Hye-Ok Kubo; Douglas A. Canders; Malcolm Scammells; Philip Frugier
Evidence of elevated levels of the proinflammatory cytokine IL-6 has been routinely observed during inflammatory responses and in a number of autoimmune diseases; multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). A major challenge in MS is to develop biomarkers that could help in understanding individual MS patients and a lot of attention has been drawn toward identification of diagnostic, prognostic, process-specific, and treatment-related biomarkers for MS. Recent studies showed that IL-6 neutralization restricted disease progression and decreased disability, myelin loss, and axonal damage. Our study suggest that IL-6 has regulatory mechanisms and a key mediator of progressive MS. Future studies need to the identification other related factor and mechanetic effects.
Keywords: Multiple sclerosis; IL-6; Proinflammatory cytokine; Myelin
1. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 2012; 8:647–56. [PubMed]
2. Rangachari M, Kuchroo VK. Using EAE to better understand principles of immune function and autoimmune pathology. J Autoimmun 2013;45:31–9. [PubMed]
3. Ponomarev ED, Shriver LP, Maresz K, Pedras-Vasconcelos J, Verthelyi D, Dittel BN. GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J Immunol 2007;178:39–48. [PubMed]
4. Romano M, Sironi M, Toniatti C, et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 1997; 6(3): 315–325. [PubMed]
5. Brosnan CF, Raine CS. Mechanisms of immune injury in multiple sclerosis.Brain Pathol 1996; 6:243–57. [PubMed]
6. Racke MK, Bonomo A, Scott DE et al. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J. Exp. Med 1994; 180:1961–6. [PubMed]
7. Ohtsuka T. Serum interleukin-6 level is reflected in elevated high-sensitivity C-reactive protein level in patients with systemic sclerosis. J Dermatol 2010; 37: 801–806. [PubMed]
8. Ishihara K, Hirano T. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 2002; 13:357–368. [PubMed]
9. Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 2011; 121:3375–3383. [PubMed]
10. Althoff K, Reddy P, Voltz N, Rose-John S, Müllberg J. Shedding of interleukin-6 receptor and tumor necrosis factor α. Eur J Biochem 2000; 267: 2624–2631. [PubMed]
11. Terao M, Murota H, Kitaba S, Katayama I. Tumor necrosis factor-α processing inhibitor-1 inhibits skin fibrosis in a bleomycin-induced murine model of scleroderma. Exp Dermatol 2010; 19:38–43. [PubMed]
12. Chalaris A, Rabe B, Paliga K, Lange H, Laskay T, Fielding CA et al. Apoptosis is a natural stimulus of IL6R shedding and contributes to the proinflammatory trans-signaling function of neutrophils. Blood 2007; 110:1748–1755. [PubMed]
13. Muangchan C, Pope JE. Interleukin 6 in systemic sclerosis and potential implications for targeted therapy. J Rheumatol 2012; 39:1120–1124. [PubMed]
14. Hügle T, O'Reilly S, Simpson R, Kraaij MD, Bigley V, Collin M et al. Tumor necrosis factor co-stimulated T-lymphocytes from patients with systemic sclerosis trigger collagen production in fibroblasts. Arthr Rheumat 2012; 65:481–491.
15. Saito F, Tasaka S, Inoue K-i, Miyamoto K, Nakano Y, Ogawa Y et al. Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice. Am J Respir Cell Mol Biol 2008; 38:566–571. [PubMed]
16. Narazaki M, Yasukawa K, Saito T, Ohsugi Y, Fukui H, Koishihara Y et al. Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood 1993; 82:1120–1126.
17. Kawaguchi Y, Hara M, Wright TM. Endogenous IL-1α from systemic sclerosis fibroblasts induces IL-6 and PDGF-A. J Clin Invest 1999; 103:1253–1260. [PubMed]
18. Radstake TRDJ, van Bon L, Broen J, Wenink M, Santegoets K, Deng Y et al. Increased frequency and compromised function of T regulatory cells in systemic sclerosis (SSc) is related to a diminished CD69 and TGFβ expression. PLoS ONE 2009; 4:e5981. [PubMed]
19. Shima Y, Kuwahara Y, Murota H, Kitaba S, Kawai M, Hirano T et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology 2010; 49:2408–2412. [PubMed]
20. Kowal-Bielecka O, Landewe R, Avouac J, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis 2008; 68:620–8. [PubMed]