INTRODUCTION: Hemozoin (malarial pigment) is a crystalline ferriprotoporphyrin IX polymer present in late stages of P. falciparum-parasitized RBCs, derived from incomplete digestion of host hemoglobin (1). We have previously shown that in human monocytes, avidly phagocytosed hemozoin or hemozoin-containing trophozoites increased monocyte MMP-9 activity and expression by enhancing production of MMP-9-related cytokines, such as TNF-alpha and IL-1-beta (2, 3). Here, the mechanism by which hemozoin enhances MMP-9 and cytokine production was studied. RESULTS: Quercetin, artemisinin and parthenolide, molecules able to inhibit three different stages of the intracellular NF-kB signalling pathway (IkB-alpha phosphorylation and following degradation; NF-kB nuclear translocation; and p65 binding to DNA, respectively) (4, 5) abrogated hemozoin-dependent increase of MMP-9, TNF-alpha and IL-1-beta either in hemozoin-fed or trophozoite-fed monocytes. Moreover, 2 h and 24 h after phagocytosis present data indicate that the NF-kB complex was present in the nuclear fraction, and, second, cytosolic IkB-alpha protein was phosphorylated and degraded. Present data suggest that hemozoin-induced upregulation of MMP-9, TNF-alpha and IL-1-beta in human monocytes may involve a NF-kB-mediated signal transduction pathway. This work was supported in the context of the Italian Malaria Network by grants from Compagnia di San Paolo-IMI and the University of Torino Intramural Funds to P.A 1. Arese P. et al. (1997) Ann. Trop. Med. Parasitol. 91, 501-516 2. Prato M. et al. (2005) J. Immunol. 175, 6436-6442 3. Prato M. et al. (2008) Malar. J. in press 4. Nair M.P. et al. (2006) Clin. Vaccine Immunol. 13, 319-328 5. Aldieri E. et al. (2003) FEBS Lett. 552, 141-144
P. Falciparum Hemozoin Increases Matrix Metalloproteinase-9, TNF-alpha and Interleukin-1-beta in Human Monocytes through NF-kappa B-dependent Pathways
PRATO, Mauro;ALDIERI, Elisabetta;GALLO, Valentina;GIRIBALDI, Giuliana;ARESE, Paolo
2008-01-01
Abstract
INTRODUCTION: Hemozoin (malarial pigment) is a crystalline ferriprotoporphyrin IX polymer present in late stages of P. falciparum-parasitized RBCs, derived from incomplete digestion of host hemoglobin (1). We have previously shown that in human monocytes, avidly phagocytosed hemozoin or hemozoin-containing trophozoites increased monocyte MMP-9 activity and expression by enhancing production of MMP-9-related cytokines, such as TNF-alpha and IL-1-beta (2, 3). Here, the mechanism by which hemozoin enhances MMP-9 and cytokine production was studied. RESULTS: Quercetin, artemisinin and parthenolide, molecules able to inhibit three different stages of the intracellular NF-kB signalling pathway (IkB-alpha phosphorylation and following degradation; NF-kB nuclear translocation; and p65 binding to DNA, respectively) (4, 5) abrogated hemozoin-dependent increase of MMP-9, TNF-alpha and IL-1-beta either in hemozoin-fed or trophozoite-fed monocytes. Moreover, 2 h and 24 h after phagocytosis present data indicate that the NF-kB complex was present in the nuclear fraction, and, second, cytosolic IkB-alpha protein was phosphorylated and degraded. Present data suggest that hemozoin-induced upregulation of MMP-9, TNF-alpha and IL-1-beta in human monocytes may involve a NF-kB-mediated signal transduction pathway. This work was supported in the context of the Italian Malaria Network by grants from Compagnia di San Paolo-IMI and the University of Torino Intramural Funds to P.A 1. Arese P. et al. (1997) Ann. Trop. Med. Parasitol. 91, 501-516 2. Prato M. et al. (2005) J. Immunol. 175, 6436-6442 3. Prato M. et al. (2008) Malar. J. in press 4. Nair M.P. et al. (2006) Clin. Vaccine Immunol. 13, 319-328 5. Aldieri E. et al. (2003) FEBS Lett. 552, 141-144
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