Serum from patients with multiple sclerosis downregulates occludin and VE-cadherin expression in cultured endothelial cells

Abstract

Disruption of the blood -brain barrier (BBB) and transendothelial migration of inflammatory cells are crucial steps in the development of demyelinating lesions in multiple sclerosis (MS). O ccludin and vascular endothelial-cadher in (VE-cadherin) are two major components of the tight junctions (TJs) in the brain microvasculature that help to create the BBB. In the present study, we investigated the effect of serum from MS patients on the expression of these two junctional markers and on the endothelial integrity. Serum from six MS patients in exacerbation, six in remission, and six normal controls (10% by volume) was incubated with cultured endothelial cells, and the expression of occludin and VE-cadherin was measured by immunoblotting. Serum from MS patients in exacerbation significantly reduced the expression of occludin and VE-cadherin compared with patients in remission and normal controls. This disintegrating effect was more pronounced for occludin than for VE-cadherin. We assume that the elevation in cytokines or other serum-soluble factors in MS patients in exacerbation likely provokes downregulation of occludin and VE-cadherin. This downregulation of TJs proteins may, therefore, contribute to the disruption of the BBB in this condition.

Keywords

blood-brain barrier endothelial cells multiple sclerosis occludin transendothelial migration VE-cadherin

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References

Noseworthy JH , Lucchinetti C , Rordriguez M , Weinshenker BG. Multiple sclerosis . N Eng J Med 2000; 343: 983-1052 .

Brosnan CF , Raine CS. Mechanisms of immune injury in multiple sclerosis . Brain Pathol 1996; 6: 243-257 .

Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm . Cell 1994; 76: 301-314 .

Anderson JM , Van Itallie CM. Tight junctions and the molecular basis for regulation of paracellular permeability . Am J Physiol 1995; 269: G467-G475 .

Dejana E , Corada M , Lampugnani MG. Endothelial cell-to-cell junctions . FASEB J 1995; 9: 910-918 .

Tsukita S , Furuse M , Itoh M. Molecular dissection of tight junctions . Cell Struct Funct 1996; 21: 381-385 .

Muresan Z , Paul DL , Goodenough DA. Occludin 1B, a variant of the tight junction protein occludin . Mol Biol Cell 2000; 11: 627-634 .

Navratil E , Couvelard A , Rey A , Henin D et al. Expression of cell adhesion molecules by microvascular endothelial cells in the cortical and subcortical regions of the normal human brain: an immunohistochemical analysis . Neuropathol Appl Neurobiol 1997; 23: 68-80 .

Oshima T , Laroux FS , Coe LL , Morise Z et al. Interferon-gamma and interleukin-10 reciprocally regulate endothelial junction integrity and barrier function . Microvasc Res 2001; 61: 130-143 .

10.

McDonald WI , Compston A , Edan G , Goodkin D et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis . Ann Neurol 2001; 50: 121-127 .

11.

Rascher G , Wolburg H. The tight junctions of the leptomeningeal blood-cerebrospinal fluid barrier during development . J Hirnforsch 1997; 38: 525-540 .

12.

Bart J , Groen HJ , Hendrikse NH , van der Graaf WT et al. The blood-brain barrier and oncology: new insights into function and modulation . Cancer Treat Rev 2000; 26: 449-462 .

13.

Chofflon M , Juillard C , Juillard P , Gauthier G et al. Tumor necrosis factor alpha production as a possible predictor of relapse in patients with multiple sclerosis . Eur Cytokine Netw 1992; 3: 523-531 .

14.

Rieckmann P , Michel U , Albrecht M , Bruck W et al. Cerebral endothelial cells are a major source for soluble intercellular adhesion molecule-1 in the human central nervous system . Neurosci Lett 1995; 186: 61-64 .