IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis
| Autor: | Jessica Carmen, Sonny Dike, Peter A. Calabresi, Erick R. Scott, Douglas A. Kerr, Chitra Krishnan, Jennifer Drummond, Sanjay C. Keswani, Timothy H. Moran, Adam I. Kaplin, Tara Martinez, Carlos A. Pardo, Mikhail V. Pletnikov, Deepa M. Deshpande, Irina Shats |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Adult
Male Pathology medicine.medical_specialty Spinal Cord Disorder Myelitis Nitric Oxide Synthase Type II Inflammation Myelitis Transverse Transverse myelitis Rats Sprague-Dawley Mice Cerebrospinal fluid Organ Culture Techniques medicine Animals Humans Spinal cord injury Spinal Cord Injuries business.industry Interleukin-6 JAK-STAT signaling pathway General Medicine Protein-Tyrosine Kinases medicine.disease Spinal cord Axons Rats STAT Transcription Factors medicine.anatomical_structure Spinal Cord Immunology Female medicine.symptom Poly(ADP-ribose) Polymerases business Research Article Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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