Interleukin-6 receptor shedding is enhanced by interleukin-1beta and tumor necrosis factor alpha and is partially mediated by tumor necrosis factor alpha-converting enzyme in osteoblast-like cells.
[en] OBJECTIVE: Interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) activation of gp130 represents an alternative pathway for osteoclast development in inflammatory conditions. The goal of the present study was to investigate changes in sIL-6R levels in response to the inflammatory cytokines IL-1beta and tumor necrosis factor alpha (TNFalpha) and to determine the role of TNFalpha-converting enzyme (TACE) in this process. METHODS: Levels of sIL-6R in the culture media of MG63 and SAOS-2 osteoblast-like cell lines after exposure to various agents were determined by immunoassay. TACE protein levels were measured by Western immunoblotting. Cells were transfected with small interfering RNA (siRNA) or with an expression plasmid for IL-6R and TACE to determine the potential involvement of TACE in IL-6R shedding. RESULTS: IL-1beta and TNFalpha increased the levels of sIL-6R in the culture media of MG63 osteoblast-like cells. This effect was not influenced by cycloheximide or 5,6-dichlorobenzimidazole riboside but was markedly inhibited by the calcium chelator EGTA and by the TACE and matrix metalloproteinase inhibitor hydroxamate (Ru36156). IL-1beta and TNFalpha had no influence on the alternatively spliced form of IL-6R RNA. Levels of sIL-6R were reduced when MG63 cells were transiently transfected with TACE siRNA. Transfection of SAOS-2 cells with expression plasmids for IL-6R and TACE produced a dose-dependent increase in sIL-6R levels. CONCLUSION: IL-1beta- and TNFalpha-mediated induction of IL-6R shedding in osteoblast-like cells is at least partly dependent on TACE activation.
Research Center/Unit :
Giga-Signal Transduction - ULiège
Disciplines :
Rheumatology
Author, co-author :
Franchimont, Nathalie
Lambert, Cécile ; Université de Liège - ULiège > Département des sciences de la motricité > Unité de recherche sur l'os et le cartillage (U.R.O.C.)
Huynen, Pascale ; Centre Hospitalier Universitaire de Liège - CHU > Microbiologie médicale
Ribbens, Clio ; Centre Hospitalier Universitaire de Liège - CHU > Rhumatologie
Relic, Biserka ; Centre Hospitalier Universitaire de Liège - CHU > Rhumatologie
Chariot, Alain ; Centre Hospitalier Universitaire de Liège - CHU > Chimie médicale
Bours, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > Génétique
Piette, Jacques ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie - Département des sciences de la vie - GIGA-Research
Merville, Marie-Paule ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Malaise, Michel ; Centre Hospitalier Universitaire de Liège - CHU > Rhumatologie
Language :
English
Title :
Interleukin-6 receptor shedding is enhanced by interleukin-1beta and tumor necrosis factor alpha and is partially mediated by tumor necrosis factor alpha-converting enzyme in osteoblast-like cells.
Publication date :
2005
Journal title :
Arthritis and Rheumatism
ISSN :
0004-3591
eISSN :
1529-0131
Publisher :
Wiley Liss, Inc., New York, United States - New York
Volume :
52
Issue :
1
Pages :
84-93
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique Télévie ULg. ARC - Université de Liège. Actions de Recherche Concertées
Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999;402:304-9.
Romas T, Gillespie MT, Martin TJ. Involvement of receptor activator of NFκB ligand and tumor necrosis factor-α in bone destruction in rheumatoid arthritis. Bone 2002;30:340-6.
Teitelbaum SL. Bone resorption by osteoclasts. Science 2000;289:1504-8.
Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S. Interleukin-1β and tumor necrosis factor-α but not interleukin-6 stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 1999;25:255-9.
Naka T, Nishimoto N, Kishimoto T. The paradigm of IL-6: from basic science to medicine. Arthritis Res 2002;4 Suppl 3:S233-42.
Wong PK, Campbell IK, Egan PJ, Ernst M, Wicks IP. The role of the interleukin-6 family of cytokines in inflammatory arthritis and bone turnover. Arthritis Rheum 2003;48:1177-89.
Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou NA. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 2003;32:1-7.
Hing L, Carlson L, Siebenlist U, Boyce BF. Mechanisms by which NF-κB regulate osteoclast numbers [abstract]. Bone 1998;23 Suppl 1:S190.
Alonzi T, Fattori E, Lazzaro D, Costa P, Probert L, Kollias G, et al. Interleukin-6 is required for the development of collagen-induced arthritis. J Exp Med 1998;187:461-8.
