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Interleukin 17, a Nitric Oxide-Producing Cytokine with a Peroxynitrite-Independent Inhibitory Effect on Proteoglycan Synthesis
SANDRINE PACQUELET, NATHALIE PRESLE, CHRISTELLE BOILEAU, HÉLÈNE DUMOND, PATRICK NETTER, JOHANNE MARTEL-PELLETIER, JEAN-PIERRE PELLETIER, BERNARD TERLAIN, and JEAN-YVES JOUZEAU
ABSTRACT.
Methods. Chondrocytes in alginate beads were stimulated with human recombinant (rh) IL-17 (0.03 to 300.0 ng/ml) and/or rhIL-1ß (0.25 to 25.0 ng/ml) in the presence or not of L-NMMA or CuDips. Alternatively, rats were injected with either IL-17 (10.0 µg) or IL-1ß (1.0 µg) into each knee joint. NO concentrations were determined by a spectrofluorimetric assay, proteoglycan synthesis by 35SO4-2 incorporation, peroxynitrite generation by immunostaining for 3-nitrotyrosine, and IL-1ß mRNA expression by reverse transcription-polymerase chain reaction. Results. IL-17 inhibited proteoglycan synthesis and increased NO production, both in vitro and in vivo, without inducing expression of IL-1ß mRNA in cartilage. Additive effects were observed when IL-17 was combined with low concentrations of IL-1. Surprisingly, a similar NO synthesis between IL-1 and IL-17 led to a less suppressive effect of IL-17 on cartilage anabolism than with IL-1. Both in vitro and in vivo, peroxynitrite formation was extensive with IL-1ß, but negligible or nonexistent with IL-17. L-NMMA and CuDips completely corrected the suppressive effect of IL-1ß on proteoglycan synthesis, unlike with IL-17. Conclusion. These data showed that NO is weakly involved in the IL-17 mediated inhibition of proteoglycan synthesis in rat. NO overload may not be predictive of any inhibitory effect on cartilage anabolism, but instead superoxide is a key regulator of NO contribution to chondrocyte dysfunction. Since IL-17 is a NO-producing cytokine with additive effects when combined with IL-1, it may play a pivotal role in cartilage destruction during rheumatoid arthritis, for which infiltrating cells produce high levels of superoxide and proinflammatory cytokines. (J Rheumatol 2002; 29:2602-10) Key Indexing Terms:
CYTOKINES
From UMR 7561 CNRS-UHP, Faculté de Médecine, Vandoeuvre-lès-Nancy, France; and Unité de Recherche en Arthrose, Centre Hospitalier de l'Université de Montréal, Hôpital Notre Dame, Montréal, Quebec, Canada. Supported by the French-Canada scientific cooperation for health (PEU-FRSQ), by the Région Lorraine, and by the Communauté Urbaine du Grand Nancy. S. Pacquelet, MSc; N. Presle, PhD; C. Boileau, MSc; H. Dumond PhD; P. Netter, MD, PhD; B. Terlain, PharmD; J-Y. Jouzeau, PharmD, PhD, UMR 7561 CNRS-UHP, Faculté de Médecine, Vandoeuvre-lès-Nancy; J. Martel-Pelletier, PhD; J-P. Pelletier, MD, Unité de Recherche en Arthrose, Centre Hospitalier de l'Université de Montréal, Hôpital Notre Dame, Montréal. Address reprint requests to Dr. P. Netter, UMR 7561 CNRS-UHP, Faculté de Médecine, Avenue de la forêt de Haye, BP 184, 54505 Vandoeuvre-lès-Nancy cedex, France. E-mail: patrick.netter@medecine.uhp-nancy.fr Submitted March 6, 2002; revision accepted May 31, 2002. |