Damiana Giacomini

Molecular Interaction of BMP-4, TGF-beta, and Estrogens in Lactotrophs: Impact on the PRL Promoter

The regulatory role of estrogen, bone morphogenetic protein-4 (BMP-4), and TGF-beta has a strong impact on hormone secretion, gene transcription, and cellular growth of prolactin (PRL)-producing cells. In contrast to TGF-beta, BMP-4 induces the secretion of PRL in GH3 cells. Therefore, we studied the mechanism of their transcriptional regulation. Both BMP-4 and TGF-beta inhibited the transcriptional activity of the estrogen receptor (ER). Estrogens had no effect on TGF-beta-specific Smad protein transcriptional activity but presented a stimulatory action on the transcriptional activity of the BMP-4-specific Smads. BMP-4/estrogen cross talk was observed both on PRL hormone secretion and on the PRL promoter. This cross talk was abolished by the expression of a dominant-negative form for Smad-1 and treatment with ICI 182780 but not by point mutagenesis of the estrogen response element site within the promoter, suggesting that Smad/ER interaction might be dependent on the ER and a Smad binding element. By serial deletions of the PRL promoter, we observed that indeed a region responsive to BMP-4 is located between -2000 and -1500 bp upstream of the transcriptional start site. Chromatin immunoprecipitation confirmed Smad-4 binding to this region, and by specific mutation and gel shift assay, a Smad binding element responsible site was characterized. These results demonstrate that the different transcriptional factors involved in the Smad/ER complexes regulate their transcriptional activity in differential ways and may account for the different regulatory roles of BMP-4, TGF-beta, and estrogens in PRL-producing cells.

Regulation of Pituitary Function by Cytokines

Research performed on the pituitary has proven that cytokines play an important role in maintaining pituitary physiology, affecting not only cell proliferation but also hormone secretion. The effects of cytokines can be autocrine or paracrine. This review gives an overview on the effects of the most studied cytokines in the pituitary. Special interest is focused on interleukin-6 (IL-6) because it has the distinctive characteristic of stimulating pituitary tumor cell growth, but has the opposite effect on normal pituitary cells. On the other hand, IL-6 is a cytokine of interest in the pituitary because recent work has shown that it promotes and maintains senescence in certain types of tumors. Given that the majority of pituitary adenomas are microadenomas and the fact that clinically inapparent pituitary tumors are quite common, senescence, perhaps mediated by IL-6, is an attractive mechanism for explaining the benign nature of pituitary tumors.

Bone Morphogenetic Protein-4 Control of Pituitary Pathophysiology

Bone morphogenetic protein-4 (BMP-4), a member of the transforming growth factor-Beta(TGF-Beta) family, is overexpressed in different prolactinoma models and induces the development of these lineage adenomas. SMAD proteins activated by growth factors of the TGF-Beta and BMP family interact with estrogen receptors to stimulate the proliferation of prolactin and growth hormone-secreting cells. Furthermore, BMP-4 presents differential expression in normal and adenomatous corticotropes and inhibitory action on corticotropinoma cell proliferation. Moreover, BMP-4 mediates the antiproliferative action of retinoic acid in these cells. The present review highlights not only the crucial and opposite role of BMP-4 in the progression of pituitary adenomas but also that BMP-4 and retinoic acid interaction might serve as a potential new mechanism target for therapeutic approaches for Cushing disease.

Pituitary Action of Cytokines: Focus on BMP-4 and gp130 Family

The anterior pituitary can develop benign tumors of different sizes, classified as micro- and macroadenomas, frequently associated with high levels of hormone production, leading to different associated syndromes like Cushing’s disease, acromegaly or prolactinomas. Much work has been done in order to understand the signaling pathways and the factors and hormones involved in the pituitary tumorigenic process. In recent years, much evidence has been collected and it is now well documented that cytokines of the gp130 family, such as interleukin-6, that use gp130 as a common signaling protein stimulate not only the proliferation but also the hormone secretion of pituitary cells. Experiments in vivo have shown that the overexpression of the gp130 receptor resulted in pituitary abnormal growth. Moreover, it has been recently described that bone morphogenetic protein-4 (BMP-4), a member of the TGF-β family, has a stimulatory role on lactosomatotropic cells promoting the development of prolactinomas but it has an inhibitory action on the corticotropic lineage. This inhibitory action prevents Cushing’s disease progression. Furthermore, BMP-4 mediates the antiproliferative action of retinoic acid in these cells. The present review highlights the most recent work about gp130 and TGF-β cytokine families and their role in pituitary tumorigenesis.

