Bedeutung von intrahypophysären Rezeptoren bakterieller Zellwandbestandteile für die Pathophysiologie und Progression von Hypophysentumoren
Final Report Abstract
Important components of the innate immune system among them TLR4, NOD1 and NOD2 receptors, that are activated by cell wall substances of bacteria during bacterial infections/inflammations, are not only expressed in immune cells but are also present in normal and tumoral epithelial cells. Through these receptors tumour development may be affected during bacterial infectious/inflammatory processes. The project aimed to demonstrate the expression of the above-mentioned receptors in pituitary adenomas and to clarify at least in part their role in growth, apoptosis (programmed cell death) and pathophysiology of pituitary tumour cells. TLR4 expression could be confirmed in pituitary adenoma cells and for the first time also the presence of NOD1 and NOD2 receptors (which were found to be up-regulated in a considerable proportion of the adenomas in comparison to normal pituitary) could be demonstrated. Using folliculostellate (FS) cells and corticotroph AtT20 cells as models of non-hormone and hormone-secreting pituitary tumour cells, it could be shown that NOD receptor ligands stimulated proliferation of these cells, had no effect on cell death, and interestingly, inhibited hormone (ACTH) synthesis and secretion. Activated TLR4 and NOD receptors also induced the production of IL-6 and VEGF, which are both critically involved in pituitary tumour progression. By studying signalling protein alterations and transcription factor activation or suppression, part of the mechanisms through which NOD receptor ligands affected growth and hormone production could be clarified. Interestingly the PI3 kinase/Akt signalling pathway was found to be critically involved in mediating the proliferative effects of NOD receptor ligands and correspondingly, inhibitors of these pathway blocked the growth stimulating effects of NOD receptor ligands. In conclusion, not only TLR4 but also NOD receptors are expressed in pituitary tumour cells and the corresponding ligands are able to influence pituitary tumor progression and pathophysiology. Thus on the one hand transient or chronic bacterial infectious/inflammatory processes may affect pituitary tumour development and function, but on the other hand TLR4 and NOD1/2 themselves or their intracellular signalling pathways may provide novel targets for the development of future medical concepts for the treatment of human pituitary adenomas.
Publications
- NOD proteins expression and function in pituitary folliculostellate cells. 10th European Congress of Endocrinology, 2008, Berlin, Germany
Correa-de-Santana E, Fröhlich B, Labeur M, Paez-Pereda M, Theodoropoulou M, Monteserin J, Renner U & Stalla GK
- NOD proteins expression and function in pituitary folliculostellate cells. 12th Annual Meeting of the Neuroendocrinology Section of the DGE, 2008, Bamberg, Germany
Correa-de-Santana E, Fröhlich B, Labeur M, Paez-Pereda M, Theodoropoulou M, Monteserin J, Renner U & Stalla GK
- NOD proteins expression and function in pituitary folliculostellate cells. VII Congress of the International Society for Neuroimmunomodulation, 2008, Rio de Janeiro, Brazil
Correa-de-Santana E, Fröhlich B, Labeur M, Paez-Pereda M, Theodoropoulou M, Monteserin J, Renner U & Stalla GK
- (2009). Intrapituitary expression and regulation of the gp130 cytokine interleukin- 6 and its implication in pituitary physiology and pathophysiology. Ann N Y Acad Sci 1153:89-97
Renner U, De Santana EC, Gerez J, Fröhlich B, Haedo M, Pereda MP, Onofri C, Stalla GK, Arzt E
- (2009). NOD2 receptors in adenopituitary folliculostellate cells: expression and function. J Endocrinol. 203:111-22
Correa-de-Santana E, Froehlich B, Labeur M, Paez-Pereda M, Theodoropoulou M, Monteserin J, Renner U, Stalla G
- Activation of NOD and TLR4 innate immune receptors in tumoral pituitary cells and their effects on downstream targets. 13. Annual Meeting of the Neuroendocrine Section of the DGE, 2009, Hamburg, Germany
Fröhlich B, Corrêa-de-Santana E, Labeur M, Paez-Pereda M, Theodoropoulou M, Renner U & Stalla GK
- TLR4 and NOD innate immune receptors modulate the response of tumor pituitary AtT-20 cells through the PI3K/Akt survival pathway. 7th Meeting of the German-Endocrine-Brain-Immune-Network (GEBIN), 2009, Frankfurt, Germany
Fröhlich B, Corrêa-de-Santana E, Labeur M, Paez-Pereda M, Theodoropoulou M, Renner U & Stalla GK
- TLR4 and NOD receptors signalling modulates PI3K/AKT-induced cell survival of pituitary tumor cell lines. 2nd European Congress of Immunology, 2009, Berlin, Germany
Correa-de-Santana E, Fröhlich B, Labeur M, Paez-Pereda M, Theodoropoulou M, Monteserin J, Renner U & Stalla GK
