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Abstract

Background

Blood–brain barrier (BBB) breakdown is an early event in the pathogenesis of multiple sclerosis (MS). In a previous study we have found a direct stabilization of barrier characteristics after treatment of bovine brain capillary endothelial cells (BCECs) with human recombinant interferon-β-1a (IFN-β-1a) in an in vitro BBB model. In the present study we examined the effect of human recombinant IFN-β-1a on the barrier properties of BCECs derived from four different species including humans to predict treatment efficacy of IFN-β-1a in MS patients.

Methods

We used primary bovine and porcine BCECs, as well as human and murine BCEC cell lines. We investigated the influence of human recombinant IFN-β-1a on the paracellular permeability for 3H-inulin and 14C-sucrose across monolayers of bovine, human, and murine BCECs. In addition, the transendothelial electrical resistance (TEER) was determined in in vitro systems applying porcine and murine BCECS.

Results

We found a stabilizing effect on the barrier characteristics of BCECs after pretreatment with IFN-β-1a in all applied in vitro models: addition of IFN-β-1a resulted in a significant decrease of the paracellular permeability across monolayers of human, bovine, and murine BCECs. Furthermore, the TEER was significantly increased after pretreatment of porcine and murine BCECs with IFN-β-1a.

Conclusion

Our data suggest that BBB stabilization by IFN-β-1a may contribute to its beneficial effects in the treatment of MS. A human in vitro BBB model might be useful as bioassay for testing the treatment efficacy of drugs in MS.

Keywords

blood–brain barrier cell culture endothelial cells immunology interferon-β multiple sclerosis

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References

1 Lassmann H Bruck W Lucchinetti C . Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 2001; 7: 115 – 121 .

2 Kermode AG Thompson AJ Tofts P MacManus DG Kendall BE Kingsley DP . Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications. Brain 1990; 113: 1477 – 1489 .

3 The IFNB Multiple Sclerosis Study Group . Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 1995; 45: 1277 – 1285 .

4 PRISMS Study Group . Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498 – 1504 .

5 Jacobs LD Cookfair DL Rudick RA Herndon RM Richert JR Salazar AM . Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996; 39: 285 – 294 .

6 Antonelli G Simeoni E Bagnato F Pozzilli C Turriziani O Tesoro R . Further study on the specificity and incidence of neutralizing antibodies to interferon (IFN) in relapsing remitting multiple sclerosis patients treated with IFN beta-1a or IFN beta-1b. J Neurol Sci 1999; 168: 131 – 136 .

7 Lublin FD Reingold SC . Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996; 46: 907 – 911 .

8 Chofflon M . Mechanisms of action for treatments in multiple sclerosis: does a heterogeneous disease demand a multi-targeted therapeutic approach? BioDrugs 2005; 19: 299 – 308 .

9 Arnason BG Dayal A Qu ZX Jensen MA Genc K Reder AT . Mechanisms of action of interferon-beta in multiple sclerosis. Springer Semin Immunopathol 1996; 18: 125 – 148 .

10.

10 Yong VW . Differential mechanisms of action of interferon-beta and glatiramer acetate in MS. Neurology 2002; 59: 802 – 808 .

11.

11 Billiau A . Interferon beta in the cytokine network: an anti-inflammatory pathway. Mult Scler 1995; 1: S2 – S4 .

12.

12 Rudick RA Ransohoff RM Peppler R VanderBrug MS Lehmann P Alam J . Interferon beta induces interleukin-10 expression: relevance to multiple sclerosis. Ann Neurol 1996; 40: 618 – 627 .

13.

13 Brod SA Marshall GD Henninger EM Sriram S Khan M Wolinsky JS . Interferon-beta 1b treatment decreases tumor necrosis factor-alpha and increases interleukin-6 production in multiple sclerosis. Neurology 1996; 46: 1633 – 1638 .

14.

14 Laske C Oschmann P Tofighi J Kuehne SB Diehl H Bregenzer T . Induction of sTNF-R1 and sTNF-R2 by interferon beta-1b in correlation with clinical and MRI activity. Acta Neurol Scand 2001; 103: 105 – 113 .

15.

15 Gaillard PJ Der Meide PH de Boer AG Breimer DD . Glucocorticoid and type 1 interferon interactions at the blood–brain barrier: relevance for drug therapies for multiple sclerosis. Neuroreport 2001; 12: 2189 – 2193 .

16.

16 Kraus J Ling AK Hamm S Voigt K Oschmann P Engelhardt B . Interferon-beta stabilizes barrier characteristics of brain endothelial cells in vitro. Ann Neurol 2004; 56: 192 – 205 .

17.

17 Meresse S Dehouck MP Delorme P Bensaid M Tauber JP Delbart C . Bovine brain endothelial cells express tight junctions and monoamine oxidase activity in long-term culture. J Neurochem 1989; 53: 1363 – 1371 .

18.

