Inhibition Of The Cd40 Pathway Of Monocyte Activation By Triazolopyrimidine

Blockade of the CD40/CD40L pathway of monocyte/macrophage activation represents a promising strategy for the treatment of several inflammatory disorders. So far, most pharmacological agents developed for that purpose target CD40L (CD154) expressed on activated T cells. Herein, we provide evidence that triazolopyrimidine, a chemical compound primarily developed for the prevention of arterial thrombosis, strongly inhibits the response of human monocytes to CD40 ligation. First, we found that triazolopyrimidine inhibits the production of IL-12, TNF-alpha, and IL-6 by monocytes activated by coculture with fibroblasts transfected with the CD40L gene as well as the induction of procoagulant activity at their membrane. This was related to a decreased expression of CD40 on monocytes exposed to triazolopyrimidine, an effect that was already apparent at the mRNA level. Furthermore, the addition of triazolopyrimidine to monocytes cultured with IL-4 and GM-CSF prevented their differentiation into fully competent dendritic cells (DC) as DC differentiated in the presence of triazolopyrimidine expressed less CD40 at their surface and were profoundly deficient in the production of IL-12 upon exposure to CD40L transfectants. We conclude that triazolopyrimidine strongly inhibits the CD40 pathway of monocyte activation at least in part by downregulating the gene expression of CD40. (C) 1999 Academic Press.