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Vol. 5. Núm. 1.
Páginas 34-39 (febrero - febrero 2009)
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Vol. 5. Núm. 1.
Páginas 34-39 (febrero - febrero 2009)
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La interleucina 6 en la fisiopatología de la artrirtis reumatoide
Interleukin 6 in the physiopathology of rheumatoid arthritis
Visitas
21464
José Luis Pablos Álvarez
Servicio de Reumatología y Unidad de Investigación, Hospital 12 de Octubre, Madrid, España
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Resumen

La interleucina (IL) 6 fue identificada en 1986 como un factor producido por los linfocitos T, con efectos estimuladores del crecimiento y síntesis de inmunoglobulinas en los linfocitos B. Pertenece a una amplia familia de citocinas que comparten el receptor de membrana gp130, mediador de una señal específica de activación del sistema Jak/STAT3 con amplios efectos en la expresión de genes proinflamatorios e inmunorreguladores.

De forma más prominente que otras citocinas, la IL-6 media potentes acciones sistémicas en órganos distantes de su origen local inflamatorio. Las más específicas afectan a la hematopoyesis y la síntesis hepática de reactantes de fase aguda. Su potencial actividad proinflamatoria y de destrucción articular, junto con su implicación en la inmunorregulación T y B, la convirtió en una diana terapéutica atractiva, confirmada por el éxito de su antagonista tocilizumab en la artritis reumatoide (AR).

Aunque son necesarios estudios más amplios sobre la participación de la IL-6 en la fisiopatología de la AR, numerosos datos indirectos permiten situarla en una posición muy relevante.

Palabras clave:
Interleucina 6
Citocinas
Artritis reumatoide
Fisiopatología
Terapia
Tocilizumab
Abstract

Interleukin (IL) 6 was identified in 1986 as a factor produced by T lymphocytes, that mediates growth and immunoglobulin synthesis on B lymphocytes. IL-6 is a member of a large cytokine family sharing a gp130 membrane receptor. This receptor mediates specific Jak/STAT3 activation, which induces widespread expression of pro-inflammatory and immunoregulatory genes.

IL-6 mediates potent systemic responses, in organs distant from its local inflammatory sources, in a prominent fashion compared to other cytokines. Most specific effects involve hematopoiesis and hepatic acute phase reactants synthesis. IL-6 became a rheumatoid arthritis (RA) target due to its pro-inflammatory and joint destructive potential, as well as its participation in T and B immunoregulation. The therapeutic success of tocilizumab has confirmed IL-6 as an RA target.

Although additional studies on the participation of IL-6 in RA physiopathology are needed, a number of indirect data point to a relevant position in this setting.

