Leukemia inhibitory factor arrests oligodendrocyte death and demyelination in spinal cord injury.
As a consequence of secondary pathophysiological mechanisms elicited after spinal cord injury (SCI), oligodendrocytes die by waves of apoptosis. This ultimately results in demyelination of intact axons leading to a loss of their conducting properties. Preservation of as few as 5% to 10% of myelinated axons in individual tracts can confer locomotor recovery. Thus, strategies aimed at rescuing mature oligodendrocytes ensheathing viable axons are likely to be of therapeutic significance. We report that leukemia inhibitory factor (LIF) can prevent oligodendrocyte apoptosis, notably contralateral to the spinal cord lesion, through the induction of the JAK/STAT and Akt signaling pathways as well as by potentiating the expression of the antiapoptotic molecule, cIAP2. Reduced oligodendrocyte apoptosis after SCI with LIF administration resulted in a substantial decrease in demyelination shown by the preservation of lamellated myelin surrounding viable axons and deposition of the degraded myelin basic protein. The data suggest that LIF signals survival in oligodendrocytes after SCI, prevents the secondary wave of demyelination, and thereby reduces inhibitory myelin deposits.
Azari
Michael F
MF
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Profyris
Christos
C
Karnezis
Tara
T
Bernard
Claude C
CC
Small
David H
DH
Cheema
Surindar S
SS
Ozturk
Ezgi
E
Hatzinisiriou
Irene
I
Petratos
Steven
S
D000818:Animals; D019771:Axotomy / Q000379:methods; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D016923:Cell Death / Q000187:drug effects; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D047468:Immunoprecipitation / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000008:administration & dosage*; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D051379:Mice; D008810:Mice, Inbred C57BL; D004676:Myelin Basic Protein / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects* / Q000502:physiology; D018121:Receptors, Cytokine / Q000378:metabolism; D053606:Receptors, OSM-LIF; D050791:STAT Transcription Factors / Q000378:metabolism; D012720:Severity of Illness Index; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases
D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D004676:Myelin Basic Protein; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050791:STAT Transcription Factors; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases