Natural haemozoin induces expression and release of human monocyte tissue inhibitor of metalloproteinase-1

• Published in: PloS one 2013-08, Vol.8 (8), p.e71468
• Main Authors: Polimeni, Manuela, Valente, Elena, Ulliers, Daniela, Opdenakker, Ghislain, Van den Steen, Philippe E, Giribaldi, Giuliana, Prato, Mauro
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Antibodies; Biology; Blocking antibodies; CCL3 protein; Cell Adhesion; Cell survival; Cytokines; Gelatinase B; Gene expression; Gene Expression Regulation - drug effects; Hemeproteins - pharmacology; Humans; IL-1β; Inflammation; Inhibitors; Kinases; Laboratories; Malaria; MAP kinase; MAP Kinase Signaling System - drug effects; Matrix metalloproteinase; Matrix Metalloproteinase 9 - metabolism; Medicine; Metalloproteinase; Mice; Monocytes; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; Monocytes - secretion; NF-kappa B - metabolism; NF-κB protein; p38 Mitogen-Activated Protein Kinases - metabolism; Parasites; Pathogenesis; Plasmodium falciparum; Proteinase; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Serum levels; Solubility; Stem cells; Tissue inhibitor of metalloproteinase 1; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - secretion; Tumor necrosis factor; Tumor necrosis factor-α; Vector-borne diseases
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0071468

Recently matrix metalloproteinase-9 (MMP-9) and its endogenous inhibitor (tissue inhibitor of metalloproteinase-1, TIMP-1) have been implicated in complicated malaria. In vivo, mice with cerebral malaria (CM) display high levels of both MMP-9 and TIMP-1, and in human patients TIMP-1 serum levels directly correlate with disease severity. In vitro, natural haemozoin (nHZ, malarial pigment) enhances monocyte MMP-9 expression and release. The present study analyses the effects of nHZ on TIMP-1 regulation in human adherent monocytes. nHZ induced TIMP-1 mRNA expression and protein release, and promoted TNF-α, IL-1β, and MIP-1α/CCL3 production. Blocking antibodies or recombinant cytokines abrogated or mimicked nHZ effects on TIMP-1, respectively. p38 MAPK and NF-κB inhibitors blocked all nHZ effects on TIMP-1 and pro-inflammatory molecules. Still, total gelatinolytic activity was enhanced by nHZ despite TIMP-1 induction. Collectively, these data indicate that nHZ induces inflammation-mediated expression and release of human monocyte TIMP-1 through p38 MAPK- and NF-κB-dependent mechanisms. However, TIMP-1 induction is not sufficient to counterbalance nHZ-dependent MMP-9 enhancement. Future investigation on proteinase-independent functions of TIMP-1 (i.e. cell survival promotion and growth/differentiation inhibition) is needed to clarify the role of TIMP-1 in malaria pathogenesis.