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  - Drechsler, Johannes
A1  - Groetzinger, Joachim
A1  - Hermanns, Heike M.
T1  - Characterization of the Rat Oncostatin M Receptor Complex Which Resembles the Human, but Differs from the Murine Cytokine Receptor
JF  - PLoS One
N2  - Evaluation of a pathophysiological role of the interleukin-6-type cytokine oncostatin M (OSM) for human diseases has been complicated by the fact that mouse models of diseases targeting either OSM or the OSM receptor (OSMR) complex cannot fully reflect the human situation. This is due to earlier findings that human OSM utilizes two receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) (type I) and gp130/OSMR (type II), both with wide expression profiles. Murine OSM on the other hand only binds to the gp130/OSMR (type II) receptor complex with high affinity. Here, we characterize the receptor usage for rat OSM. Using different experimental approaches (knock-down of the OSMR expression by RNA interference, blocking of the LIFR by LIF-05, an antagonistic LIF variant and stably transfected Ba/F3 cells) we can clearly show that rat OSM surprisingly utilizes both, the type I and type II receptor complex, therefore mimicking the human situation. Furthermore, it displays cross-species activities and stimulates cells of human as well as murine origin. Its signaling capacities closely mimic those of human OSM in cell types of different origin in the way that strong activation of the Jak/STAT, the MAP kinase as well as the PI3K/Akt pathways can be observed. Therefore, rat disease models would allow evaluation of the relevance of OSM for human biology.
KW  - in vitro
KW  - leukemia-inhibitory factor
KW  - ciliary neurotrophic factor
KW  - T cell development
KW  - swiss model
KW  - fetal liver
KW  - interleukin-6-type cytokines
KW  - rheumatoid arthritis
KW  - signal transduction
KW  - growth regulator
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133879
VL  - 7
IS  - 8
ER  -