Activation of mesangial cells by platelets in systemic lupus erythematosus via a CD154-dependent induction of CD40

Background. Platelets are potential contributors to glomerular injury via the release of chemotactic and/or mitogenic mediators upon activation or through direct CD154/CD40-dependent interaction with cell components of the glomerulus. We examined whether platelets could activate mesangial cells and the potential role of the platelet-associated CD154. Methods. Thrombin-activated platelets from systemic lupus erythematosus (SLE) patients or from disease or healthy controls were grown with human mesangial cells in the presence or not of a neutralizing anti-CD154 antibody either in contact or in a noncontact setting, the platelets and mesangial cells being separated by a pore size semipermeable membrane. The induction of mesangial cell surface antigens was assayed by flow cytometry. The quantification of mesangial cell proliferation was performed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and the production of transforming growth factor-beta 1 (TGF-beta 1), platelet-derived growth factor (PDGF) and soluble CD40 were measured by enzyme-linked immunosorbent assay (ELISA). Results. Activated platelets from patients with SLE could induce an up-regulation of the expression of CD40 on mesangial cells with a concomitant release of soluble CD40. This induction required a direct contact between platelets and mesangial cells and was dependent upon the platelet-associated CD154. Pathologic consequences of the up-regulation of CD40 were a CD40-dependent stimulation of the proliferation of mesangial cells and a CD40-dependent increased production of TGF-beta 1 by these cells. Conclusion. Platelets from patients with SLE can activate mesangial cells through CD40/CD154 interactions, leading to an induction of proliferation of the mesangial cells and an enhanced production of TGF-beta 1, a profibrotic cytokine.