Interferon-beta inhibits the expression of metalloproteinases in rat glial cell cultures: implications for multiple sclerosis pathogenesis and treatment

Abstract

Matrix metalloproteinases (MMPs) have been identified as mediators of brain injury in multiple sclerosis (MS) and it has recently been reported that treatment of MS patients with interferon-beta (IFN-b) reduces MMP-9 serum levels and in vitro release from monocytes. We investigated whether IFN-b is able to modulate the expression of MMPs in glial cell cultures. Rat microglial and astrocyte cultures were treated with different doses of IFN-b, then activated by exposure to LPS. In another set of experiments cells were simultaneously activated with LPS and treated with IFN-b. C ulture supernatants collected from astrocytes and microglia were subjected to zymography for the assessment of MMP-2 and MMP-9. Increased amounts of MMP-9 and MMP-2 were observed in supernatants from LPS-treated astrocytes in comparison with supernatants from nontreated control cells. MMP-9 also increased in LPS-treated microglia. The treatment of astrocytes and microglia with IFN-b inhibited dose-dependently the expression of both MMP-2 and MMP-9 in LPS-treated astrocytes and of MMP-9 in LPS-treated microglia. These results demonstrate a modulating effect of IFN-b on the release of MMPs from C NS cells. This effect represents an additional mechanism by which IFN-b may decrease the development of new C NS lesions in the course of MS.

Keywords

astrocytes blood-brain barrier demyelination IFN-β microglia MMPs multiple sclerosis

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References

Raine CS , Cannella B , Duijvestijn AM , Cross AH. Homing to central nervous system vasculature by antigen-specific lymphocytes. II. Lymphocyte/endothelial cell adhesion during the initial stages of autoimmune demyelination . Lab Invest 1990; 63: 476-489 .

Hickey WF , Hsu BL , Kimura H. T-lymphocyte entry into the central nervous system . J Neurosci Res 1991; 28: 254-260 .

Woessner JF. Matrix metalloproteinases and their inhibitors in connective tissue remodelling . FASEB J 1991; 5: 2145-2154 .

Van den Steen PE , Dubois B , Nelissen I , Rudd PM , Dwek RA , Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9) . Crit Rev Biochem Mol Biol 2002; 37: 375-536 .

Gottschall PE , Yu X. Cytokines regulate gelatinase A and B (matrix metalloproteinase 2 and 9) activity in cultured rat astrocytes . J Neurochem 1995; 64: 1513-1520 .

Colton CA , Keri JE , Chen WT , Monsky WL. Protease production by cultured microglia: substrate gel analysis and immobilized matrix degradation . J Neurosci Res 1993; 35: 297-304 .

Gottschall PE , Yu X , Bing B. Increased production of gelatinase B (matrix metalloproteinase-9) and interleukin-6 by activated rat microglia in culture . J Neurosci Res 1995; 42: 335-342 .

Maeda A , Sobel RA. Matrix metalloproteinases in the normal human central nervous system, microglial nodules and multiple sclerosis lesions . J Neuropathol Exp Neurol 1996; 55: 300-309 .

Cuzner ML , Gveric D , Strand C , Loughlin AJ , Paemen L , Opdenakker G et al. The expression of tissue-type plasminogen activator, matrix metalloproteases and endogenous inhibitors in the central nervous system in multiple sclerosis: comparison of stages in lesion evolution . J Neuropathol Exp Neurol 1996; 55: 1194-1204 .

10.

Gijbels K , Masure S , Carton H , Opdenakker G. Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders . J Neuroimmunol 1992; 41: 29-34 .

11.

Paemen L , Olsson T , Soderstrom M , Van Damme J , Opdenakker G. Evaluation of gelatinases and IL-6 in the cerebrospinal fluid of patients with optic neuritis, multiple sclerosis and other inflammatory neurological diseases . Eur J Neurol 1994; 1: 55-63 .

12.

Leppert D , Ford J , Stabler G , Grygar C , Lienert C , Huber S et al. Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis . Brain 1998; 121: 2327-2334 .

13.

Liuzzi GM , Trojano M , Fanelli M , Avolio C , Fasano A , Livrea P et al. Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis . Mult Scler 2002; 8: 222-228 .

14.

Leppert D , Waubant E , Burk MR , Oksenberg JR , Hauser SL. Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis . Ann Neurol 1996; 40: 846-852 .

15.

Stuve O , Dooley NP , Uhm JH , Antel JP , Francis GS , Williams G et al. Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9 . Ann Neurol 1996; 40: 853-863 .

16.

Trojano M , Avolio C , Liuzzi GM , Ruggieri M , Defazio G , Liguori M et al. Changes of serum sICAM-1 and MMP-9 induced by rIFNbeta-1b treatment in relapsing-remitting MS . Neurology 1999; 53: 1402-1408 .

17.

Bartholome EJ , Van Aelst I , Koyen E , Kiss R , Willems F , Goldman M et al. Human monocyte-derived dendritic cells produce bioactive gelatinase B: inhibition by IFN-beta . J Interferon Cytokine Res 2001; 21: 495-501 .

18.

