Monocyte activation and disease activity in multiple sclerosis. A longitudinal analysis of serum MRP8/14 levels Sarah Floris a , Annette van der Goes a , Joep Killestein b , Dirk L. Knol c , Frederik Barkhof d , Chris H. Polman b , Christine D. Dijkstra a , Helga E. de Vries a, * , Jan F. Meilof b a Department of Molecular Cell Biology, VU Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands b Department of Neurology, VU Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands c Department of Clinical Epidemiology and Biostatistics, VU Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands d Department of Radiology, MS-MRI Center, VU Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands Received 2 July 2003; received in revised form 3 November 2003; accepted 5 November 2003 Abstract In active multiple sclerosis (MS) lesions macrophages expressing myeloid related protein (MRP) 8/14 are present. The aim of this study was to determine whether serum levels of MRP8/14 complexes are related to disease activity in MS. In a longitudinal study of 16 relapsing remitting (RR) MS patients that underwent monthly gadolinium diethylentriaminepenta acid (Gd-DTPA) magnetic resonance imaging (MRI), the relation between serum MRP8/14 levels and disease activity was investigated. Patients were participating in a monoclonal antibody study targeting a specific T cell population (Vh5.2/5.3 + T-cells). In time, within patients large variations in serum MRP8/14 levels were observed. Serum MRP8/14 levels were not related to changes in clinical disease activity or increase in Gd-DTPA lesion enhancement. Neither did comparison of active (>1 relapse in follow-up period) with inactive (0 – 1 relapse) MS patients reveal any differences in MRP8/14 levels. Therefore, we conclude that although MRP8/14 expression is a good histopathological marker for monocyte activation, serum levels of these proteins do not correlate with disease activity in RR MS. D 2004 Elsevier B.V. All rights reserved. Keywords: Multiple sclerosis; MRP8/14; Longitudinal; Macrophage; Blood – brain barrier; MRI 1. Introduction Myeloid related proteins (MRP8 (S100A8), MRP14 (S100A9) and MRP8/14 complex) are members of the S100 family of calcium binding proteins. S100 proteins play a role in cell differentiation, cell cycle progression and cytoskeleton – membrane interactions (Heizmann and Cox, 1998; Schafer and Heizmann, 1996). In general, MRPs are expressed in high concentrations by granulocytes and during early differentiation stages of monocytes, but are absent in lymphocytes and mature tissue macrophages (Goebeler et al., 1993; Hogg et al., 1989; Roth et al., 1993; Zwadlo et al., 1986). MRPs can be found in the cytoplasm as well as on the cell surfaces, and are secreted in a tubulin-dependent way when activated monocytes come into contact with inflammatory endothelium (Frosch et al., 2000; Hetland et al., 1998; Rammes et al., 1997). Secreted MRPs are present in body fluids like serum, saliva and synovial fluid (Sorg, 1992). The function of these secreted proteins is largely unknown, but has been related to monocyte migration (Eue et al., 2000; Kerkhoff et al., 1999). In mice, MRP8 is one of the strongest granulocyte attracting chemokines (Xu and Geczy, 2000; Yen et al., 1997). Furthermore, binding of MRP14 to neutrophils induces MAC-1 activation (Newton and Hogg, 1998). It has been shown that the concentration of the hetero- dimer MRP8/14 in serum is a marker for acute inflammation (Sorg, 1992). Serum concentration of MRP8/14 has been related to disease activity in inflammatory diseases like colitis ulcerosa (Lugering et al., 1995) and rheumatoid arthritis (Frosch et al., 2000), and in transplant rejection (Burkhardt et al., 2001). Multiple sclerosis (MS) is characterized by the presence of sclerotic lesions or plaques, scattered throughout the brain (Lucchinetti et al., 2000; De Groot et al., 2001). Early events in the development of MS lesions are increased 0165-5728/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2003.11.005 * Corresponding author. Tel.: +31-20-4448077; fax: +31-20-4448081. E-mail address: HE.deVries@VUMC.nl (H.E. de Vries). www.elsevier.com/locate/jneuroim Journal of Neuroimmunology 148 (2004) 172 – 177