title: IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis.
abstract: 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Adam I
authors.initials: AI
authors.lastname: Kaplin
authors.forename: Deepa M
authors.initials: DM
authors.lastname: Deshpande
authors.forename: Erick
authors.initials: E
authors.lastname: Scott
authors.forename: Chitra
authors.initials: C
authors.lastname: Krishnan
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Carmen
authors.forename: Irina
authors.initials: I
authors.lastname: Shats
authors.forename: Tara
authors.initials: T
authors.lastname: Martinez
authors.forename: Jennifer
authors.initials: J
authors.lastname: Drummond
authors.forename: Sonny
authors.initials: S
authors.lastname: Dike
authors.forename: Mikhail
authors.initials: M
authors.lastname: Pletnikov
authors.forename: Sanjay C
authors.initials: SC
authors.lastname: Keswani
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Pardo
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Kerr
mesh_terms: 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
chemical_list: D015850:Interleukin-6; D050791:STAT Transcription Factors; D052247:Nitric Oxide Synthase Type II; D011065:Poly(ADP-ribose) Polymerases; D011505:Protein-Tyrosine Kinases