Ž . Journal of Neuroimmunology 115 2001 161–167 www.elsevier.comrlocaterjneuroin T lymphocytes conditioned with Interferon b induce membrane and soluble VCAM on human brain endothelial cells Peter A. Calabresi a, ) , Alexandre Prat b , Katherine Biernacki b , Jessica Rollins a , Jack P. Antel b a Department of Clinical Neurosciences, Rhode Island Hospital–Brown UniÕersity, ProÕidence, RI, USA b Montreal Neurological Institute, McGill UniÕersity, Montreal, Canada Received 5 July 2000; received in revised form 19 December 2000; accepted 9 January 2001 Abstract Ž . Vascular cell adhesion molecule VCAM -1 plays a critical role in mediating inflammatory cell adhesion and migration. Factors Ž . Ž. regulating the expression of membrane m VCAM and its cleaved counterpart soluble s VCAM are poorly understood. We previously Ž . Ž . demonstrated that serum sVCAM levels are increased in multiple sclerosis MS patients treated with interferon beta 1b IFNb1b , which correlated with a reduction in gadolinium enhancing lesions on magnetic resonance imaging. However, subsequent studies have shown that IFNb does not directly induce VCAM expression on endothelial cells. We demonstrate here that co-culture with IFNb-conditioned T Ž . cells induces mVCAM on human brain endothelial cells HBEC . Further, rapid shedding of sVCAM occurs, which mirrors the response Ž . after in vivo IFNb treatment. The VCAM induction is mediated partially through tumor necrosis factor TNF a and can be abrogated by sTNF receptor. VCAM could also be induced on astroglioma lines using IFNb-conditioned T cells, which suggests the effect is not specific for HBEC. Kinetic studies demonstrated an increase in the sVCAM to mVCAM ratio over time, which may contribute to the ultimate therapeutic effect of IFNb in patients. These data have important implications for understanding the events occurring at the blood brain barrier in vivo, and for determining the mechanism of action of IFNb in MS. q 2001 Elsevier Science B.V. All rights reserved. Keywords: VCAM-1; Blood–brain barrier; Interferon b; Multiple sclerosis; Leukocyte 1. Introduction The migration of activated T cells from the peripheral Ž . blood to the central nervous system CNS is though to be a critical event in the pathogenesis of the multiple sclerosis Ž . Ž MS lesion Martin and McFarland, 1995; Cannella and . Raine, 1995; Williams et al., 1994 . This process involves complex interactions between a vast array of adhesion Ž molecules, cytokines and chemokines Ransohoff et al., AbbreÕiations: HBEC, human brain endothelial cells; IFN, interferon; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; PB, peripheral blood; MNC, mononuclear cell; CNS, central nervous system; Interleukin, Il; EAE, experimental allergic encephalomyelitis; ICAM, intercellular adhesion molecule ) Corresponding author. Department of Neurology, University of Maryland School of Medicine, Bressler Research Building, 655 W. Baltimore St., Room 12-027, Baltimore, MD, 21201, USA. Tel.: q 1-410- 706-3433; fax: q 1-410-706-0186. Ž . E-mail address: pcala001@umaryland.edu P.A. Calabresi . . 1996; Lee and Benveniste, 1999 . Several studies suggest Ž . that vascular cell adhesion molecule VCAM -1 is impor- tant in mediating firm adhesion of lymphocytes to vascular Ž endothelial cells Wong et al., 1999; Bevilacqua, 1993; . Carlos and Harlan, 1994 . VCAM is not constitutively expressed, but may be up regulated by the cytokines tumor Ž . Ž . necrosis factor TNF a , interferon IFN g, and inter- Ž. Ž leukin Il -1b McCarron et al., 1992; Pober et al., 1986; . Wong and Dorovini-Zis, 1995 . Several studies revealed endothelial cell VCAM expression in chronic active MS plaques, but others have suggested that astrocytes are also Ž . a major source of VCAM Oh et al., 1998 . The specific Ž . ligand for VCAM is the very late antigen VLA -4, which is expressed on T lymphocytes and macrophages and has been implicated in the encephalitogenicity of T cell clones in the animal model of MS, experimental allergic en- Ž .Ž . cephalomyelitis EAE Baron et al., 1993 . Further, anti- VLA-4 antibody has been shown to block the development of EAE and its efficacy for treatment of MS is now being Ž . evaluated in clinical trials Yednock et al., 1992 . 0165-5728r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. Ž . PII: S0165-5728 01 00253-3