al, 2017). Consistently, TNF-α displayed an inhibition on GDNF levels in a recent report (Di Persio et al, 2020), and IL-1β compromised neuronal survival by blocking the production of BDNF (Tong et al, 2008). In the present study, CA pretreatment downregulated the productions of GFAP and Ibal-1 in the SN, correspondingly, CA prevented the reduction in striatal BDNF and GDNF coupled with a clearly decreased concentration of TNF-α and IL-1β in the striatum and serum.…”

Neuroprotection of chicoric acid in a mouse model of Parkinson's disease involves gut microbiota and TLR4 signaling pathway

“…In the present study, the MPTP mice displayed the decline in striatal BDNF and GDNF accompanied by increased TNF-α and IL-1β, which is consistent with the previous findings that TNF-α exerted an inhibition on GDNF levels and IL-1β contributed to neuronal survival by blocking the production of BDNF. 38,39 In addition, Rajkumar Verma et al found that higher degrees of TNF-α and IL-1β could conduce to the decline in BDNF expression. 40 However, CA played an inhibitory role on neuroinflammation and prevented the reduction in neurotrophins of PD mice, resulting in the survival of dopaminergic neurons and improvement of motor function.…”

TNFα stimulates the proliferation of immature Sertoli cells by attenuating UPS‐degradation of cyclin D1 and leads to the delay of BTB maturation in pubertal rats

“…strated the downregulation of glial cell line-derived neurotrophic factor, a soluble molecule crucial for spermatogonial stem cell renewal and proliferation in the testis, by TNFα through a NFκB-dependent mechanism 66. In our study, after confirming the involvement of NFκB in TNFα-induced immature SC proliferation, we analyzed the role of NFκB in the regulation of Fbxo4 and cyclin D1.…”