Haemozoin enhances cytokine-mediated TIMP-1 expression and release from human monocytes through p38 MAPK- and NF-kappaB-dependent mechanisms.

The involvement of Matrix metalloproteinase-9 (MMP-9) and its endogenous inhibitor (Tissue inhibitor of Metalloproteinase-1, TIMP-1) in complicated malaria has been proposed recently. In vivo, mice with cerebral malaria displayed high levels of both molecules, whereas in human patients TIMP-1 serum levels were correlated to disease severity. In vitro, malarial pigment haemozoin (HZ) was shown to enhance monocytic MMP-9 expression. Here the in vitro effects of HZ on TIMP-1 regulation in human monocytes were studied. Natural (n) HZ induced TIMP-1 mRNA expression and protein release, and promoted TNFalpha/IL-1beta/MIP-1alpha production. Blocking antibodies/recombinant cytokines abrogated/mimicked nHZ effects on TIMP-1, respectively. Either p38 MAPK or NF-kappaB inhibitors blocked all nHZ effects. Lipid-free HZ did not reproduce nHZ effects on TIMP-1, TNFalpha and IL-1beta; HZ lipoperoxidation derivative 15-HETE did. Finally, nHZ enhanced total gelatinolytic activity. Collectively these data suggest that in human monocytes the lipoperoxidation products of HZ, such as 15-HETE, induce TIMP-1 expression/release through p38 MAPK-/NF-kappaB-dependent and inflammation-mediated mechanisms. Although TIMP-1 induction is not sufficient to counterbalance HZ-enhanced MMP-9 activity, some recently reported MMP-independent TIMP-1 properties could explain several crucial features of HZ-fed monocytes, including prolonged survival, miscarried maturation to dendritic cells and erythropoiesis inhibition, thereby confirming TIMP-1 role as marker of disease severity.