Keywords:
Interleukin 6
Cytokines
Rheumatoid arthritis
Physiopathology
Therapy
Tocilizumab
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Bibliografía
[1.]
T. Kishimoto.
Interleukin-6: from basic science to medicine. 40 years in immunology.
[2.]
T. Hirano, K. Yasukawa, H. Harada, T. Taga, Y. Watanabe, T. Matsuda, et al.
Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin.
Nature, 324 (1986), pp. 73-76
[3.]
T. Hirano, T. Taga, N. Nakano, K. Yasukawa, S. Kashiwamura, K. Shimizu, et al.
Purification o homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2).
Proc Natl Acad Sci U S A, 2 (1985), pp. 5490-5494
[4.]
M. Jourdan, R. Bataille, J. Seguin, X.G. Zhang, P.A. Chaptal, B. Klein.
Constitutive production of interleukin-6 and immunologic features in cardiac myxomas.
Arthritis Rheum, 33 (1990), pp. 398-402
[5.]
J. Gauldie, C. Richards, W. Northemann, G. Fey, H. Baumann.
IFN beta 2/BSF2/IL-6 is the monocyte-derived HSF that regulates receptor-specific acute phase gene regulation in hepatocytes.
Ann N Y Acad Sci, 557 (1989), pp. 46-58
[6.]
T. Hirano, T. Matsuda, M. Turner, N. Miyasaka, G. Buchan, B. Tang, et al.
Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis.
Eur J Immunol, 18 (1988), pp. 1797-1801
[7.]
K. Yoshizaki, T. Matsuda, N. Nishimoto, T. Kuritani, L. Taeho, K. Aozasa, et al.
Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease.
Blood, 74 (1989), pp. 1360-1367
[8.]
G.S. Firestein, J.M. Alvaro-Gracia, R. Maki.
Quantitative analysis of cytokine gene expression in rheumatoid arthritis.
J Immunol, 144 (1990), pp. 3347-3353
[9.]
S. Rose-John, J. Scheller, G. Elson, S.A. Jones.
Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer.
J Leukoc Biol, 80 (2006), pp. 227-236
[10.]
P.C. Heinrich, I. Behrmann, S. Haan, H.M. Hermanns, G. Müller-Newen, F. Schaper.
Principles of interleukin (IL)-6-type cytokine signalling and its regulation.
Biochem J, 374 (2003), pp. 1-20
[11.]
J.V. Castell, T. Andus, D. Kunz, P.C. Heinrich.
Interleukin-6. The major regulator of acute-phase protein synthesis in man and rat.
Ann N Y Acad Sci, 557 (1989), pp. 87-99
[12.]
N.C. Andrews.
Anemia of inflammation: the cytokine-hepcidin link.
J Clin Invest, 113 (2004), pp. 1251-1253
[13.]
M. Peters, A.M. Muller, S. Rose-John.
Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis.
Blood, 92 (1998), pp. 3495-3504
[14.]
S.C. Manolagas, R.L. Jilka.
Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis.
N Engl J Med, 332 (1995), pp. 305-311
[15.]
S. Ohshima, Y. Saeki, T. Mima, M. Sasai, K. Nishioka, S. Nomura, et al.
Interleukin 6 plays a key role in the development of antigen-induced arthritis.
Proc Natl Acad Sci U S A, 95 (1998), pp. 8222-8226
[16.]
B.K. Finck, B. Chan, D. Wofsy.
Interleukin 6 promotes murine lupus in NZB/NZW F1 mice.
J Clin Invest, 94 (1994), pp. 585-591
[17.]
S. Serada, M. Fujimoto, M. Mihara, N. Koike, Y. Ohsugi, S. Nomura, et al.
IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis.
Proc Natl Acad Sci U S A, 105 (2008), pp. 9041-9046
[18.]
S. Glund, A. Krook.
Role of interleukin-6 signalling in glucose and lipid metabolism.
Acta Physiol, 192 (2008), pp. 37-48
[19.]
V. Wallenius, K. Wallenius, B. Ahrén, M. Rudling, H. Carlsten, S.L. Dickson, et al.
Interleukin-6-deficient mice develop mature-onset obesity.
Nat Med, 8 (2002), pp. 75-79
[20.]
Y.H. Lee, R.E. Pratley.
The evolving role of inflammation in obesity and the metabolic syndrome.
Curr Diab Rep, 5 (2005), pp. 70-75
[21.]
G.J. Veldhuis, P.H. Willemse, D.T. Sleijfer, W.T. Van der Graaf, H.J. Groen, P.C. Limburg, et al.
Toxicity and efficacy of escalating dosages of recombinant human interleukin-6 after chemotherapy in patients with breast cancer or non-small-cell lung cancer.
J Clin Oncol, 13 (1995), pp. 2585-2593
[22.]
R.N. Maini, P.C. Taylor, J. Szechinski, K. Pavelka, J. Bröll, G. Balint, et al.
CHARISMA Study Group. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate.
Arthritis Rheum, 54 (2006), pp. 2817-2829
[23.]
L.S. Knudsen, M. Klarlund, H. Skjødt, T. Jensen, M. Ostergaard, K.E. Jensen, et al.
