Marta Labeur

Max Planck Institute of Psychiatry

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Eduardo Arzt

Fundación Ciencias Exactas y Naturales

Marcelo Páez-Pereda

Max Planck Institute of Psychiatry

Marily Theodoropoulou

LMU Klinikum

Günter K. Stalla

Medicover

Ulrich Renner

Max Planck Institute of Psychiatry

Herta Flor

Central Institute of Mental Health

Johanna Stalla

Max Planck Institute of Psychiatry

Mariana Haedo

Rakuten (United States)

Damiana Giacomini

Consejo Nacional de Investigaciones Científicas y Técnicas

Johannes M. H. M. Reul

University of Bristol

Cooperative Institutions

Max Planck Institute of Psychiatry

Max Planck Society

Ludwig-Maximilians-Universität München

Helmholtz Zentrum München

University of Buenos Aires

Consejo Nacional de Investigaciones Científicas y Técnicas

Fundación Ciencias Exactas y Naturales

LMU Klinikum

Technical University of Munich

University of Michigan–Ann Arbor

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

TMEFF2: a new endogenous modulator of the CRH signaling in corticotroph cells

Experimental and Clinical Endocrinology & Diabetes (2010)

Marta Labeur Barbara Wölfel Markus Panhuysen Johanna Stalla GK Stalla

We have previously demonstrated that retinoic acid (RA) inhibits CRH signaling in corticotroph cells. In order to elucidate the mechanisms controlling RA action, cDNA microarray analysis was perfomed. From 87 genes regulated by RA in the corticotroph cell line AtT-20, we selected TMEFF2 for further studies. TMEFF2 is a transmembrane protein containing an altered epidermal growth factor (EGF)-like motif, two follistatin-like domains and a cytosolic tail which a putative G protein-activating motif. TMEFF2 is predominantly expressed in brain and prostate and has been implicated in cell signaling, neuronal cell survival and tumor suppression. Although TMEFF2 function is unknown, its structural domains suggest that it may have a role in the regulation of growth factor signalling. Since there is no previous evidence for an involvement of TMEFF2 in Cushing's disease or CRH signalling, we have studied the effects of TMEFF2 on the signal transduction pathway of CRH. Our results show that CRH-signaling is under the inhibitory effects of endogenous TMEFF2. TMEFF2 expression in corticotroph cells inhibits the effects of CRH on the production of intracellular cAMP, CREB and POMC transcriptional activity. Regulation of CRH activity by TMEFF2 does not require the cytoplasmic tail, while deletion of the follistatin and EGF modules abolishes the inhibitory function of TMEFF2. Moreover, a soluble secreted protein containing these three extracellular domains is sufficient for CRH signaling inhibition. TMEFF2-induced inhibition depends on serum components. Furthermore, TMEFF2 seems to regulate non-cannonical Activin/BMP-4 signaling, leading to the inhibition of the PI3K pathway (Akt) and Erk1/2 activation. Whether TMEFF2 acts upstream to Akt to regulate cAMP production and PKA activity remains to be elucidated. We found that TMEFF2 expression in human Cushing's adenoma is reduced as compared to the normal human pituitary, which may indicate that TMEFF2 acts as a tumor suppressor in these adenomas. Consistent with this hypothesis, the overexpression of TMEFF2 decreased cell proliferation in corticotroph cells. Our results also indicate a potential therapeutic use of TMEFF2 or factors that stimulate TMEFF2 activity for the treatment of corticotroph tumors in order to reduce their ACTH secretion and proliferation.

