TY  - JOUR
A1  - Gresle, Melissa M.
A1  - Alexandrou, Estella
A1  - Wu, Qizhu
A1  - Egan, Gary
A1  - Jokubaitis, Vilija
A1  - Ayers, Margaret
A1  - Jonas, Anna
A1  - Doherty, William
A1  - Friedhuber, Anna
A1  - Shaw, Gerry
A1  - Sendtner, Michael
A1  - Emery, Ben
A1  - Kilpatrick, Trevor
A1  - Butzkueven, Helmut
T1  - Leukemia Inhibitory Factor Protects Axons in Experimental Autoimmune Encephalomyelitis via an Oligodendrocyte-Independent Mechanism
JF  - PLoS One
N2  - Leukemia inhibitory factor (LIF) and Ciliary Neurotrophic factor (CNTF) are members of the interleukin-6 family of cytokines, defined by use of the gp130 molecule as an obligate receptor. In the murine experimental autoimmune encephalomyelitis (EAE) model, antagonism of LIF and genetic deletion of CNTF worsen disease. The potential mechanism of action of these cytokines in EAE is complex, as gp130 is expressed by all neural cells, and could involve immuno-modulation, reduction of oligodendrocyte injury, neuronal protection, or a combination of these actions. In this study we aim to investigate whether the beneficial effects of CNTF/LIF signalling in EAE are associated with axonal protection; and whether this requires signalling through oligodendrocytes. We induced MOG\(_{35-55}\) EAE in CNTF, LIF and double knockout mice. On a CNTF null background, LIF knockout was associated with increased EAE severity (EAE grade 2.1\(\pm\)0.14 vs 2.6\(\pm\)0.19; P<0.05). These mice also showed increased axonal damage relative to LIF heterozygous mice, as indicated by decreased optic nerve parallel diffusivity on MRI (1540\(\pm\)207 \(\mu\)m\(^2\)-/s vs 1310\(\pm\)175 \(\mu\)m\(^2\)-/s; P<0.05), and optic nerve (-12.5%) and spinal cord (-16%) axon densities; and increased serum neurofilament-H levels (2.5 fold increase). No differences in inflammatory cell numbers or peripheral auto-immune T-cell priming were evident. Oligodendrocyte-targeted gp130 knockout mice showed that disruption of CNTF/LIF signalling in these cells has no effect on acute EAE severity. These studies demonstrate that endogenous CNTF and LIF act centrally to protect axons from acute inflammatory destruction via an oligodendrocyte-independent mechanism.
KW  - receptor
KW  - ciliary neurotrophic factor
KW  - mulitple-sclerosis patients
KW  - factor prevents
KW  - demyelination
KW  - survival
KW  - neurons
KW  - injury
KW  - degeneration
KW  - motoneurons
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134617
VL  - 7
IS  - 10
ER  - 
TY  - JOUR
A1  - Götz, Rudolf
A1  - Sendtner, Michael
T1  - Cooperation of Tyrosine Kinase Receptor TrkB and Epidermal Growth Factor Receptor Signaling Enhances Migration and Dispersal of Lung Tumor Cells
JF  - PLoS ONE
N2  - TrkB mediates the effects of brain-derived neurotrophic factor (BDNF) in neuronal and nonnneuronal cells. Based on recent reports that TrkB can also be transactivated through epidermal growth-factor receptor (EGFR) signaling and thus regulates migration of early neurons, we investigated the role of TrkB in migration of lung tumor cells. Early metastasis remains a major challenge in the clinical management of non-small cell lung cancer (NSCLC). TrkB receptor signaling is associated with metastasis and poor patient prognosis in NSCLC. Expression of this receptor in A549 cells and in another adenocarcinoma cell line, NCI-H441, promoted enhanced migratory capacity in wound healing assays in the presence of the TrkB ligand BDNF. Furthermore, TrkB expression in A549 cells potentiated the stimulatory effect of EGF in wound healing and in Boyden chamber migration experiments. Consistent with a potential loss of cell polarity upon TrkB expression, cell dispersal and de-clustering was induced in A549 cells independently of exogeneous BDNF. Morphological transformation involved extensive cytoskeletal changes, reduced E-cadherin expression and suppression of E-cadherin expression on the cell surface in TrkB expressing tumor cells. This function depended on MEK and Akt kinase activity but was independent of Src. These data indicate that TrkB expression in lung adenoma cells is an early step in tumor cell dissemination, and thus could represent a target for therapy development.
KW  - metastasis
KW  - neurons
KW  - non-small cell lung cancer
KW  - neuron migration
KW  - adenocarcinoma of the lung
KW  - vector cloning
KW  - lung and intrathoracic tumors
KW  - secondary lung tumors
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119578
SN  - 1932-6203
VL  - 9
IS  - 6
ER  -