Abstract
Tumor necrosis factor (TNF)–α converting enzyme (TACE, also called ADAM17) is a key sheddase that releases TNF–α from its inactive cell–bound precursor. TACE protein expression levels in peripheral blood mononuclear cells were measured by Western blot analysis in 20 healthy controls and 80 multiple sclerosis (MS) patients before and after treatment with IFNβ [20 patients with primary progressive (PP) MS, 20 patients with secondary progressive (SP) MS, and 40 patients with relapsing– remitting (RR) MS (20 patients during clinical remission and 20 patients in relapse)]. TNF–α serum levels were also measured by enzyme–linked immunoassay in the MS patients and healthy controls. TACE protein expression levels were lower in healthy controls and PPMS patients compared with SPMS patients and RRMS patient during clinical remission. No differences in TACE protein levels were observed between RRMS patients in relapse and during remission. TACE protein levels were increased in PPMS patients treated with IFNβ. Serum TNF–α levels were higher in RRMS patients in relapse compared with RRMS patients during remission, and positive and negative correlations were found between TACE protein expression and serum TNF–α levels in RRMS patients during relapse and during remission respectively. These findings point to different regulatory mechanisms of the TACE–TNF–α pathway in the clinical MS subtypes and expand the role of TACE in MS pathogenesis.
Similar content being viewed by others
References
Compston A, Coles A (2002) Multiple sclerosis. Lancet 359:1221–1231
Leppert D, Ford J, Stabler G,Grygar C, Lienert C, Huber S, Miller KM, Hauser SL, Kappos L (1998) Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain 121:2327–2334
Galboiz Y, Shapiro S, Lahat N, Rawashdeh H, Miller A (2001) Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-beta therapy in relapsing and secondary progressive multiple sclerosis patients. Ann Neurol 50:443–551
Avolio C, Ruggieri M, Giuliani F, Liuzzi GM, Leante R, Riccio P, Livrea P, Trojano M (2003) Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes. J Neuroimmunol 136:46–53
Black RA (2002) Tumor necrosis factor-alpha converting enzyme. Int J Biochem Cell Biol 34:1–5
Moro MA, Hurtado O, Cardenas A, Romera C, Madrigal JLM, Fernandez-Tome P, Leza JC, Lorenzo P, Lizasoain I (2003) Expression and function of TACE (TNF-alpha converting enzyme) in the central nervous system. Neurosignals 12:53–58
Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN, Boyce RW, Nelson N, Kozlosky CJ, Wolfson MF, Rauch CT, Cerretti DP, Paxton RJ, March CJ, Black RA (1998) An essential role for ectodomain shedding in mammalian development. Science 282:1281–1284
Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton RA, Shows D, Peschon JJ, Black RA (2000) Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. J Biol Chem 275:14608–14614
Althoff K, Reddy P, Voltz N, Rose-John S, Mullberg J (2000) Shedding of interleukin- 6 receptor and tumor necrosis factor alpha. Contribution of the stalk sequence to the cleavage pattern of transmembrane proteins. Eur J Biochem 267:2624–2631
Budagian V, Bulanova E, Orinska Z, Ludwig A, Rose-John S, Saftig P, Borden EC, Bulfone-Paus S (2004) Natural soluble interleukin-15Ralpha is generated by cleavage that involves the tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17). J Biol Chem 279:40368–40375
Garton KJ, Gough PJ, Blobel CP, Murphy G, Greaves DR, Dempsey PJ, Raines EW (2001) Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem 276:37993–38001
Condon TP, Flournoy S, Sawyer GJ, Baker BF, Kishimoto TK, Bennett CF (2001) ADAM17 but not ADAM10 mediates tumor necrosis factor-alpha and L-selectin shedding from leukocyte membranes. Antisense Nucleic Acid Drug Dev 11:107–116