10.1055/s-0030-1267015

Cite

Citations (4)

Author Index Vol. 71, Suppl. 2, 2009

Hormone Research in Paediatrics (2009)

Gavin Kelsey Thomas Eggermann Linda Johnston Wiestske Ester Janina Caliebe

10.1159/000217314

Cite

Citations (0)

Altered Neuroimmunoendocrine Communication during a Condition of Chronically Increased Brain Corticotropin‐Releasing Hormone Drive^a

Annals of the New York Academy of Sciences (1998)

Johannes M. H. M. Reul Marta Labeur G. Jan Wiegers Astrid C. E. Linthorst

Presently, it is clear that the brain, immune system, and endocrine system build a complex network of interactions at various levels. Inflammation, which may be regarded as a stressful challenge, initiates apart from immunological, autonomic, and neuroendocrine responses also profound behavioral (e.g., immobility, social disinterest) changes. Key mediators herein are corticotropin-releasing hormone (CRH) and cytokines, such as interleukin-1 beta (IL-1 beta). Currently, the behavioral changes, collectively termed sickness behavior, are thought to be adaptive responses to support the body's efforts to fight the infection. Using in vivo microdialysis and biotelemetry in freely moving animals, we have studied the monoaminergic circuits in the brain implicated in the regulation of physiological and behavioral responses to a peripheral inflammatory challenge (see also chapter of Linthorst and Reul in this volume). To expand our insight into the relationship between hypersecretion of CRH and physiological and behavioral abnormalities associated with stress-related disorders, a series of experiments was conducted with long-term centrally CRH-infused rats. These rats showed reduced body weight gain, decreased food intake, elevated plasma ACTH and corticosterone levels, thymus involution and immunosuppression, but, paradoxically, enhanced IL-1 beta mRNA expression in spleen macrophages. After a peripheral endotoxic challenge on the seventh day of treatment, the CRH-infused rats produced aberrant (i.e., blunted and/or delayed) HPA axis, fever, behavioral, and hippocampal serotonergic responses. However, endotoxin-induced plasma IL-1 and IL-6 bioactivities were significantly enhanced in these animals. The data show that chronically elevated central CRH levels as occurring during chronic stress result in defective central nervous system and immune system responses to an acute (inflammatory) challenge. These observations provide evidence that chronic CRH hypersecretion is an important factor in the etiology of stress-related disorders.

Corticotropin-releasing hormone

10.1111/j.1749-6632.1998.tb09583.x

Cite

Citations (36)

Molecular mechanisms of glucocorticoid receptor signaling.

PubMed (2010)

Marta Labeur Herta Flor

This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR). Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glu-cocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress.

Transrepression

Homeostasis

Source

Cite

Citations (17)

Effect of long-term intracerebroventricular (ICV) infusion of corticotropin releasing hormone on endocrine and immune function in the rat

Journal of Neuroimmunology (1994)

Marta Labeur Eduardo Arzt G. Jan Wiegers Herta Flor Johannes M. H. M. Reul

Corticotropin-releasing hormone

10.1016/0165-5728(94)90398-0

Cite

Citations (0)

Effects of interferon-γ on normal and tumoral pituitary cells in culture

Experimental and Clinical Endocrinology & Diabetes (2004)

Marta Labeur M Papazoglou Marily Theodoropoulou Johanna Stalla Eduardo Arzt

Interferon-γ (IFN-γ) is a pleiotropic cytokine involved in antiproliferative and antiviral responses, immune surveillance and tumor suppression. It exerts its effects by interacting with a specific receptor composed of two ligand-binding α chains (IFN-γRα) and two signal-transducing β chains (IFN-γRβ). A regulatory interaction between IFN-γ and the HPA axis has been proposed. However, although IFN-γ is known to be involved in the regulation of ACTH secretion, contradictory results have been shown in the literature in different species. Moreover, the effects of IFN-γ on POMC transcription, corticotroph cell proliferation and receptor subunit expression in normal and corticotroph tumor pituitary cell cultures have not been thoroughly characterised yet. Therefore, we examined the effects of IFN-γ in the murine and human system. We detected the expression of IFN-γRα and IFN-γRβ in tumor mouse corticotroph AtT-20 cells. Furthermore, we identified both receptors in normal human pituitary as well as in corticotroph human adenoma tissue. In normal human pituitary cells IFN-γRα immunoreactivity was observed in ACTH, TSH, GH and LH immunopositive cells, while IFN-γRβ immunoreactivity only colocalised with ACTH. We found that IFN-γ inhibited POMC transcription, and partially inhibited CRH-induced POMC promoter activity in AtT-20 cells. Moreover, IFN-γ inhibited basal ACTH secretion in AtT-20 cells, but not in normal murine pituitary cells. First results showed the inhibition of ACTH production by IFN-γ in human corticotroph tumor. Finally, we observed a dose-dependent inhibition of AtT-20 cell growth between day 3 and 5 of incubation with IFN-γ. Our results indicate that IFN-γ affects ACTH synthesis in tumor corticotroph cells but not in normal murine cells. In AtT-20 cells IFN-γ inhibits ACTH secretion by directly regulating POMC promoter activity. The effects of IFN-γ are probably mediated by the IFN-γ receptor whose two subunits, IFN-γRα and IFN-γRβ, are expressed in both normal and tumoral corticotrophs. These results open the possibility of a potential therapeutic use of IFN-γ in corticotroph tumors.

