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Role of 4‐hydroxynonenal in the hemozoin‐mediated inhibition of differentiation of human monocytes to dendritic cells induced by GM‐CSF/IL‐4
Author(s) -
Skorokhod Oleksii,
Schwarzer Evelin,
Grune Tilman,
Arese Paolo
Publication year - 2005
Publication title -
biofactors
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.204
H-Index - 94
eISSN - 1872-8081
pISSN - 0951-6433
DOI - 10.1002/biof.5520240133
Subject(s) - hemozoin , chemistry , 4 hydroxynonenal , monocyte , in vitro , microbiology and biotechnology , mhc class ii , cellular differentiation , dendritic cell , antigen , major histocompatibility complex , immunology , biochemistry , biology , heme , lipid peroxidation , oxidative stress , gene , enzyme
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.