CD154/CD40-Mediated Expression of CD154 in Endothelial Cells: Consequences for Endothelial Cell–Monocyte Interaction

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Abstract
Objective— CD40 ligand (CD154) expressed on activated T helper cells is a key costimulatory molecule for antigen-presenting cells expressing the corresponding receptor CD40. Moreover, CD40 stimulation in nonimmune cells, such as endothelial cells, may play an important role in atherogenesis. One gene product that is induced in endothelial cells on exposure to CD154 is CD154 itself. Methods and Results— In human primary cultured endothelial cells, constitutive CD154 expression was virtually absent and insensitive to proinflammatory cytokines such as tumor necrosis factor α and/or interferon-γ. However, CD154 expression was markedly induced, both on the mRNA and protein level, after CD40 stimulation. Moreover, CD40-positive human monocytes (THP-1 cell line) transmigrating through CD154-expressing endothelial cells responded with an increased expression of interleukin-1β (IL-1β) mRNA, indicative of their activation. This increase in IL-1β expression was confirmed on the protein level and could be abrogated by prior treatment of the endothelial cells with a neutralizing anti-CD154 antibody. Conclusions— By way of CD154-induced CD154 expression, human endothelial cells thus seem capable of influencing the progression of proinflammatory reactions, including atherogenesis through activation of extravasating monocytes.