Interleukin-6: From basic biology to selective blockade of pro-inflammatory activities

被引：324

作者：

Scheller, Juergen ^{[1
]}

Garbers, Christoph ^{[2
]}

Rose-John, Stefan ^{[2
]}

机构：

[1] Univ Dusseldorf, Fac Med, Inst Biochem & Mol Biol 2, Dusseldorf, Germany

[2] Univ Kiel, Inst Biochem, D-24098 Kiel, Germany

来源：

SEMINARS IN IMMUNOLOGY | 2014年 / 26卷 / 01期

关键词：

ADAM17; Inflammation; Interleukin-6; Soluble receptor; Trans-signaling; sgp130Fc; SOLUBLE IL-6 RECEPTOR; DOUBLE-TRANSGENIC MICE; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MEMBRANE-PROXIMAL DOMAIN; RANGE THERMAL-STRESS; T-CELLS; RHEUMATOID-ARTHRITIS; MOLECULAR SWITCH; TH17; CELLS; IN-VIVO;

D O I：

10.1016/j.smim.2013.11.002

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

Cytokines receptors exist in membrane bound and soluble form. A soluble form of the human IL-6R is generated by limited proteolysis and alternative splicing. The complex of IL-6 and soluble IL-6R stimulates target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. We have named this process trans-signaling. Soluble gp130 is the natural inhibitor of IL-6/soluble IL-6R complex responses. Recombinant soluble gp130 protein is a molecular tool to discriminate between gp130 responses via membrane bound and soluble IL-6R responses. Neutralizing monoclonal antibodies for global blockade of IL-6 signaling and the sgp130Fc protein for selective blockade of IL-6 trans-signaling have been used in several animal models of human diseases. Using the sgp130Fc protein or sgp130Fc transgenic mice we demonstrate in models of inflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis pancreatitis, colon cancer, ovarian cancer and pancreatic cancer, that IL-6 transsignaling via the soluble IL-6R is the crucial step in the development and the progression of the disease. Therefore, sgp130Fc is a novel therapeutic agent for the treatment of chronic inflammatory diseases and cancer and it undergoes phase I clinical trials as an anti-inflammatory drug since June 2013. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：2 / 12

页数：11

共 129 条

[1]

Unraveling Viral Interleukin-6 Binding to gp130 and Activation of STAT-Signaling Pathways Independently of the Interleukin-6 Receptor [J].

Adam, Nina ;

Rabe, Bjoern ;

Suthaus, Jan ;

Groetzinger, Joachim ;

Rose-John, Stefan ;

Scheller, Juergen .

JOURNAL OF VIROLOGY, 2009, 83 (10) :5117-5126

[2]

Interleukin 6 is required for the development of collagen-induced arthritis [J].

Alonzi, T ;

Fattori, E ;

Lazzaro, D ;

Costa, P ;

Probert, L ;

Kollias, G ;

De Benedetti, F ;

Poli, V ;

Ciliberto, G .

JOURNAL OF EXPERIMENTAL MEDICINE, 1998, 187 (04) :461-468

[3]

Conservation of IL-6 trans-signaling mechanisms controlling L-selectin adhesion by fever-range thermal stress [J].

Appenheimer, Michelle M. ;

Girard, Rachael A. ;

Chen, Qing ;

Wang, Wan-Chao ;

Bankert, Katherine C. ;

Hardison, Joy ;

Bain, Mark D. ;

Ridgley, Frank ;

Sarcione, Edward J. ;

Buitrago, Sandra ;

Kothlow, Sonja ;

Kaspers, Bernd ;

Robert, Jacques ;

Rose-John, Stefan ;

Baumann, Heinz ;

Evans, Sharon S. .

EUROPEAN JOURNAL OF IMMUNOLOGY, 2007, 37 (10) :2856-2867

[4]

Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation:: Evidence in Crohn disease and experimental colitis in vivo [J].

Atreya, R ;

Mudter, J ;

Finotto, S ;

Müllberg, J ;

Jostock, T ;

Wirtz, S ;

Schütz, M ;

Bartsch, B ;

Holtmann, M ;

Becker, C ;

Strand, D ;

Czaja, J ;

Schlaak, JF ;

Lehr, HA ;

Autschbach, F ;

Schürmann, G ;

Nishimoto, N ;

Yoshizaki, K ;

Ito, H ;

Kishimoto, T ;

Galle, PR ;

Rose-John, S ;

Neurath, MF .

NATURE MEDICINE, 2000, 6 (05) :583-588

[5]

Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells [J].

Audet, J ;

Miller, CL ;

Rose-John, S ;

Piret, JM ;

Eaves, CJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (04) :1757-1762

[6]

Selective proteolytic cleavage of IL-2 receptor and IL-6 receptor ligand binding chains by neutrophil-derived serine proteases at foci of inflammation [J].

Bank, U ;

Reinhold, D ;

Schneemilch, C ;

Kunz, D ;

Synowitz, HJ ;

Ansorge, S .

JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, 1999, 19 (11) :1277-1287

[7]

Minimal Interleukin 6 (IL-6) Receptor Stalk Composition for IL-6 Receptor Shedding and IL-6 Classic Signaling [J].

Baran, Paul ;

Nitz, Rebecca ;

Groetzinger, Joachim ;

Scheller, Juergen ;

Garbers, Christoph .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (21) :14756-14768

[8]

Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model [J].

Barkhausen, Tanja ;

Tschernig, Thomas ;

Rosenstiel, Philip ;

van Griensven, Martijn ;

Vonberg, Ralf-Peter ;

Dorsch, Martina ;

Mueller-Heine, Annika ;

Chalaris, Athena ;

Scheller, Juergen ;

Rose-John, Stefan ;

Seegert, Dirk ;

Krettek, Christian ;

Waetzig, Georg H. .

CRITICAL CARE MEDICINE, 2011, 39 (06) :1407-1413

[9]

TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling [J].

Becker, C ;

Fantini, MC ;

Schramm, C ;

Lehr, HA ;

Wirtz, S ;

Nikolaev, A ;

Burg, J ;

Strand, S ;

Kiesslich, R ;

Huber, S ;

Ito, H ;

Nishimoto, N ;

Yoshizaki, K ;

Nishimoto, N ;

Galle, PR ;

Blessing, M ;

Rose-John, S ;

Neurath, MF .

IMMUNITY, 2004, 21 (04) :491-501

[10]

Becker C, 2005, CELL CYCLE, V4, P217

← 1 2 3 4 5 6 7 8 9 10 →