Rat Anterior Pituitary Folliculostellate Cells Are Targets of Interleukin-1β and a Major Source of Intrapituitary Follistatin

Bilezikjian, Louise M.; Leal, Ângela M. O.; Blount, Amy L.; Corrigan, A; Turnbull, Andrew V.; Vale, Wylie

doi:10.1210/en.2002-220703

Cited by 53 publications

(51 citation statements)

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“…Several lines of evidence suggest that this reflects the transcriptional activation of the follistatin gene in pituitary gonadotropes (39). To better understand this mechanism and identify a suitable cell line for further studies, activin effects on follistatin mRNA expression were evaluated in greater detail in RAP cells and compared with those of gonadotrope-derived ␣T3-1 cells.…”

Section: Activin Increases Follistatin Transcript Levels Of Primary Ratmentioning

confidence: 99%

“…In L␤T2 cells, the same fragment is a target of GnRH (37) but not of activin A in ␣T3-1 cells (38). On the other hand, a luciferase reporter construct designated rFS(rin3)-luc that incorporates ϳ2.8 kb of the 5Ј-flanking sequence and extends into the third intron of the rat follistatin gene is induced by activin in ␣T3-1 cells (39). Finally, it has been reported that the human follistatin promoter is activated in HepG2 cells by Smad signaling, downstream of activin or TGF-␤ (40,41).…”

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confidence: 99%

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A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene

Blount

Vaughan

Vale

et al. 2008

Journal of Biological Chemistry

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Activins are members of the evolutionarily conserved transforming growth factor-␤ (TGF-␤) 3 superfamily of factors implicated in the control of a wide array of cellular processes of embryonic and adult tissues (1-3). Activin A and activin B are homodimers of inhibin ␤A and ␤B subunits, respectively, with established roles in the control of many cell types including those throughout the reproductive axis (1, 4 -6). The inhibin ␤A and ␤B subunits are both expressed in the pituitary and activin B arising from gonadotropes is a critical component of the network of autocrine or paracrine factors of this tissue (7). By exerting control on FSH␤ expression, activin B is hypothesized to locally provide a positive signal for the differential production of FSH over LH and to thereby facilitate the cyclic fluctuations of these hormones during the estrus cycle (7,8). The actions of activins are strictly controlled by the concerted actions and the preferential usage of several extracellular modulators (9, 10). Of these, inhibin and follistatin have established roles in the regulation of pituitary gonadotropes (7).Follistatins are cysteine-rich glycoproteins that bind and bioneutralize activin with high affinity at a 2:1 molar ratio (11-13). They also bind and inactivate myostatin and some bone morphogenetic proteins with varying degrees of affinity (14). Structural studies of the follistatin-activin complex have elucidated the basis for this interaction and provided clues about the determinants of follistatin binding to other ligands (15,16). The follistatin gene comprising 6 exons produces two alternatively spliced mRNA transcripts and the corresponding proteins of 315 or 288 amino acids (FS315 or FS288) (17, 18). The two isoforms, FS315 and FS288, are differentially expressed in most tissues (19,20). The FS315 form is the predominant circulating form, whereas the shorter FS288 form lacking the C-terminal tail associates tightly with heparan sulfate chains of cell surface proteoglycans and is presumed to be the form that acts locally to modulate activin signaling (2,(21)(22)(23). This local function of follistatin is, in turn, controlled by the actions of activin. In cultured rat anterior pituitary cells, activin increases steadystate follistatin mRNA and secreted protein levels (24 -28). Given that inhibin antagonizes the activin-induced rise in pituitary follistatin, this pinpoints gonadotropes as the primary targets of this action of activin (28,29).Activin signals by sequentially binding to activin-specific Type II (ActRII or ActRIIB) then Type I (ALK4) serine/threonine kinase receptors to form a multimeric complex (3,30,31). In this complex, the Type II receptors trans-phosphorylate ALK4 and allow it to transiently interact and phosphorylate the downstream signaling proteins, Smad2 and Smad3, at their C-terminal SSXS motifs (31-33). The phosphorylated forms of Smad2 and Smad3 in turn translocate to the nucleus where they bind to DNA targets and regulate transcription in association with the common Smad4/DPC4 and other p...

