IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis.
Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.
Kaplin
Adam I
AI
Department of Psychiatry and Behavioral Sciences, Bloomberg School of Public Health, Baltimore, Maryland, USA.
Deshpande
Deepa M
DM
Scott
Erick
E
Krishnan
Chitra
C
Carmen
Jessica S
JS
Shats
Irina
I
Martinez
Tara
T
Drummond
Jennifer
J
Dike
Sonny
S
Pletnikov
Mikhail
M
Keswani
Sanjay C
SC
Moran
Timothy H
TH
Pardo
Carlos A
CA
Calabresi
Peter A
PA
Kerr
Douglas A
DA
D000328:Adult; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000008:administration & dosage / Q000134:cerebrospinal fluid*; D008297:Male; D051379:Mice; D009188:Myelitis, Transverse / Q000134:cerebrospinal fluid* / Q000150:complications / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009924:Organ Culture Techniques; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000134:cerebrospinal fluid* / Q000150:complications / Q000473:pathology
D015850:Interleukin-6; D050791:STAT Transcription Factors; D052247:Nitric Oxide Synthase Type II; D011065:Poly(ADP-ribose) Polymerases; D011505:Protein-Tyrosine Kinases