Programmed cell senescence: role of IL-6 in the pituitary

Abstract

IL-6 is a pleiotropic cytokine with multiple pathophysiological functions. As a key factor of the senescence secretome, it can not only promote tumorigenesis and cell proliferation but also exert tumor suppressive functions, depending on the cellular context. IL-6, as do other cytokines, plays important roles in the function, growth and neuroendocrine responses of the anterior pituitary gland. The multiple actions of IL-6 on normal and adenomatous pituitary function, cell proliferation, angiogenesis and extracellular matrix remodeling indicate its importance in the regulation of the anterior pituitary. Pituitary tumors are mostly benign adenomas with low mitotic index and rarely became malignant. Premature senescence occurs in slow-growing benign tumors, like pituitary adenomas. The dual role of IL-6 in senescence and tumorigenesis is well represented in pituitary tumor development, as it has been demonstrated that effects of paracrine IL-6 may allow initial pituitary cell growth, whereas autocrine IL-6 in the same tumor triggers senescence and restrains aggressive growth and malignant transformation. IL-6 is instrumental in promotion and maintenance of the senescence program in pituitary adenomas.

Cholest-4,6-Dien-3-One Promote Epithelial-To-Mesenchymal Transition (EMT) in Biliary Tree Stem/Progenitor Cell Cultures In Vitro

“…hBTSCs cultured under chronic exposure of cholest-4,6-dien-3-one showed significantly higher IL6 levels (3.05 ± 0.69 pg/mL; p < 0.001; N = 6) when compared to hBTSCs culture in basal condition (0.94 ± 0.11 pg/mL; N = 6) (Figure 2B). As observed in previous studies [28,29,30], our data suggest that high IL6 levels induce cell senescence in hBTSC cultures when cultured in KM supplemented with cholest-4,6-dien-3-one.…”

“…Here we showed increased interleukin 6 (IL-6) production and secretion in hBTSCs in vitro. In previous studies, a strong link between IL-6 secretion and senescence was demonstrated [28,29,30]. One of the limitation of our study is the lack of a detailed analysis of the SASP profile of cells treated with cholest-4,6-dien-3-one and untreated ones.…”

Pituitary tumour fibroblast-derived cytokines influence tumour aggressiveness

“…In GH3 cells, IL-6 stimulates cell proliferation and DNA synthesis, as well as GH and prolactin release (Arzt et al 1993). IL-6 can also be secreted by non-tumoural folliculo-stellate cells, which can have paracrine effect on pituitary tumour cells causing increased proliferation and aggressiveness (Renner et al 1998, Haedo et al 2009, Sapochnik et al 2017a. Our study shows that TAFderived IL-6 levels were higher in PitNETs with cavernous sinus invasion, supporting a possible role for the paracrine effects of IL-6 on pituitary tumour invasiveness.…”

Pivotal role of NF-κB in cellular senescence of experimental pituitary tumours

“…Moreover, persistent SASP may help tumour cells to migrate and invade (Coppe et al 2008, Tammela et al 2017. It was also demonstrated that endogenous IL-6, as a SASP component, and hormone secretion (Chesnokova et al 2013, Sapochnik et al 2017 underlie the senescence-associated slow proliferation rate and benign nature of pituitary tumours. In contrast, other evidence indicates that senescence and pituitary stem cell associated persistent activation of SASP drive paracrine NF-κB in senescence of pituitary tumours B Mongi-Bragato et al…”