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Section: Activin Increases Follistatin Transcript Levels Of Primary Ratmentioning

confidence: 99%

mentioning

confidence: 99%

A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene

Blount

Vaughan

Vale

et al. 2008

Journal of Biological Chemistry

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“…This SBE1 element preferentially binds Smad3 and mediates downstream effects of activin A. Luciferase reporter constructs that incorporate up to 2.86 kb of the upstream promoter of the rat Fst, but lack the intronic SBE1 enhancer, are unresponsive to activin signaling in either ␣T3-1 or L␤T2 cells (29,35,41). By contrast, the same reporters display both basal and Smad-dependent inducible activity when transfected into HepG2 or HEK293T cells, indicating that the function of SBE1 is dispensable in these cell types.…”

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confidence: 99%

FoxL2 and Smad3 Coordinately Regulate Follistatin Gene Transcription

Blount

Schmidt

Justice

et al. 2009

Journal of Biological Chemistry

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Follistatin is a transcriptional target and a modulator of activin action. Through an autocrine/paracrine loop, activin controls follistatin levels and thus regulates its own bioavailability. In gonadotropic ␣T3-1 cells, activin induces follistatin transcription primarily through the action of Smad3 at an intronic Smad-binding element (SBE1). Using a proteomics approach, we searched for endogenous ␣T3-1 proteins that participate in SBE1-mediated transcription. We identified

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“…Moreover, release and hypophyseal expression of IL-6 are considerably reduced in mutant mice for IL-1b [75]. It has also been demonstrated that IL-1b increases the production of IL-6 in cultures of rat folliculo-stellate cells [76]; these cells are considered a source of organspecific stem cells in the anterior pituitary gland [77,78], and they have been shown to be major producers of IL-6 in the adult pituitary [79]. These data, along with the similarity in the time-space expression of IL-1b and IL-6, and the coexpression of both interleu- kins in pituitary cells detected by us, suggest that IL-1b could exert a control on IL-6 expression during embryonic development, similarly to adult folliculo-stellate cells.…”

Section: Possible Interaction Between Il-1b and Il-6 In The Developinmentioning

confidence: 99%

Prenatal expression of interleukin 1β and interleukin 6 in the rat pituitary gland

et al. 2008

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a b s t r a c tIt is known that interleukin 1b (IL-1b) and interleukin 6 (IL-6) are expressed post-natally in normal and tumoral cells in the anterior pituitary, and that they play a role in both the liberation of different hormones and in the growth, proliferation and tumor formation of the pituitary gland. However, their expression and role during embryonic and fetal development remain unknown. We have performed an immunocytochemistry study of prenatal expression and distribution of IL-1b and IL-6 in isolated embryonic rat Rathke's pouch prior to birth, more specifically between 13.5 and 19.5 days p.c. Western-blot analysis carried out on 19.5-day p.c. embryos showed positive immunolabelling for IL-1b and IL-6. These interleukins were initially expressed simultaneously in the rostral and ventral portions of Rathke's pouch in 15.5-day p.c. embryos, and this expression progressed caudodorsally in later developmental stages, extending to most of the hypophysis before birth. The number of cells expressing these interleukins increased throughout this period: 48.22% of anterior pituitary cells expressed IL-6 in 19.5-day embryos, whilst IL-1b was positive in 39.8% of the cells. Moreover, we have demonstrated that some adenohypophyseal cells co-express both interleukins. Such findings represent the first step towards an understanding of the physiological role of these interleukins in anterior pituitary development.

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Rat Anterior Pituitary Folliculostellate Cells Are Targets of Interleukin-1β and a Major Source of Intrapituitary Follistatin

Cited by 53 publications

References 59 publications

A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene

A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene

FoxL2 and Smad3 Coordinately Regulate Follistatin Gene Transcription

Prenatal expression of interleukin 1β and interleukin 6 in the rat pituitary gland

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