18 Booher J Sensenbrenner M . Growth and cultivation of dissociated neurons and glial cells from embryonic chick, rat and human brain in flask cultures. Neurobiology 1972; 2: 97 – 105 .

19.

19 Cecchelli R Dehouck B Descamps L Fenart L Buee-Scherrer V Duhem C . In vitro model for evaluating drug transport across the blood–brain barrier. Adv Drug Deliv Rev 1999; 36: 165 – 178 .

20.

20 Descamps L Cecchelli R Torpier G . Effects of tumor necrosis factor on receptor-mediated endocytosis and barrier functions of bovine brain capillary endothelial cell monolayers. J Neuroimmunol 1997; 74: 173 – 184 .

21.

21 Franke H Galla H Beuckmann CT . Primary cultures of brain microvessel endothelial cells: a valid and flexible model to study drug transport through the blood–brain barrier in vitro. Brain Res Brain Res Protoc 2000; 5: 248 – 256 .

22.

22 Schuller AM Windolf J Blaheta R Cinatl J Kreuter J Wimmer-Greinecker G . Degradation of microvascular brain endothelial cell beta-catenin after co-culture with activated neutrophils from patients undergoing cardiac surgery with prolonged cardiopulmonary bypass. Biochem Biophys Res Commun 2005; 329: 616 – 623 .

23.

23 Reiss Y Hoch G Deutsch U Engelhardt B . T cell interaction with ICAM-1-deficient endothelium in vitro: essential role for ICAM-1 and ICAM-2 in transendothelial migration of T cells. Eur J Immunol 1998; 28: 3086 – 3099 .

24.

24 Stins MF Prasadarao NV Ibric L Wass CA Luckett P Kim KS . Binding characteristics of S fimbriated Escherichia coli to isolated brain microvascular endothelial cells. Am J Pathol 1994; 145: 1228 – 1236 .

25.

25 Stins MF Gilles F Kim KS . Selective expression of adhesion molecules on human brain microvascular endothelial cells. J Neuroimmunol 1997; 76: 81 – 90 .

26.

26 Siflinger-Birnboim A Del Vecchio PJ Cooper JA Blumenstock FA Shepard JM Malik AB . Molecular sieving characteristics of the cultured endothelial monolayer. J Cell Physiol 1987; 132: 111 – 117 .

27.

27 Krüger PG . Mast cells and multiple sclerosis: a quantitative analysis. Neuropathol Appl Neurobiol 2001; 27: 275 – 280 .

28.

28 Ibrahim MZ Reder AT Lawand R Takash W Sallouh-Khatib S . The mast cells of the multiple sclerosis brain. J Neuroimmunol 1996; 70: 131 – 138 .

29.

29 Fischer S Renz D Schaper W Karliczek GF . Effects of barbiturates on hypoxic cultures of brain derived microvascular endothelial cells. Brain Res 1996; 707: 47 – 53 .

30.

30 Defazio G Trojano M Ribatti D Nico B Giorelli M De Salvia R . ICAM 1 expression and fluid phase endocytosis of cultured brain microvascular endothelial cells following exposure to interferon beta-1a and TNFalpha. J Neuroimmunol 1998; 88: 13 – 20 .

31.

31 Huynh HK Oger J Dorovini-Zis K . Interferon-beta downregulates interferon-gamma-induced class II MHC molecule expression and morphological changes in primary cultures of human brain microvessel endothelial cells. J Neuroimmunol 1995; 60: 63 – 73 .

32.

32 Martin R . Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis and their application for new therapeutic strategies. J Neural Transm Suppl 1997; 49: 53 – 67 .

33.

33 Hertz F Deghenghi R . Effect of rat and beta-human interferons on hyperacute experimental allergic encephalomyelitis in rats. Agents Actions 1985; 16: 397 – 403 .

34.

34 Bekisz J Schmeisser H Hernandez J Goldman ND Zoon KC . Human interferons alpha, beta and omega. Growth Factors 2004; 22: 243 – 251 .

35.

35 Paty DW Li DK . Interferon beta-1b is effective in relapsing-remitting 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 .

36.

36 Pozzilli C Bastianello S Koudriavtseva T Gasperini C Bozzao A Millefiorini E . Magnetic resonance imaging changes with recombinant human interferon-beta-1a: a short term study in relapsing–remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 1996; 61: 251 – 258 .

37.

37 Kraus J Bauer R Chatzimanolis N Engelhardt B Tofighi J Bregenzer T . Interferon-beta(1b) leads to a short-term increase of soluble but long-term stabilisation of cell surface bound adhesion molecules in multiple sclerosis. J Neurol 2004; 251: 464 – 472 .

38.

38 Floris S Ruuls SR Wierinckx A van der Pol SM Dopp E van der Meide PH . Interferon-beta directly influences monocyte infiltration into the central nervous system. J Neuroimmunol 2002; 127: 69 – 79 .

Interferon-β stabilizes barrier characteristics of the blood–brain barrier in four different species in vitro

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