Role of 4-hydroxynonenal in the hemozoin-mediated inhibition of differentiation of human monocytes to dendritic cells induced by GM-CSF/IL-4

In falciparum malaria, rupture of parasitized RBC liberates hemozoin (HZ), polymerized heme that contains and generates lipoperoxidation products. In HZ and HZ-loaded monocytes 4-HNE attained approx. 50 and 15 microM, respectively. In malaria, HZ-loaded monocytes are precursors of dendritic cells (DC). Here, the role of 4-HNE as inhibitor of DC differentiation was examined. 4-HNE in HZ was quantified after derivatization by HPLC. DC were differentiated in vitro from human monocytes supplemented with GM-CSF/IL-4 and analyzed for surface antigens and 4-HNE-adducts by FACScan after labelling with specific antibodies. HZ-loading, or treatment with 4-HNE induced large numbers of 4-HNE-protein-adducts on the monocyte membrane. As low as 10 nM 4-HNE inhibited up-regulation of functionally important DC differentiation markers. 1 microM 4-HNE elicited inhibition of up-regulation of DC differentiation markers as follows: MHC-class I and II, -29% and -40%; CD1a, -16%; CD40, -25%; CD54, -27%; and CD83 (the most important DC differentiation marker), -45%, with no signs of apoptosis. The sequence of additions was important, as the inhibitory effect was reduced when 4-HNE was added after GM-CSF/IL-4, indicating that GM-CSF/IL-4 receptors could be modified by 4-HNE. In conclusion, inhibition of DC differentiation by 4-HNE may play a role in malaria immunodepression.