Artikel
The transmembrane chemokines CXCL16 and CX3CL1 transduce proliferative and anti-apoptotic effects in human meningiomas by “inverse signaling”
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Autoren
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Kirsten Hattermann
- Klinik für Neurochirurgie, UKSH, Campus Kiel
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Kareen Bartsch
- Anatomisches Institut, CAU zu Kiel
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Henrike Gebhardt
- Klinik für Neurochirurgie, UKSH, Campus Kiel
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Anne Dorothée Schmitt
- Anatomisches Institut, CAU zu Kiel
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Maximilian Mehdorn
- Anatomisches Institut, CAU zu Kiel
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Janka Held-Feindt
- Anatomisches Institut, CAU zu Kiel
| Veröffentlicht: | 2. Juni 2015 |
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Gliederung
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Objective: Chemokines and their receptors play a decisive role in tumor progression and metastasis. Since the molecular mechanisms involved in progression of meningiomas are not fully understood, we investigate the expression and functional role of the transmembrane (tm)chemokines CXCL16 and CX3CL1 in these tumors.
Method: We examined the expression of CXCL16/CXCR6 and CX3CL1/CX3CR1 in matched probes of solid and cultured human meningiomas by qPCR, double-immunofluorescence and immunocytochemistry. We observed binding of fluorescent-labeled soluble (s)CXCL16 and sCX3CL1 to their transmembrane counterparts, and measured induction of signaling effects by Western Blot (p42/44, Akt) and immunocytochemistry (NF<FONT face=symbol>k</FONT>B). We determined the influence of sCXCL16 and sCX3CL1 on proliferation by MTT assay and rescue from apoptosis by cCaspase 3/7 activity assay. After generating siRNA CXCL16 knock-down variants, we investigated binding and influence of sCXCL16 on signaling effects as well.
Results: We determined a distinct expression of CXCL16/CXCR6 and CX3CL1/CX3CR1 in solid human meningioma samples, and double-immunostaining showed a predominant expression of the chemokine/-receptor pairs in meningioma cells, in infiltrating microglia /macrophages and endothelial cells. Cultured human meningioma cells were characterized only by the expression of the chemokine ligands CXCL16 and CX3CL1, lacking the corresponding receptors. Cultured human tmCXCL16-/CX3CL1-positive meningiomas bound sCXCL16/CX3CL1 and responded after stimulation with the chemokines with phosphorylation of p42/44 and Akt. Enhanced proliferation and rescue from apoptosis were measurable in human tmCXCL16/CX3CL1-positive meningioma cells after stimulation with sCXCL16/CX3CL1. Intracellular signaling effects and binding experiments were reduced after specific CXCL16 siRNA transfection of human meningioma cells.
Conclusions: We conclude that the transmembrane ligand itself acts as a receptor and generates auto- /paracrine signals ("inverse signaling").
