Induction and regulation of monocyte procoagulant activity

Abstract

Monocyte (MO) procoagulant activity (PCA) is induced by various stimuli including allogeneic stimulation, immunocomplexes, and bacterial products. Antigen-antibody complex stimulation therefore represents a pathway for MO PCA induction. Activation of MO PCA has been demonstrated in immunocomplex disease and could represent a major pathology in transplanted immunocomplex disease patients. Stimulation of monocytes via their FcRI receptor has been demonstrated to induce TNF and PGE2. This report demonstrates that stimulation of the high-density FcRI receptor-bearing (FcRI+) MO by resetting with anti-Rh coated erythrocytes also induces significant PCA levels (P less than 0.001). Muramyl dipeptide (MDP), a Gram-positive bacterial cell wall analogue, further increased PCA levels in the FcRI stimulated MO subpopulation (P less than 0.003). Although increased PCA levels were also induced in the FcRI- MO subpopulation by MDP (P less than 0.003), the FcRI+ MO responded with much greater levels of PCA and PGE2 (P less than 0.001). Greater PCA levels in the FcRI-positive MO subpopulation may indicate that stimulation of MO through their FcRI represents a different pathway from allogenic PCA activation, which can be augmented by subsequent bacterial challenge. A novel inhibitory effect of IL-4 on MO PCA induction is also demonstrated. IL-4 downregulated MO PCA levels either after isolation stimulation (55 +/- 19%), FcRI stimulation (57 +/- 12%), or FcRI plus MDP stimulation (60 +/- 13%). PCA and PGE2 levels were concomitantly downregulated by IL-4 both in the FcRI-stimulated, FcRI+ and in the MDP-stimulated FcRI- MO subpopulations. Since indomethacin blocked MDP induced MO PGE2 production without affecting MO PCA levels, PGE2 production is not required for FcRI-stimulated PCA induction.