Abstract
(English)
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Introduction
At the inflammatory site, infiltrating immune cells are in close proximity. Di-rect cell-cell contact with stimulated but not resting T lymphocytes is a potent mechanism inducing cytokine production in monocytes. In contrast with other tar-get cells (microvascular endothelial cells and fibroblasts), this activity was not due to membrane-associated cytokines on stimulated T cells such as IL-1 and TNF (1-3). Furthermore, antibodies directed against known cell surface antigens (CD2, CD11a, CD11b, CD11c, CD14, CD18, CD23, CD29, CD40, CD40L, CD54, CD69, CTLA4, CD95, CD95L) or membrane-associated cytokines (IFNy, IL-2, GM-CSF, IL-1, TNFa, LT) failed to abolish T cell signaling of monocyte/macrophages and THP-1 cells upon direct cellular contact. Therefore, this signaling was due to uniden-tified factors expressed at the surface of stimulated T cells that are referred to Surface Activating Factors on stimulated T lymphocytes (SAFT). Since pro-in-flammatory cytokines are involved in inflammatory processes during MS pathogene-sis, this study was undertaken to assess whether SAFTs might play a part in MS. Different approaches were undertaken to determine whether SAFTs play a role in the pathogenesis of MS.
Preliminary characterization of SAFTs
After the set-up of a fractionation strategy (4), large scale preparation of SAFT was carried out. Membranes of 15 x 109 stimulated HUT-78 cells were solubi-lized in CHAPS and subjected to serial chromatography. The results confirm that SAFT is a glycoprotein with a MW = 40,000. Five bands were recovered in the Mr = 30,000 to 45,000 in unreduced SDS-PAGE. These bands are currently subjected to microsequencing.
Effect of IFN-b on SAFTs
Increasing evidence suggests that the administration of interferon-b (IFN-b displays some efficacy in the treatment of patients with relapsing-remitting MS. However, the mechanisms of action of IFN-b remain unclear. We determined that in PBMC cultures IFN-b favored the production of cytokine antagonists over that of pro-inflammatory cytokines, therefore IFN-b induces an imbalance supporting anti-inflammatory processes (5). This effect was due to the effect of IFN-b on both T lymphocytes and monocytes. Indeed, when T lymphocytes were stimulated in the presence of IFN-b, their ability to activate monocytes by direct contact was inhibited. Similarly, when monocytes were activated by membranes of stimulated T cells in the presence of IFN-b their production of IL-1b and metalloproteinases was diminished (Brunner and Burger, manuscript in preparation).
Conclusion and relevance
Saft might be a preferential mechanism by which stimulated T cells activate monocytes. A better understanding of the cell surface molecules on stimulated T lymphocytes triggering the induction of cytokines and metalloenzymes on mono-cytes may provide the basis for the development of novel agents interfering with heightened inflammatory response induced by cell-cell contact and leading to tissue destruction in chronic inflammatory diseases such as MS.
References
1. Burger, D., Rezzonico, R., Li, J. M., Modoux, C., Welgus, H. G., and Dayer, J. M. (1998) Arthritis Rheum. 41, 1748-1759
2. Lou, J., Ythier, A., Burger, D., Zheng, L., Juillard, P., Lucas, R., Dayer, J. M., and Grau, G. E. (1997) J. Neuroimmunol 77, 107-115
3. Rezzonico, R., Burger, D., and Dayer, J. M. (1998) J. Biol. Chem. 273, 18720-18728
4. Burger, D., Modoux, C., Vey, E., and Dayer, J. M. (1996) Eur. Cytokine Netw. 7, 561(Abstract)
5. Coclet-Ninin, J., Dayer, J. M., and Burger, D. (1997) Eur. Cytokine. Netw. 8, 345-349
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