Ohshima S, Saeki Y, Mima T, Sasai M, Nishioka K, Nomura S, et al. Interleukin-6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci USA 1998;95:8222-6.
Sasai M, Saeki Y, Ohshima S, Nishioka K, Mima T, Tanaka T, et al. Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice. Arthritis Rheum 1999;42:1635-43.
Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, 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 1996;11:88-95.
Helle M, Brakenhoff JP, de Groot ER, Aarden LA. Interleukin 6 is involved in interleukin 1-induced activities. Eur J Immunol 1988;18:957-9.
Littlewood AJ, Russell J, Harvey GR, Hughes DE, Russell RG, Gowen M. The modulation of the expression of IL-6 and its receptor in human osteoblasts in vitro. Endocrinology 1991;129:1513-20.
Franchimont N, Durant D, Rydziel S, Canalis E. Platelet-derived growth factor induces interleukin-6 transcription in osteoblasts through the activator protein-1 complex and activating transcription factor-2. J Biol Chem 1999;274:6783-9.
Franchimont N, Rydziel S, Canalis E. Transforming growth factor-β increases interleukin-6 transcripts in osteoblasts. Bone 2000;26:249-53.
Udagawa N, Takahashi N, Katagiri T, Tamura T, Wada S, Findlay DM, et al. Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors. J Exp Med 1995;182:1461-8.
Rose-John S, Ehlers M, Grotzinger J, Mullberg J. The soluble interleukin-6 receptor. Ann N Y Acad Sci 1995;762:207-20.
Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J 2001;15:43-58.
Lust JA, Donovan KA, Kline MP, Greipp PR, Kyle RA, Maihle NJ. Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine 1992;4:96-100.
Mullberg J, Schooltink H, Stoyan T, Gunther M, Graeve L, Buse G, et al. The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol 1993;23:473-80.
Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U S A 1993;90:11924-8.
Franchimont N, Rydziel S, Delany AM, Canalis E. Interleukin-6 and its soluble receptor cause a marked induction of collagenase 3 expression in rat osteoblast cultures. J Biol Chem 1997;272:12144-50.
Franchimont N, Rydziel S, Canalis E. Interleukin 6 is autoregulated by transcriptional mechanisms in cultures of rat osteoblastic cells. J Clin Invest 1997;100:1797-803.
Bellido T, Stahl N, Farruggella TJ, Borba V, Yancopoulos GD, Manolagas SC. Detection of receptors for interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in bone marrow stromal/osteoblastic cells. J Clin Invest 1996;97:431-7.
Black RA, Rauch CT, Kozloosky CJ, Peschon JJ, Slack JL, Wolfson MF, et al. A metalloproteinase disintegrin that releases tumor necrosis factor-α from cells. Nature 1997;385:729-33.
Ohta S, Harigai M, Tanaka M, Kawaguchi Y, Sugiura T, Takagi K, et al. Tumor necrosis factor-α (TNF-α) converting enzyme contributes to production of tumor necrosis factor-α in synovial tissues from patients with rheumatoid arthritis. J Rheumatol 2001;28:1756-63.
Althoff K, Reddy P, Voltz N, Rose-John S, Mullberg J. Shedding of interleukin-6 receptor and tumor necrosis factor α: contribution of the stalk sequence to the cleavage pattern of transmembrane proteins. Eur J Biochem 2000;267:2624-31.
Mullberg J, Vollmer P, Althoff K, Marz P, Rose-John S. Membrane protein secretases: generation and function of the soluble interleukin-6 receptor. Biochem Soc Trans 1999;27:211-9.
Gallea-Robache S, Morand V, Millet S, Bruneau JM, Bhatnagar N, Chouaib S, et al. A metalloproteinase inhibitor blocks the shedding of soluble cytokine receptors and processing of transmembrane cytokine precursors in human monocytic cells. Cytokine 1997;9:340-6.
Lum L, Wong BR, Josien R, Becherer JD, Erdjument-Bromage H, Schlondorff J, et al. Evidence for a role of a tumor necrosis factor-α (TNF-α)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J Biol Chem 1999;274:13613-8.
Doggrell SA. TAGE inhibition: a new approach to treating inflammation. Expert Opin Investig Drugs 2002;11:1003-6.
Newton RC, Solomon KA, Covington MB, Decicco CP, Haley PJ, Friedman SM, et al. Biology of TACE inhibition. Ann Rheum Dis 2001;60 Suppl 3:iii25-32.
