Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination.
Enhancement of oligodendrocyte survival through activation of leukemia inhibitory factor receptor (LIFR) signaling is a candidate therapeutic strategy for demyelinating disease. However, in other cell types, LIFR signaling is under tight negative regulation by the intracellular protein suppressor of cytokine signaling 3 (SOCS3). We, therefore, postulated that deletion of the SOCS3 gene in oligodendrocytes would promote the beneficial effects of LIFR signaling in limiting demyelination. By studying wild-type and LIF-knockout mice, we established that SOCS3 expression by oligodendrocytes was induced by the demyelinative insult, that this induction depended on LIF, and that endogenously produced LIF was likely to be a key determinant of the CNS response to oligodendrocyte loss. Compared with wild-type controls, oligodendrocyte-specific SOCS3 conditional-knockout mice displayed enhanced c-fos activation and exogenous LIF-induced phosphorylation of signal transducer and activator of transcription 3. Moreover, these SOCS3-deficient mice were protected against cuprizone-induced oligodendrocyte loss relative to wild-type animals. These results indicate that modulation of SOCS3 expression could facilitate the endogenous response to CNS injury.
Emery
Ben
B
Department of Neurobiology, Stanford University, Stanford, CA 94305, USA.
Cate
Holly S
HS
Marriott
Mark
M
Merson
Tobias
T
Binder
Michele D
MD
Snell
Cameron
C
Soo
Pik Ying
PY
Murray
Simon
S
Croker
Ben
B
Zhang
Jian-Guo
JG
Alexander
Warren S
WS
Cooper
Helen
H
Butzkueven
Helmut
H
Kilpatrick
Trevor J
TJ