Abstract
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.
Highlights
As a consequence of the global eradication program launched by charity foundations [1], World Health Organization (WHO) officially registered in 2010 a decline in estimated malaria cases and deaths, with 655,000 deaths counted among more than 200 million clinical cases worldwide, of which 91% were due to Plasmodium falciparum [2]
After centrifugation at 5,000g on a discontinuous Percoll-mannitol density gradient, nHZ was collected from the 0–40% interphase. nHZ was washed five times with 1.0 ml sense primer (10 mM) HEPES containing 10 mM mannitol at 4uC and once with phosphatebuffered saline (PBS). nHZ was treated with DNase to remove any adhering nuclear material as previously described [26]. nHZ was stored at 20% (v/v) in PBS at 220uC or immediately used for opsonization and phagocytosis
TIMPs were originally characterized as endogenous matrix metalloproteinases (MMPs) inhibitors due to their ability to bind zinc in the MMP active site and thereby antagonize the effects of activated/cleaved MMPs and block enzyme activity
Summary
As a consequence of the global eradication program launched by charity foundations [1], World Health Organization (WHO) officially registered in 2010 a decline in estimated malaria cases and deaths, with 655,000 deaths counted among more than 200 million clinical cases worldwide, of which 91% were due to Plasmodium falciparum [2]. Human matrix metalloproteinases (MMPs) are a family of proteolytic enzymes involved in wide variety of biological functions including modulation of inflammatory response, disruption of inter-endothelial tight junctions, and degradation of sub-endothelial basal lamina [4,5,6,7]. As such, they are good candidate molecules and there is growing evidence that MMPs play critical roles in malaria in both animal and human disease models (see [8,9,10] for more extensive reviews). Malarial pigment (nHZ, natural haemozoin), a waste product of haemoglobin digestion by Plasmodium parasites, induces MMP-9 release from human monocytes [11,12,13,14] and endothelial cells [9,15,16], and synthetic
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