Artikel
Upregulation of cytokine activated IL6-r/STAT3 signalling correlates with glioma grade
Hochregulation der Zytokine-aktivierten IL6-r/STAT3 Signalkaskade korreliert mit dem WHO-Grad von Gliomen
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Autoren
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N. Thon
- Neurochirurgische Klinik und Poliklinik, Klinikum Großhadern, Ludwig-Maximilians-Universität, München
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M. Duy
- Neurochirurgische Klinik und Poliklinik, Klinikum Großhadern, Ludwig-Maximilians-Universität, München
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J. Hegermann
- Neurochirurgische Klinik und Poliklinik, Klinikum Großhadern, Ludwig-Maximilians-Universität, München
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O. Schnell
- Neurochirurgische Klinik und Poliklinik, Klinikum Großhadern, Ludwig-Maximilians-Universität, München
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J.-C. Tonn
- Neurochirurgische Klinik und Poliklinik, Klinikum Großhadern, Ludwig-Maximilians-Universität, München
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R. Goldbrunner
- Neurochirurgische Klinik und Poliklinik, Klinikum Großhadern, Ludwig-Maximilians-Universität, München
| Veröffentlicht: | 11. April 2007 |
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Gliederung
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Objective: The family of interleukin-6 type cytokines (e.g. IL-6, oncogene M, CNTF and LIF) has pleiotrophic effects on a variety of different cell types and activate target genes involved in cell survival, proliferation and inhibition of apoptosis via IL-6 receptor activated STAT3 signalling, indicating an important role of IL6-r/STAT3 in tumour development and progression. Although IL-6 expression in gliomas has been reported so far, no data has been published on the expression and activation of the IL6-r/STAT3 signalling pathway in gliomas of different grades so far.
Methods: In order to asses IL-6 receptor mediated activation of STAT3 signalling in gliomagenesis we investigated the expression of the IL6-r single transmembrane proteins gp80, gp130 and LIFα and the downstream activation of STAT3 by specific phosphorylation (S727) in tissue samples of human gliomas WHO° II-IV (n=10) and non-neoplastic brain tissues (n=5) using IHC, Western Blot and RT-PCR analysis. The effects of IL6 incubation on the proliferation of primary cell cultures harvested from human glioblastomas and non neoplastic brain tissues have been analysed using BrdU-labelling in vitro.
Results: IHC and Western blot analysis revealed a constitutive upregulation and cellular co-expression of IL6-r proteins gp80, gp130 and LIFα correlating with glioma grade compared to normal brain tissue controls. Furthermore an increasing proportion of ubiquitously expressed STAT3 showed specific IL6-r mediated activation by phosphorylation at serine 727 residues again correlating with WHO grade. In vitro IL-6 family cytokine stimulation significantly increased proliferation of primary cell cultures from WHO°IV gliomas compared to non neoplastic brain controls.
Conclusions: Here we report for the first time the constitutive expression and activation of IL6-r/STAT3 signalling correlating with glioma grade with proliferation enhancing effects of IL-6 stimulation in vitro. We hypothesize that selective activation of the IL6-r/STAT3 signalling significantly contributes to tumour cell proliferation and might play a crucial role in the malignant alterations in gliomas of different grades.