Corticotropic cell

10.1055/s-2004-832890

Cite

Citations (0)

Retinoic acid and PPAR-γ ligands synergistically inhibit ACTH secretion and proliferation in murine corticotroph tumor cells

Experimental and Clinical Endocrinology & Diabetes (2005)

Marta Labeur M Papazoglou Marily Theodoropoulou Johanna Stalla S Laupheimer

In most cases of endogenous Cushing's syndrome increased production of cortisol by the adrenals is due to an ACTH-secreting pituitary adenoma. In a previous work we found that in the presence of retinoic acid (RA), the retinoid receptors (RAR and RXR) inhibited POMC transcription, ACTH production and proliferation in ACTH-secreting AtT-20 tumor cells. In the same line of investigation, the peroxisome proliferator activated receptor-γ (PPAR-γ) ligand, rosiglitazone, was shown by others to induce cell-cycle arrest, apoptosis, and suppression of ACTH secretion in corticotroph tumor cells. Like the RAR, PPAR-γ forms an heterodimer with the RXR protein. Recent studies in pancreatic and breast cancer cell lines have demonstrated that the RXR shares synergistic growth-inhibitory actions with PPAR-γ ligands.

Corticotropic cell

Retinoid X receptor

ACTH receptor

10.1055/s-2005-862943

Cite

Citations (0)

Expression and functionality of NOD molecules in the adenopituitary folliculostellate cells

Experimental and Clinical Endocrinology & Diabetes (2007)

Eliane Corrêa-de-Santana Marily Theodoropoulou Marcelo Páez-Pereda Chiara Onofri Marta Labeur

The follicullostellate (FS) cells of the pituitary share properties with dendritic cells and also with macrophages. A contingent of FS cells express MHC class I and MHC class II and also several lymphoid markers and lymphatic markers. Therefore, FS cells were found to regulate the secretion of hormones by endocrine cells inside of the pituitary and to be a source of growth factors such as basic fibroblast growth factor (bFGF), vascular endothelial growth factors (VEGF), as well as, cytokines as leukaemia inhibitor factor (LIF) and interleukin-6 (IL-6). Functionally, it was suggested that FS cells are capable of initiating immune responses and act as part of a neuroendocrine immune regulation system. Understanding of the way macrophages and others cells respond to endotoxins and development of innate immunity, a major step was archived with the discovery of Toll-like receptors (TLRs). Toll receptors are members of a membrane-anchored proteins that upon stimulation recruits proteins kinases and activates nuclear factor kB (NF-κB). Recently, nucleotide-binding oligomerization domain (NOD) proteins, NOD1 and NOD2 were found to represent an intracellular pathogen sensing system identified in both immune and non immune cell types. NOD1 and NOD2 ligands are muramyl dipeptide (MDP) and diaminopimelic acid (DAP), components of bacterial cell-wall peptidoglycan present in most bacterial species. After activation, NOD molecules recruit and phosphorylate RICK, an effector molecule that leads to NF-κB activation and translocation to the nucleus. Considering characteristics of FS cells and the function of NOD molecules, we decided to investigate the expression and function of NOD in FS cells. Here we show the expression of NOD1 and NOD2 in normal human pituitaries and in FS cell line (TtT-GF) by RT-PCR. In addition, we observed that activation of NOD1 and NOD2 molecules in combination with TLR2/4 agonist leads to the activation of NF-κB and significantly augments IL-6 production. In addition, we next observed that NOD2-silenced TtT-GF cells but not NOD1-silenced cells failed to induce NF-κB activity and increase IL-6 levels after stimulation with LPS. Interestingly, LPS, MDP or MDP plus LPS when added to STAT-3-silenced TtT-GF cells inhibited NF-κB expression and activation. These observations indicate that NOD agonists in combination with TLR agonists are synergistically involved in the function of folliculostellate cells by modulating cytokine production and signaling.