Proost P , Van Damme J , Opdenakker G. Leukocyte gelatinase B cleavage releases encephalitogens from human myelin basic protein . Biochem Biophys Res Commun 1993; 192: 1175-1181 .

19.

Nakajima K , Hamanoue M , Shimojo M , Takei N , Kohsaka S. Characterization of microglia isolated from a primary culture of embryonic rat brain by a simplified method . Biomed Res 1989; 10: 411-423 .

20.

Gebicke-Haerter PJ , Bauer J , Schobert A , Northoff H. Lipopolysaccharide-free conditions in primary astrocyte cultures allow growth and isolation of microglial cells . J Neurosci 1989; 9: 183-194 .

21.

McCarthy KD , de Vellis J. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue . J Cell Biol 1980; 85: 890-902 .

22.

Liuzzi GM , Santacroce MP , Peumans WJ , Van Damme EJ , Dubois B , Opdenakker G et al. Regulation of gelatinases in microglia and astrocyte cell cultures by plant lectins . Glia 1999; 27: 53-61 .

23.

Rosenberg GA. Matrix metalloproteinases in neuroinflammation . Glia 2002; 39: 279-291 .

24.

Opdenakker G , Van Damme J. Cytokine-regulated proteases in autoimmune diseases . Immunol Today 1994; 15: 103-107 .

25.

Yong VW , Power C , Forsyth P , Edwards DR. Metalloproteinases in biology and pathology of the nervous system . Nat Rev Neurosci 2001; 2: 502-511 .

26.

Fosang AJ , Hardingham TE. Isolation of the N-terminal globular protein domains from cartilage proteoglycans. identification of G2 domain and its lack of interaction with hyaluronate and link protein . Biochem J 1989; 261: 801-809 .

27.

Lein M , Nowak L , Jung K , Koenig F , Lichtinghagen R , Schnorr D et al. Analytical aspects regarding the measurement of metalloproteinases and their inhibitors in blood . Clin Biochem 1997; 30: 491-496 .

28.

Vos CM , Sjulson L , Nath A , McArthur JC , Pardo CA , Rothstein J et al. Cytotoxicity by matrix metalloprotease-1 in organotypic spinal cord and dissociated neuronal cultures . Exp Neurol 2000; 163: 324-330 .

29.

Gearing AJ , Beckett P , Cristodoulou M , Churchill M , Clements J , Davidson AH et al. Processing of tumor necrosis factor-alpha precursor by metalloproteinases . Nature 1994; 370: 555-557 .

30.

Chandler S , Miller KM , Clements JM , Lury J , Corkill D , Anthony DC et al. Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview . J Neuroimmunol 1997; 72: 155-161 .

31.

Ozenci V , Rinaldi L , Teleshova N , Matusevicius D , Kivisakk P , Kouwenhoven M et al. Metalloproteinases and their tissue inhibitors in multiple sclerosis . J Autoimmun 1999; 12: 297-303 .

32.

Anthony DC , Ferguson B , Matyzak MK , Miller KM , Esiri MM , Perry VH. Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke . Neuropathol Appl Neurobiol 1997; 23: 406-415 .

33.

Cossins JA , Clements JM , Ford J , Miller KM , Pigott R , Vos W et al. Enhanced expression of MMP-7 and MMP-9 in demyelinating multiple sclerosis lesions . Acta Neuropathol (Berl) 1997; 94: 590-598 .

34.

Paty DW , Li DK. Interferon beta-1b is effective in relapsingremitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group . Neurology 1993; 43: 662-667 .

35.

Yong VW , Antel JP. Major histocompatibility complex molecules on glial cells . Semin Neurosci 1992; 4: 231-240 .

36.

Yong VW , Chabot S , Stuve O , Williams G. Interferon beta in the treatment of multiple sclerosis: mechanisms of action . Neurology 1998; 51: 682-689 .

37.

Uhm JH , Dooley NP , Stuve O , Francis GS , Duquette P , Antel JP et al. Migratory behavior of lymphocytes isolated from multiple sclerosis patients: effects of interferon beta-1b therapy . Ann Neurol 1999; 46: 319-324 .

38.

Waubant E , Gee L , Bacchetti P , Sloan R , Cotleur A , Rudick R et al. Relationship between serum levels of IL-10, MRI activity and interferon beta-1a therapy in patients with relapsing remitting MS . J Neuroimmunol 2001; 112: 139-145 .

39.

Ma Z , Qin H , Benveniste EN. Transcriptional suppression of matrix metalloproteinase-9 gene expression by IFN-g and IFN-b: critical role of STAT-1a . J Immunol 2001; 167: 5150-5159 .

40.

Sanceau J , Boyd DD , Seiki M , Bauvois B. Interferons inhibit tumor necrosis factor-alpha-mediated matrix metalloproteinase-9 activation via interferon regulatory factor-1 binding competition with NF-kappa B . J Biol Chem 2002; 277: 35766-35775 .

41.

Cuzner ML , Opdenakker G. Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system . J Neuroimmunol 1999; 94: 1-14 .

42.

Noronha A , Toscas A , Jensen MA. Interferon beta decreases T cell activation and interferon gamma production in multiple sclerosis . J Neuroimmunol 1993; 46: 145-153 .