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-Inducible Macrophage Nitric Oxide Generation Through Extracellular Signal-Regulated Kinase- and NF-
B-Dependent Pathways 1
* Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec, Pavillon Centre Hospitalier de l’Université Laval, and Département de Biologie médicale, Faculté de Médecine, Université Laval, Ste-Foy, Québec, Canada;
Research Institute of McGill University Health Centre, Centre for the Study of Host Resistance, and Departments of Medicine, Microbiology and Immunology, McGill University, Montréal, Québec, Canada; and
Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, and Milton S. Hershey Medical Center, Hershey, PA 17003
NO overproduction has been suggested to contribute to the immunopathology related to malaria infection. Even though a role for some parasite molecules (e.g., GPI) in NO induction has been proposed, the direct contribution of hemozoin (HZ), another parasite metabolite, remains to be established. Therefore, we were interested to determine whether Plasmodium falciparum (Pf) HZ and synthetic HZ, 
-hematin, alone or in combination with IFN-
, were able to induce macrophage (M
) NO synthesis. We observed that neither Pf HZ nor synthetic HZ led to NO generation in B10R murine M; however, they significantly increased IFN--mediated inducible NO synthase (iNOS) mRNA and protein expression, and NO production. Next, by investigating the transductional mechanisms involved in this cellular regulation, we established that HZ induces extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase phosphorylation as well as NF-
B binding to the iNOS promoter, and enhances the IFN--dependent activation of both second messengers. Of interest, cell pretreatment with specific inhibitors against either NF-B or the ERK1/2 pathway blocked the HZ + IFN--inducible NF-B activity and significantly reduced the HZ-dependent increase on IFN--mediated iNOS and NO induction. Even though selective inhibition of the Janus kinase 2/STAT1
pathway suppressed NO synthesis in response to HZ + IFN-, HZ alone did not activate this signaling pathway and did not have an up-regulating effect on the IFN--induced Janus kinase 2/STAT1 phosphorylation and STAT1 binding to the iNOS promoter. In conclusion, our results suggest that HZ exerts a potent synergistic effect on the IFN--inducible NO generation in M via ERK- and NF-B-dependent pathways.
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