Inhibition of the CD40 pathway of monocyte activation by triazolopyrimidine

Blockade of the CD40/CD40L pathway of monocyte/macrophage activation repres ents a promising strategy for the treatment of several inflammatory disorde rs. So far, most pharmacological agents developed for that purpose target C D40L (CD154) expressed on activated T cells. Herein, we provide evidence th at triazolopyrimidine, a chemical compound primarily developed for the prev ention of arterial thrombosis, strongly inhibits the response of human mono cytes to CD40 ligation. First, we found that triazolopyrimidine inhibits th e production of IL-12, TNF-alpha, and IL-6 by monocytes activated by cocult ure with fibroblasts transfected with the CD40L gene as well as the inducti on of procoagulant activity at their membrane. This was related to a decrea sed expression of CD40 on monocytes exposed to triazolopyrimidine, an effec t that was already apparent at the mRNA level. Furthermore, the addition of triazolopyrimidine to monocytes cultured with IL-4 and GM-CSF prevented th eir differentiation into fully competent dendritic cells (DC) as DC differe ntiated in the presence of triazolopyrimidine expressed less CD40 at their surface and were profoundly deficient in the production of IL-12 upon expos ure to CD40L transfectants. We conclude that triazolopyrimidine strongly in hibits the CD40 pathway of monocyte activation at least in part by downregu lating the gene expression of CD40. (C) 1999 Academic Press.