Garton KJ, Gough PJ, Philalay J, Wille PT, Blobel CP, Whitehead RH, Dempsey PJ, Raines EW (2003) Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-alpha-converting enzyme (ADAM 17). J Biol Chem 278:37459–37464
Sharief MK, Hentges R (1991) Association between tumor necrosis factoralpha and disease progression in patients with multiple sclerosis. N Engl J Med 325:467–472
Bertolotto A, Malucchi S, Capobianco M, Manzardo E, Guastamacchia G, Milano E, Audano L, Mutani R (1999) Quantitative PCR reveals increased levels of tumor necrosis factor-alpha mRNA in peripheral blood mononuclear cells of multiple sclerosis patients during relapses. J Interferon Cytokine Res 19:575–581
Seifert T, Kieseier BC, Ropele S, Strasser-Fuchs S, Quehenberger F, Fazekas F, Hartung HP (2002) TACE mRNA expression in peripheral mononudear cells precedes new lesions on MRI in multiple sclerosis. Mult Scler 8:447–451
Kieseier BC, Pischel H, Neuen-Jacob E, Tourtellotte WW, Hartung HP (2003) ADAM-10 and ADAM-17 in the inflamed human CNS. Glia 42:398–405
Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 46:907–911
Montalban X (2004) Overview of European pilot study of interferon β- 1b in primary progressive multiple sclerosis. Mult Scler 10:S62–S64
Hurtado O, Lizasoain I, Fernandez-Tome P, Moro MA, Alvarez-Barrientos A, Leza JC, Lorenzo P, et al. (2002) TACE/ADAM17-TNF-a pathway in rat cortical cultures after exposure to oxygen-glucose-deprivation or glutamate. J Cereb Blood Flow Metabolism 22:576–585
Schlöndorff J, Becherer JD, Blobel CP (2000) Intracellular maturation and localization of the tumour necrosis factor a convertase (TACE). Biochem J 347:131–138
Thompson AJ, Polman CH, Miller DH, McDonald WI, Brochet B, Filippi M, Montalban X, De Sa J (1997) Primary progressive multiple sclerosis. Brain 120:1085–1096
Revesz T, Kidd D, Thompson AJ, Barnard RO, McDonald WI (1994) A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain 117:759–765
Giovannoni G, Lai M, Thorpe J, Kidd D, Chamoun V, Thompson AJ, Miller DH, Feldmann M, Thompson EJ (1997) Longitudinal study of soluble adhesion molecules in multiple sclerosis: correlation with gadolinium enhanced magnetic resonance imaging. Neurology 48:1557–1565
Duran I, Martinez-Caceres EM, Rio J, Barbera N, Marzo ME, Montalban X (1999) Immunological profile of patients with primary progressive multiple sclerosis. Expression of adhesion molecules. Brain 122:2297–2307
Sastre-Garriga J, Comabella M, Brieva L, Rovira A, Tintore M,Montalban X (2004) Decreased MMP-9 production in primary progressive multiple sclerosis patients. Mult Scler 10:376–380
Vladic A, Horvat G, Vukadin S, Sucic Z, Simaga S (2002) Cerebrospinal fluid and serum protein levels of tumour necrosis factor-alpha (TNF-alpha) interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R gp80) in multiple sclerosis patients. Cytokine 20:86–89
Rovaris M, Barnes D, Woodrofe N, du Boulay GH, Thorpe JW, Thompson AJ, McDonald WI, Miller DH (1996) Patterns of disease activity in multiple sclerosis patients: a study with quantitative gadolinium-enhanced brain MRI and cytokine measurement in different clinical subgroups. J Neurol 243:536–542
Vikas V, Link H (1996) Review: cytokines and the pathogenesis of multiple sclerosis. J Neurosci Res 45:322–333
Hollifield RD, Harbige LS, Pham-Dinh D, Sharief MK (2003) Evidence for cytokine dysregulation in multiple sclerosis: peripheral blood mononuclear cell production of pro-inflammatory and anti-inflammatory cytokines during relapse and remission. Autoimmunity 36:133–141
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Comabella, M., Romera, C., Camiña, M. et al. TNF–α converting enzyme (TACE) protein expression in different clinical subtypes of multiple sclerosis. J Neurol 253, 701–706 (2006). https://doi.org/10.1007/s00415-006-0090-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-006-0090-6