Interleukin-6 (IL-6) is overproduced in the joints of patients with rheumatoid arthritis (RA) and, based on its multiple stimulatory effects on cells of the immune system and on vascular endothelia, osteoclasts, and synovial fibroblasts, is believed to participate in the development and clinical manifestations of this disease. In this study we have analysed the effect of ablating cytokine production in two mouse models of arthritis: collagen-induced arthritis (CIA) in DBA/1J mice and the inflammatory polyarthritis of tumor necrosis factor α (TNF-α) transgenic mice. IL-6 was ablated by intercrossing an IL-6 null mutation into both arthritis-susceptible genetic backgrounds and disease development was monitored by measuring clinical, histological, and biochemical parameters. Two opposite responses were observed; while arthritis in TNF-α transgenic mice was not affected by inactivation of the IL-6 gene, DBA/1J, IL-6−/− mice were completely protected from CIA, accompanied by a reduced antibody response to type II collagen and the absence of inflammatory cells and tissue damage in knee joints. These results are discussed in the light of the present knowledge of cytokine networks in chronic inflammatory disorders and suggest that IL-6 receptor antagonists might be beneficial for the treatment of RA.
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16 February 1998
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February 16 1998
Interleukin 6 Is Required for the Development of Collagen-induced Arthritis
Tonino Alonzi,
Tonino Alonzi
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
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Elena Fattori,
Elena Fattori
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
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Domenico Lazzaro,
Domenico Lazzaro
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
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Patrizia Costa,
Patrizia Costa
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
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Lesley Probert,
Lesley Probert
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
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George Kollias,
George Kollias
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
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Fabrizio De Benedetti,
Fabrizio De Benedetti
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
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Valeria Poli,
Valeria Poli
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
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Gennaro Ciliberto
Gennaro Ciliberto
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
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Tonino Alonzi
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
Elena Fattori
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
Domenico Lazzaro
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
Patrizia Costa
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
Lesley Probert
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
George Kollias
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
Fabrizio De Benedetti
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
Valeria Poli
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
Gennaro Ciliberto
From the *Istituto Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; the ‡Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the §Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy
We wish to thank Mr. M. Aquilina and Mrs. S. Germoni (Istituto Ricerche di Biologia Molecolare; IRBM) for animal care, H. Bazin for the generous gift of LO-DNP-57 antibody, and Drs. A. Nicosia, M. Sollazzo, and C. Toniatti, and Mrs. J. Clench (IRBM) for critically reading the manuscript.
Address correspondence to Gennaro Ciliberto, IRBM P. Angeletti, Via Pontina Km 30,600, 00040 Pomezia, Rome, Italy. Phone: 39-6-91093205; Fax: 39-6-91093654; E-mail: [email protected]
The present address of T. Alonzi and V. Poli is Department of Biochemistry, Wellcome Trust Building, University of Dundee, Dundee DD1 4HN, UK.
1
Abbreviations used in this paper: CII, type II collagen; CIA, collagen-induced arthritis; DIL, DBA/1J, IL-6; DIL-6, DBA/1J mice crossed with IL-6–deficient mice; gp, glycoprotein; RA, rheumatoid arthritis; sIL-6Rα, soluble IL-6 receptor subunit α; TIL, TNF, IL-6; TIL-6, TNF-α transgenic mice crossed with IL-6–deficient mice.
Received:
September 15 1997
Revision Received:
November 26 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 187 (4): 461–468.
Article history
Received:
September 15 1997
Revision Received:
November 26 1997
Citation
Tonino Alonzi, Elena Fattori, Domenico Lazzaro, Patrizia Costa, Lesley Probert, George Kollias, Fabrizio De Benedetti, Valeria Poli, Gennaro Ciliberto; Interleukin 6 Is Required for the Development of Collagen-induced Arthritis . J Exp Med 16 February 1998; 187 (4): 461–468. doi: https://doi.org/10.1084/jem.187.4.461
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