Affiliations: Department of Genetics, Biology and Biochemistry,
University of Torino, Torino, Italy | Institut für Umweltmedizinische Forschung,
Heinrich-Heine-Universität, Düsseldorf, Germany
Note: [] Address for correspondence: Professor Paolo Arese, Dipartimento
di Genetica, Biologia e Biochimica, Via Santena 5 bis, 10126 Torino, Italy.
Tel.: +39 0116706686; Fax: +39 0116706590; E-mail: paolo.arese@unito.it
Abstract: 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 μM, 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 μM 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.
