INTRODUCTION: Growing evidence on the involvement of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in clinical progress towards complicated malaria has been emerging in the last decade. A role for deregulated MMP/TIMP balances in blood-brain barrier (BBB) damage during cerebral malaria (CM) was suggested in vivo (1,2), whereas malarial pigment (HZ, haemozoin) was shown to enhance in vitro inflammation-dependent MMP-9 expression and release through activation of the NF-kappaB pathway in human monocytes (3-6). Moreover, high serum levels of TIMP-1, endogenous inhibitor of MMP-9, were found in patients with severe malaria (7). In the present study, the effects of HZ on TIMP-1 mRNA expression and protein release were studied in human monocytes, along with dependence on production of pro-inflammatory molecules and involvement of NF-kappaB activation. RESULTS: HZ promoted TIMP-1 mRNA expression and protein release. As expected, HZ also enhanced Macrophage Inflammatory Protein-1alpha (MIP-1alpha), Tumor Necrosis Factor alpha (TNFalpha) and Interleukin-1beta (IL-1beta) mRNA expression and protein release. All the HZ effects on TIMP-1 were mimicked by recombinant (r) human (h) MIP-1alpha, rhTNFalpha and rhIL-1beta, while they were abrogated by anti-hMIP-1alpha, anti-TNFalpha and anti-IL-1beta antibodies. Quercetin, artemisinin and parthenolide, three NF-kappaB inhibitors previously shown to inhibit the HZ-enhanced release of MMP-9, TNFalpha and IL-1beta (5), abrogated the HZ effects on MIP-1alpha and TIMP-1 release. In conclusion, the present data show that phagocytosis of HZ by human monocytes promotes an inflammation-mediated increase of expression and release of TIMP-1 through activation of the NF-kappaB pathway and fit with previous evidence suggesting a role for TIMP-1 in clinical diagnosis as a marker for severe malaria. 1. Van den Steen P.E. et al. (2006) Lab. Invest. 86, 873-888. 2. Szklarczyk A. et al. (2007). J. Neurovirol. 13, 2-10. 3. Prato M. et al. (2005). J. Immunol. 175, 6436-6442. 4. Prato M. et al. (2008). Malar. J. 7, 157. 5. Prato M. et al. (2010). Cell. Microbiol. 12, 1780-1791. 6. Giribaldi G. et al.(2010) Infect. Immun. 78, 4912-4921. 7. Dietmann A. et al. (2008). J. Infect. Dis. 197, 1614-1620.
Haemozoin-dependent pro-inflammatory molecules promote Tissue Inhibitor of Metalloproteinase-1 expression and release through activation of NF-kappaB pathway in human adherent monocytes
GIRIBALDI, Giuliana;ULLIERS, Daniela;VALENTE, Elena;KHADJAVI, AMINA;MANDILI, GIORGIA;POLIMENI, Manuela;PRATO, Mauro
2011-01-01
Abstract
INTRODUCTION: Growing evidence on the involvement of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in clinical progress towards complicated malaria has been emerging in the last decade. A role for deregulated MMP/TIMP balances in blood-brain barrier (BBB) damage during cerebral malaria (CM) was suggested in vivo (1,2), whereas malarial pigment (HZ, haemozoin) was shown to enhance in vitro inflammation-dependent MMP-9 expression and release through activation of the NF-kappaB pathway in human monocytes (3-6). Moreover, high serum levels of TIMP-1, endogenous inhibitor of MMP-9, were found in patients with severe malaria (7). In the present study, the effects of HZ on TIMP-1 mRNA expression and protein release were studied in human monocytes, along with dependence on production of pro-inflammatory molecules and involvement of NF-kappaB activation. RESULTS: HZ promoted TIMP-1 mRNA expression and protein release. As expected, HZ also enhanced Macrophage Inflammatory Protein-1alpha (MIP-1alpha), Tumor Necrosis Factor alpha (TNFalpha) and Interleukin-1beta (IL-1beta) mRNA expression and protein release. All the HZ effects on TIMP-1 were mimicked by recombinant (r) human (h) MIP-1alpha, rhTNFalpha and rhIL-1beta, while they were abrogated by anti-hMIP-1alpha, anti-TNFalpha and anti-IL-1beta antibodies. Quercetin, artemisinin and parthenolide, three NF-kappaB inhibitors previously shown to inhibit the HZ-enhanced release of MMP-9, TNFalpha and IL-1beta (5), abrogated the HZ effects on MIP-1alpha and TIMP-1 release. In conclusion, the present data show that phagocytosis of HZ by human monocytes promotes an inflammation-mediated increase of expression and release of TIMP-1 through activation of the NF-kappaB pathway and fit with previous evidence suggesting a role for TIMP-1 in clinical diagnosis as a marker for severe malaria. 1. Van den Steen P.E. et al. (2006) Lab. Invest. 86, 873-888. 2. Szklarczyk A. et al. (2007). J. Neurovirol. 13, 2-10. 3. Prato M. et al. (2005). J. Immunol. 175, 6436-6442. 4. Prato M. et al. (2008). Malar. J. 7, 157. 5. Prato M. et al. (2010). Cell. Microbiol. 12, 1780-1791. 6. Giribaldi G. et al.(2010) Infect. Immun. 78, 4912-4921. 7. Dietmann A. et al. (2008). J. Infect. Dis. 197, 1614-1620.
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