Biomarkers of inflammation in patients with unclassified polyarthritis and early rheumatoid arthritis. Relationship to disease activity and radiographic outcome.
J Rheumatol, 35 (2008), pp. 1277-1287
[24.]
R.H. Straub, U. Müller-Ladner, T. Lichtinger, J. Schölmerich, H. Menninger, B. Lang.
Decrease of interleukin 6 during the first 12 months is a prognostic marker for clinical outcome during 36 months treatment with disease-modifying anti-rheumatic drugs.
Br J Rheumatol, 36 (1997), pp. 1298-1303
[25.]
K. Miyazawa, A. Mori, H. Okudaira.
IL-6 synthesis by rheumatoid synoviocytes is autonomously upregulated at the transcriptional level.
J Allergy Clin Immunol, 103 (1999), pp. S437-S444
[26.]
S. Kotake, K. Sato, K.J. Kim, N. Takahashi, N. Udagawa, I. Nakamura, et al.
Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation.
J Bone Miner Res, 11 (1996), pp. 88-95
[27.]
C.T. Weaver, L.E. Harrington, P.R. Mangan, M. Gavrieli, K.M. Murphy.
Th17: an effector CD4 T cell lineage with regulatory T cell ties.
Immunity, 24 (2006), pp. 677-688
[28.]
L. Zhou, J.E. Lopes, M.M. Chong, I.I. Ivanov, R. Min, G.D. Victora, et al.
TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function.
Nature, 453 (2008), pp. 236-240
[29.]
S. Dominitzki, M.C. Fantini, C. Neufert, A. Nikolaev, P.R. Galle, J. Scheller, et al.
Trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+CD25 T cells.
J Immunol, 179 (2007), pp. 2041-2045
[30.]
S. Nadkarni, C. Mauri, M.R. Ehrenstein.
Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta.
J Exp Med, 204 (2007), pp. 33-39
[31.]
P.K. Wong, J.M. Quinn, N.A. Sims, A. Van Nieuwenhuijze, I.K. Campbell, I.P. Wicks.
Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis.
Arthritis Rheum, 54 (2006), pp. 158-168
[32.]
H. Hata, N. Sakaguchi, H. Yoshitomi, Y. Iwakura, K. Sekikawa, Y. Azuma, et al.
Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice.
J Clin Invest, 114 (2004), pp. 582-588
[33.]
K. Iwanami, I. Matsumoto, Y. Tanaka-Watanabe, A. Inoue, M. Mihara, Y. Ohsugi, et al.
Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase.
Arthritis Rheum, 58 (2008), pp. 754-763
[34.]
C. Gabay.
Interleukin-6 and chronic inflammation.
Arthritis Res Ther, 8 (2006), pp. S3
[35.]
M. Kopf, H. Baumann, G. Freer, M. Freudenberg, M. Lamers, T. Kishimoto, et al.
Impaired immune and acute-phase responses in interleukin-6-deficient mice.
Nature, 368 (1994), pp. 339-342
[36.]
F. Legendre, J. Dudhia, J.P. Pujol, P. Bogdanowicz.
JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down-regulation of type II collagen, aggrecan core, and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression.
J Biol Chem, 278 (2003), pp. 2903-2912
[37.]
N. Nishimoto, Y. Kanakura, K. Aozasa, T. Johkoh, M. Nakamura, S. Nakano, et al.
Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease.
Blood, 106 (2005), pp. 2627-2632
[38.]
S. Yokota, T. Miyamae, T. Imagawa, N. Iwata, S. Katakura, M. Mori, et al.
Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis.
Arthritis Rheum, 52 (2005), pp. 818-825
[39.]
Hirao M, Hashimoto J, Tsuboi H, Nampei A, Nakahara H, Yoshio N, et al. Laboratory and febrile features after joint surgery in rheumatoid arthritis patients treated with tocilizumab. Ann Rheum Dis. 2008 Jun 2. [Epub ahead of print]. doi:10.1136/ard.2008.090068
[40.]
J.S. Smolen, A. Beaulieu, A. Rubbert-Roth, C. Ramos-Remus, J. Rovensky, E. Alecock, et al.
OPTION Investigators. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.
[41.]
H. Nakahara, J. Song, M. Sugimoto, K. Hagihara, T. Kishimoto, K. Yoshizaki, et al.
Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis.
Arthritis Rheum, 48 (2003), pp. 1521-1529
[42.]
E.M. Paleolog, S. Young, A.C. Stark, R.V. McCloskey, M. Feldmann, R.N. Maini.
Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor and interleukin-1 in rheumatoid arthritis.
[43.]
N. Nishimoto, J. Hashimoto, N. Miyasaka, K. Yamamoto, S. Kawai, T. Takeuchi, et al.
Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab.
Ann Rheum Dis, 66 (2007), pp. 1162-1167
Copyright © 2009. Elsevier España S.L. Barcelona
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