title: Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury.
abstract: Endogenous neural stem/progenitor cells (NSPCs) have recently been shown to differentiate exclusively into astrocytes, the cells that are involved in glial scar formation after spinal cord injury (SCI). The microenvironment of the spinal cord, especially the inflammatory cytokines that dramatically increase in the acute phase at the injury site, is considered to be an important cause of inhibitory mechanism of neuronal differentiation following SCI. Interleukin-6 (IL-6), which has been demonstrated to induce NSPCs to undergo astrocytic differentiation selectively through the JAK/STAT pathway in vitro, has also been demonstrated to play a critical role as a proinflammatory cytokine and to be associated with secondary tissue damage in SCI. In this study, we assessed the efficacy of rat anti-mouse IL-6 receptor monoclonal antibody (MR16-1) in the treatment of acute SCI in mice. Immediately after contusive SCI with a modified NYU impactor, mice were intraperitoneally injected with a single dose of MR16-1 (100 microg/g body weight), the lesions were assessed histologically, and the functional recovery was evaluated. MR16-1 not only suppressed the astrocytic diffentiation-promoting effect of IL-6 signaling in vitro but inhibited the development of astrogliosis after SCI in vivo. MR16-1 also decreased the number of invading inflammatory cells and the severity of connective tissue scar formation. In addition, we observed significant functional recovery in the mice treated with MR16-1 compared with control mice. These findings suggest that neutralization of IL-6 signaling in the acute phase of SCI represents an attractive option for the treatment of SCI.
authors.affiliation: Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Okada
authors.forename: M
authors.initials: M
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Mikami
authors.forename: T
authors.initials: T
authors.lastname: Shimazaki
authors.forename: M
authors.initials: M
authors.lastname: Mihara
authors.forename: Y
authors.initials: Y
authors.lastname: Ohsugi
authors.forename: Y
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: K
authors.initials: K
authors.lastname: Yoshizaki
authors.forename: T
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Toyama
authors.forename: H
authors.initials: H
authors.lastname: Okano
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects*; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D001973:Bromodeoxyuridine / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D051959:ELAV Proteins; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000276:immunology*; D020127:Recovery of Function; D050796:STAT3 Transcription Factor; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013194:Staining and Labeling; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D000906:Antibodies; D039481:CD11b Antigen; D004268:DNA-Binding Proteins; D051959:ELAV Proteins; D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D001973:Bromodeoxyuridine