Zhang Y, Xu J, Levin J, Hegen M, Li G, Robertshaw H, et al. Identification and characterization of 4-[[4-(2-butynyloxy)phenyl] sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1), a novel dual tumor necrosis factor-α-converting enzyme/matrix metalloprotease inhibitor for the treatment of rheumatoid arthritis. J Pharmacol Exp Ther 2004;309:348-55.
Conway JG, Andrews RC, Beaudet B, Bickett DM, Boncek V, Brodie TA, et al. Inhibition of tumor necrosis factor-α (TNF-α) production and arthritis in the rat by GW3333, a dual inhibitor of TNF-α-converting enzyme and matrix metalloproteinases. J Pharmacol Exp Ther 2001;298:900-8.
Stewart K, Walsh S, Screen J, Jefferiss CM, Chainey J, Jordan GR, et al. Further characterization of cells expressing STRO-1 in cultures of adult human bone marrow stromal cells. J Bone Miner Res 1999;14:1345-56.
Towler DA, St. Arnaud R. Use of culture osteoblastic cells to identify and characterize transcriptional regulatory complexes. In: Principles of bone biology. 2nd ed. Vol. 2. New York: Academic Press; 2002. p. 1503-27.
Franchimont N, Gangji V, Durant D, Canalis E. Interleukin-6 with its soluble receptor enhances the expression of insulin-like growth factor-I in osteoblasts. Endocrinology 1997;138:5248-55.
Delidow BC., Lynch JP, Peluso JJ, White B. Polymerase chain reaction. In: Harwood A, editor. Methods in molecular biology. Vol. 58. Basic DNA and RNA protocols. Totowa (NJ): Humana Press; 1996. p. 275-92.
Bonizzi G, Piette J, Schoonbroodt S, Merville MP, Bours V. Role of the protein kinase C λ/ι isoform in nuclear factor-κB activation by interleukin-1β and tumor necrosis factor-α: cell type specificities. Biochem Pharmacol 1999;57:713-20.
Scherr M, Morgan MA, Eder M. Gene silencing mediated by small interfering RNAs in mammalian cells. Curr Med Chem 2003;10:245-56.
Schooltink H, Stoyan T, Lenz D, Schmitz H, Hirano T, Kishimoto T, et al. Structural and functional studies on the human hepatic interleukin-6 receptor: molecular cloning and overexpression in HepG2 cells. Biochem J 1991;277:659-64.
Itai T, Tanaka M, Nagata S. Processing of tumor necrosis factor by the membrane-bound TNF-α-converting enzyme, but not its truncated soluble form. Eur J Biochem 2001;268:2074-82.
Jones SA, Horiuchi S, Novick D, Yamamoto N, Fuller GM. Shedding of the soluble IL-6 receptor is triggered by Ca2+ mobilization, while basal release is predominantly the product of differential mRNA splicing in THP-1 cells. Eur J Immunol 1998;28:3514-22.
Doedens JR, Black RA. Stimulation-induced down-regulation of tumor necrosis factor-α converting enzyme. J Biol Chem 2000;275:14598-607.
Zhang Z, Kolls JK, Oliver P, Good D, Schwarzenberger PO, Joshi MS, et al. Activation of tumor necrosis factor-α-converting enzyme-mediated ectodomain shedding by nitric oxide. J Biol Chem 2000;275:15839-44.
Fan H, Turck CW, Derynck R. Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-α converting, enzyme and of an alternatively translated polypeptide. J Biol Chem 2003;278:18617-27.
Jones SA, Novick D, Horiuchi S, Yamamoto N, Szalai AJ, Fuller GM. C-reactive protein: a physiological activator of interleukin-6 receptor shedding. J Exp Med 1999;189:599-604.
Taga T, Kishimoto T. Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 1997;15:797-819.
Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S, et al. 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. Nat Med 2000;6:583-8.
Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, et al. An essential role for ectodomain shedding in mammalian development. Science 1998;282:1281-4.
Boissy P, Lenhard TR, Kirkegaard T, Peschon JJ, Black RA, Delaisse JM, et al. An assessment of ADAMs in bone cells: absence of TACE activity prevents osteoclast recruitment and the formation of the marrow cavity in developing long bones. FEBS Lett 2003;553:257-61.
Black RA, White JM. ADAMs: focus on the protease domain. Curr Opin Cell Biol 1998;10:654-9.
Chesneau V, Becherer JD, Zheng Y, Erdjument-Bromage H, Tempst P, Blobel CP. Catalytic properties of ADAM19. J Biol Chem 2003;278:22331-40.
