REVIEW ARTICLE Role of interleukin-6 in the pathogenesis of neuromyelitis optica Akiyuki Uzawa Masahiro Mori and Satoshi Kuwabara Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan Keywords anti-aquaporin 4 antibody; biomarker; cytokine; interleukin-6; neuromyelitis optica; pathogenesis Correspondence Akiyuki Uzawa, MD, PhD, Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel: +81-43-226-2129 Fax: +81-43-226-2160 Email: auzawa@chiba-u.jp Received: 26 February 2013; revised: 8 April 2013; accepted: 14 April 2013. Abstract Neuromyelitis optica (NMO) is an inflammatory disorder of the central ner- vous system that predominantly affects the optic nerves and spinal cord. NMO is characterized by anti-aquaporin 4 (AQP4) antibody-mediated astro- cytopathy. Recent studies have improved our knowledge of NMO. Interleu- kin-6 presumably plays an important role in the immunopathogenesis of NMO, because it is involved in the production of anti-AQP4 antibody in the peripheral circulation and in the enhancement of inflammation in the cen- tral nervous system. Significant advances in the understanding of the patho- genesis of NMO will help develop new treatments. The present review focuses on the current research addressing the role of interleukin-6 in NMO. (Clin. Exp. Neuroimmunol. doi: 10.1111/cen3.12024, May 2013) Introduction Neuromyelitis optica (NMO) is an autoimmune inflammatory disorder of the central nervous system (CNS) that is clinically characterized by severe involvement of the optic nerves and spinal cord. 1 Until recently, NMO was considered a rare variant of multiple sclerosis (MS). However, the discovery of the disease-specific serum, anti-aquaporin-4 (AQP4), antibody in NMO 2,3 was a breakthrough in NMO research. Several lines of evidence based on pathology, 4,5 neuroimaging 6 and immunological findings, 7 and on responses to immunotherapies between NMO and MS 8–10 have been accumulated. Based on these extensive data, NMO is now consid- ered as an anti-AQP4 antibody-mediated astrocytop- athy that is distinct from demyelinating disorders, such as MS. 11 Both T and B-cells might be implicated in the peripheral/CNS immune responses and pathogenesis of NMO. Although various cytokines have been associated with the pathogenesis of NMO, recent investigations have shown that interleukin-6 (IL-6) might function as an amplifier and effector in NMO. 7,12,13 IL-6 is a pro-inflammatory cytokine with a wide variety of functions: it causes potent B-cell stimulation, and acts on T cells. 14 IL-6 is produced by monocytes and macrophages after the stimulation of Toll-like receptors with distinct pathogen-associ- ated molecular patterns; 15 damage-associated molec- ular patterns from damaged or dying cells stimulate Toll-like receptors to produce IL-6. 16 IL-6 is also essential for the differentiation of IL-17-secreting CD4+ T cells (Th17) from naive CD4 T cells; 17 how- ever, IL-6 inhibits regulatory T cells. 18 Th17 cells are responsible for organ-specific autoimmune dis- eases, 18,19 and IL-6 might contribute to autoimmu- nological inflammation. The “IL-6-amplifier” is a synergistic activation mechanism for nuclear factor- jB/signal transducer and activator of transcription 3 (STAT3) in type 1 collagen + cells, and is marked by the hyperinduction of chemokines and subsequent local inflammation that leads to autoimmune dis- eases. This mechanism could also play an important role in NMO pathogenesis. 20 Cerebrospinal fluid (CSF) cytokine analyses have shown the significant upregulation of Th2-related cytokines and Th17-related cytokines, such as IL-6, IL-8 and the granulocyte colony-stimulating factor (G-CSF), in the active phase of NMO patients. 7 Among these significantly elevated cytokines, the level of IL-6 in CSF can be a biomarker of the prog- nosis and disease activity of NMO. 12 Therefore, in the present review, we focused on the current research on the roles of IL-6 in the pathogenesis of NMO. © 2013 Japanese Society for Neuroimmunology 167 Clinical and Experimental Neuroimmunology 4 (2013) 167–172 Clinical & Experimental Neuroimmunology