Involvement of p38 MAPK in haemozoin-dependent MMP-9 enhancement in human monocytes

Authors

  • Amina Khadjavi,

    1. Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Turin, Italy
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  • Elena Valente,

    1. Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Turin, Italy
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  • Giuliana Giribaldi,

    1. Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Turin, Italy
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    • The authors contributed equally to this work.

  • Mauro Prato

    Corresponding author
    1. Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Turin, Italy
    2. Dipartimento di Neuroscienze, Università di Torino, Turin, Italy
    • Correspondence to: Mauro Prato, Dipartimento di Neuroscienze, Università di Torino, Corso Raffaello 30, 10125 Turin, Italy.

      E-mail: mauro.prato@unito.it

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    • The authors contributed equally to this work.


Abstract

The lipid moiety of natural haemozoin (nHZ, malarial pigment) was previously shown to enhance expression and release of human monocyte matrix metalloproteinase-9 (MMP-9), and a major role for 15-(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid (15-HETE), a nHZ lipoperoxidation product, was proposed. Here, the underlying mechanisms were investigated, focusing on the involvement of mitogen-activated protein kinases (MAPKs). Results showed that nHZ promoted either early or late p38 MAPK phosphorylation; however, nHZ did not modify basal phosphorylation/expression ratios of extracellular signal-regulated kinase-1/2 and c-jun N-terminal kinase-1/2. 15-HETE mimicked nHZ effects on p38 MAPK, whereas lipid-free synthetic (s)HZ and delipidized (d)HZ did not. Consistently, both nHZ and 15-HETE also promoted phosphorylation of MAPK-activated protein kinase-2, a known p38 MAPK substrate; such an effect was abolished by SB203580, a synthetic p38 MAPK inhibitor. SB203580 also abrogated nHZ-dependent and 15-HETE-dependent enhancement of MMP-9 mRNA and protein (latent and activated forms) levels in cell lysates and supernatants. Collectively, these data suggest that in human monocytes, nHZ and 15-HETE upregulate MMP-9 expression and secretion through activation of p38 MAPK pathway. The present work provides new evidence on mechanisms underlying MMP-9 deregulation in malaria, which might be helpful to design new specific drugs for adjuvant therapy in complicated malaria. Copyright © 2013 John Wiley & Sons, Ltd.

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