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  • Cytokines and hormones influence both gap

    2022-01-19

    Cytokines and hormones influence both gap junctions [106] and endocrine activity in the pituitary [3]. Long-term treatment (2 h) with the proinflammatory cytokines interleukin-1β (Il-1β) and tumor necrosis factor-α (TNF-α) transiently increases Cx43 expression and cell coupling in TtT/GF IWP-2 [105]. Conversely, a short-term treatment transiently reduces cell coupling and induces Cx43 dephosphorylation in S368 and phosphorylation in tyrosine [107]. Exposing TtT/GF cells to proinflammatory cytokines more IWP-2 than 48 h induces cell apoptosis [108]. Growth factors also impact on connexin expression and connexin-mediated intercellular communication in TtT/GF cells. Adenosine probably of lactotrope origin increases cytokine release, Cx43 expression and dye transfer in TtT/GF cells [109]. Incubation of the cells with bFGF for periods exceeding 2 h transiently increases expression of Cx43 and Cx50, and cell coupling [78,110]. Short-term 30 min exposure to bFGF increases Cx43 phosphorylation in S368 and inhibits cell coupling [78]. Since Cx43 and Cx50 colocalize and their growth factor-enhanced expressions coincide with increased cell coupling, these connexins likely contribute to intercellular communication in FS cells [78]. The localization of Cx46 in lysosomes may indicate a further processing of this connexin, in particular the cleavage of full length molecules. The association of Cx46 with Nopp-140, a nucleolar factor involved in rRNA processing, and the fact that short-term treatment with bFGF decreases nuclear Cx46 fragments is indicative of an inhibitory effect of nuclear Cx46 in bFGF-induced cell proliferation [78]. Collectively, these experimental observations provide evidence of the contribution of cell gap junctions in FS cell activities. Hence, by targeting gap junctions in FS cells toxicants may impact the physiology of the anterior pituitary. The bFGF is a growth factor characterized by its mitogenic and differentiating activities. The FS cells are the major source of bFGF in the anterior pituitary [111,112]. bFGF stimulates both its own synthesis in TtT/GF cells as well as the proliferation of these cells in an autocrine manner [113]. Sustained exposure of TtT/GF cells to bFGF increases development of cytoplasmic process and cell coupling [110]. TGFβ3-induced release of bFGF by FS cells requires functional gap junctions [72]. In the pituitary, bFGF modulates proliferation and secretory activity in lactotrope cells [[114], [115], [116], [117], [118]]. Co-culturing TtT/GF cells and Prl secreting cells increases both basal and TRH-induced Prl release by Prl secreting cells [119] and Cx43 expression in TtT/GF cells [109]. These observations indicate that bFGF, FS cell coupling and lactotrope cell activity are physiologically linked. By disrupting the link between these entities toxicants may cause to a deregulation of lactotrope cellular activity which in turn results in hyperprolactinemia and prolactinoma development. Gap junctions [59], bFGF [120], estrogen [121] and FS cells [122,123] are involved in the development of prolactinomas. That estrogen causes lactotrope hypertrophy and hyperplasia and induces prolactinoma formation is well documented [35,42,95,122]. bFGF increases the sensitivity of lactotropes to estradiol [103] and up-regulates pituitary-tumor transforming gen (PTTG) expression in pituitary adenomas [124]. FS cells are sensitive to estrogens [125]. A mathematical model suggests that FS cell network can be affected by estradiol [23]. FS cells are scarce within prolactinomas albeit they surround the tumours [95]. Estrogen analogs stimulate proliferation [88], Cx43 expression [126] and bFGF secretion in FS cells [103,126]. Carbenoxolone, a gap junction inhibitor, was recently shown to reduce diethylstilbestrol-induced prolactinomas as well as anterior pituitary Cx43 and bFGF expression in rats [126]. Moreover, Cx43 silencing blocks the estradiol-induced development of prolactinomas in rats [127]. Environmental pollutants like BPA and pharmaceuticals like contraceptives that possess estrogenic activity could target FS cell gap junctions to increase bFGF secretion and as a consequence induce lactotrope hyperplasia.