Molecular transduction mechanisms of cytokine–hormone interactions: role of gp130 cytokines

Highly sophisticated mechanisms confer on the immune system the capacity to respond with a certain degree of autonomy. However, the final outcome of an immune response depends on the interaction of the immune system with other systems. The immune and neuroendocrine systems have an intimate cross‐communication that makes possible a satisfactory response to environmental changes. Part of this interaction occurs through cytokines and steroid hormones. The last step of this cross‐talk is the molecular level. As a model of interaction, this review focuses on the gp130 cytokine family. These cytokines, as well as their receptors, are expressed in pituitary cells. They regulate hormone production as well as growth of pituitary cells. During acute or chronic inflammation or infection, systemic, hypothalamic and hypophyseal gp130 cytokines act on anterior pituitary cells, integrating the neuroendocrine–immune response. Disruptions of these pathways may lead not only to abnormal growth of pituitary cells but also to immune disorders, for which, based on recent findings, targeting these cytokines might be a novel therapeutic approach.

Differential gene expression in models of pituitary prolactin-producing tumoral cells.

Although several genes and signalling pathways have been identified as important effectors in the development of pituitary tumours, our understanding of pituitary tumorigenesis remains incomplete and is the focus of much current research. Use of the mRNA differential display technique in prolactinomas from D2-receptor knockout mice and in stable GH3 cell line clones with enhanced tumorigenicity in vivo has led to the identification of two genes that are involved in the pathogenic process – BMP-4 and RSUME. Bone morphogenetic protein-4 (BMP-4) has been found to have a crucial role in prolactinoma development and also in signalling crosstalk with oestrogens. In contrast, BMP-4 has an inhibitory role in corticotrophinomas. RSUME (RWD-containing sumoylation enhancer) was identified from a transformed lactosomatotrophic cell line that had increased tumorigenic and angiogenic potential. Expression of RSUME was induced under hypoxic conditions and it has a potential role during vascularization. The differential expression and action of BMP-4 in prolactinomas and corticotrophinomas highlights the importance of studying a gene with contrasting actions in two cell lineages of the same organ in order to understand the pituitary transformation process. Both BMP-4 and RSUME may be interesting targets for inhibiting steps involved in pituitary tumorigenesis.

Cytokines and Genes in Pituitary Tumorigenesis: RSUME Role in Cell Biology

Cytokines of the IL-6 or gp130 family regulate many cellular responses and play regulatory roles in numerous tissues, and are placed as auto-paracrine regulators of pituitary function acting in normal and tumoral anterior pituitary cells. Especially, IL-6 has a regulatory role in the hormone secretion and growth of the anterior pituitary and is involved in adenoma pathogenesis. Recently, IL-6 has been shown to mediate oncogene-induced senescence (OIS). IL-6 might participate in such a process in adenomas pituitary as well. From pituitary tumoral gp130 overexpressing cells, an unknown protein, RSUME, has been cloned. RSUME is induced by hypoxia in pituitary tumors and regulate pathways involved in angiogenic and tumorigenic processes (NF-kappaB/IkappaB and HIF-1alpha pathways). Thus, it could have an important role in the development of the pituitary tumors.

Inflammatory Mediator Action on the Anterior Pituitary Gland

Abstract Interleukin-1 (IL-1), IL-6, and other cytokines mainly produced by endotoxin [lipopolysaccharide (LPS)]-activated monocytes and macrophages, are known to be responsible for the acute phase and inflammatory response. These cytokines also influence the secretion of anterior pituitary hormones and play an important role in the interaction between the immune and the endocrine systems. Moreover, IL-1, IL-6, and their receptors are expressed and produced within the anterior pituitary influencing the growth and function of pituitary cells. Thus, we propose that they act as autocrine or paracrine regulators of pituitary homeostasis. In addition, intrapituitary production of IL-1 and IL-6 is also induced by LPS showing another link between the immune and the endocrine systems. The present review summarizes the actual knowledge about the actions of IL-1 and IL-6 (and related cytokines) known to regulate the anterior pituitary physiology and the involvement of LPS in modulating these intrapituitary cytokine pathways.