NOD1

Muramyl dipeptide

Innate lymphoid cell

10.1055/s-2007-990429

Cite

Citations (1)

Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression

Endocrinology (1995)

Marta Labeur

Journal Article Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression Get access M S Labeur, M S Labeur 1Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Federal Republic of Germany. Search for other works by this author on: Oxford Academic Google Scholar E Arzt, E Arzt 1Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Federal Republic of Germany. Search for other works by this author on: Oxford Academic Google Scholar G J Wiegers, G J Wiegers 1Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Federal Republic of Germany. Search for other works by this author on: Oxford Academic Google Scholar F Holsboer, F Holsboer 1Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Federal Republic of Germany. Search for other works by this author on: Oxford Academic Google Scholar J M Reul J M Reul 1Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Federal Republic of Germany. Search for other works by this author on: Oxford Academic Google Scholar Endocrinology, Volume 136, Issue 6, 1 June 1995, Pages 2678–2688, https://doi.org/10.1210/endo.136.6.7750492 Published: 01 June 1995

Splenocyte

Corticotropin-releasing hormone

10.1210/en.136.6.2678

Cite

Citations (15)

TMEFF2 is an endogenous inhibitor of the CRH signal transduction pathway

Journal of Molecular Endocrinology (2015)

Marta Labeur Barbara Wölfel Johanna Stalla Günter K. Stalla

TMEFF2 is a transmembrane protein with unknown function, containing an altered epidermal growth factor (EGF)-like motif, two follistatin-like domains, and a cytosolic tail with a putative G-protein-activating motif. TMEFF2 is predominantly expressed in brain and prostate and has been implicated in cell signaling, neuronal cell survival, and tumor suppression. We found that expression of TMEFF2 in pituitary corticotrope cells inhibits the effects of corticotropin-releasing hormone (CRH) on the production of intracellular cAMP, and CREB, and transcription of Pomc. Regulation of the activity of CRH by TMEFF2 requires neither the cytoplasmic tail nor the EGF domain, while deletion of the follistatin modules abolishes the inhibitory function of TMEFF2. Moreover, a soluble secreted protein containing the complete extracellular domain is sufficient for inhibition of CRH signaling. TMEFF2-induced inhibition depends on serum components. Furthermore, TMEFF2 regulates the non-canonical activin/BMP4 signaling, PI3K, and Ras/ERK1/2 pathways. Thus, TMEFF2 inhibits the CRH signaling pathway and the PI3K/AKT and Ras/ERK1/2 pathways, contributing to a significant inhibition of transcription of Pomc. We found that expression of TMEFF2 in human Cushing's adenoma is reduced when compared with normal human pituitary, which may indicate that TMEFF2 acts as a tumor suppressor in these adenomas. Furthermore, the overexpression of TMEFF2 decreased proliferation of corticotrope cells. Our results indicate a potential therapeutic use of TMEFF2 or factors that stimulate the activity of TMEFF2 for the treatment of corticotrope tumors in order to reduce their secretion of ACTH and proliferation.

10.1530/jme-14-0225

Cite

Citations (12)