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J. Biol. Chem., Vol. 283, Issue 8, 4850-4865, February 22, 2008

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Interleukin-6 (IL-6) and/or Soluble IL-6 Receptor Down-regulation of Human Type II Collagen Gene Expression in Articular Chondrocytes Requires a Decrease of Sp1·Sp3 Ratio and of the Binding Activity of Both Factors to the COL2A1 Promoter^*

Benoît Porée¹, Magdalini Kypriotou², Christos Chadjichristos, Gallic Beauchef³, Emmanuelle Renard⁴, Florence Legendre, Martine Melin^¶, Sylviane Gueret^¶, Daniel-Jean Hartmann^¶, Frédéric Malléin-Gerin^||, Jean-Pierre Pujol, Karim Boumediene, and Philippe Galéra⁵

From the Laboratoire de Biochimie du Tissu Conjonctif, Université de Caen/Basse-Normandie, IFR ICORE 146, Faculté de Médecine, CHU niveau 3, Avenue de la Côte de Nacre, 14032 Caen Cedex, the Laboratoire des Biomatériaux, Université Claude Bernard, 8, Avenue Rockefeller, 69373 Lyon Cedex 08, ^¶Novotec, 13-15 Rue J. Monod, 69007 Lyon, and the ^||Laboratoire de Biologie et Ingénierie du Cartilage, Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS/UCB Lyon 1-IFR 128 BioSciences Lyon-Gerland, 7 passage du Vercors, 69367 Lyon Cedex 07, France

Type II collagen is composed of 1(II) chains encoded by the COL2A1 gene. Alteration of this cartilage marker is a common feature of osteoarthritis. Interleukin-6 (IL-6) is a pro-inflammatory cytokine that needs a soluble form of receptor called sIL-6R to exert its effects in some cellular models. In that case, sIL-6R exerts agonistic action. This mechanism can make up for the partial or total absence of membrane-anchored IL-6 receptors in some cell types, such as chondrocytes. Our study shows that IL-6, sIL-6R, or both inhibit type II collagen production by rabbit articular chondrocytes through a transcriptional control. The cytokine and/or sIL-6R repress COL2A1 transcription by a -63/-35 sequence that binds Sp1·Sp3. Indeed, IL-6 and/or sIL-6R inhibit Sp1 and Sp3 expression and their binding activity to the 63-bp promoter. In chromatin immunoprecipitation experiments, IL-6·sIL-6R induced an increase in Sp3 recruitment to the detriment of Sp1. Knockdown of Sp1·Sp3 by small interference RNA and decoy strategies were found to prevent the IL-6- and/or sIL-6R-induced inhibition of COL2A1 transcription, indicating that each of these Sp proteins is required for down-regulation of the target gene and that a heterotypic Sp1·Sp3 complex is involved. Additionally, Sp1 was shown to interact with Sp3 and HDAC1. Indeed, overexpression of a full-length Sp3 cDNA blocked the Sp1 up-regulation of the 63-bp COL2A1 promoter activity, and by itself, inhibits COL2A1 transcription. We can conclude that IL-6, sIL-6R, or both in combination decrease both the Sp1·Sp3 ratio and DNA-binding activities, thus inhibiting COL2A1 transcription.

Received for publication, August 2, 2007 , and in revised form, November 6, 2007.

^* This work was supported in part by the Regional Council of Lower Normandy. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Fellow of the French Ministry of Research and Technology.

² Fellow of the Regional Council of Lower Normandy and the French Ministry of Regional Development.

³ Fellow of the Regional Council of Lower Normandy and Johnson & Johnson Consumer France Laboratories (Campus de Maigremont, 27100 Val de Reuil, France).

⁴ Fellow of the Regional Council of Lower Normandy and Pierre Fabre Laboratories (Vigoulet-Auzil, BP74, 31322 Castanet-Tolosan, France).

⁵ To whom correspondence should be addressed. Tel.: 33-02-31-06-31-06 (ext. 8003); Fax: 33-02-31-06-82-24; E-mail: philippe.galera{at}unicaen.fr.

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