Disruption of JNK2 decreases the cytokine response to Plasmodium falciparum glycosylphosphatidylinositol in vitro and confers protection in a cerebral malaria model.
Host inflammatory responses to Plasmodium falciparum GPI (pfGPI) anchors are believed to play an important role in the pathophysiology of severe malaria. However, relatively little is known about the signal transduction pathways involved in pfGPI-stimulated inflammatory response and its potential contribution to severe malaria syndromes. In this study, we investigated the role of MAPK activation in pfGPI-induced cytokine secretion and examined the role of selected MAPKs in a model of cerebral malaria in vivo. We demonstrate that ERK1/2, JNK, p38, c-Jun, and activating transcription factor-2 became phosphorylated in pfGPI-stimulated macrophages. A JNK inhibitor (1,9-pyrazoloanthrone) inhibited pfGPI-induced phosphorylation of JNK, c-Jun, and activating transcription factor-2 and significantly decreased pfGPI-induced TNF-alpha secretion. pfGPI-stimulated JNK and c-Jun phosphorylation was absent in Jnk2(-/-) macrophages but unchanged in Jnk1(-/-) and Jnk3(-/-) macrophages compared with wild-type macrophages. Jnk2(-/-) macrophages secreted significantly less TNF-alpha in response to pfGPI than macrophages from Jnk1(-/-), Jnk3(-/-), and wild-type counterparts. Furthermore, we demonstrate a role for JNK2 in mediating inflammatory responses and severe malaria in vivo. In contrast to wild-type or Jnk1(-/-) mice, Jnk2(-/-) mice had lower levels of TNF-alpha in vivo and exhibited significantly higher survival rates when challenged with Plasmodium berghei ANKA. These results provide direct evidence that pfGPI induces TNF-alpha secretion through activation of MAPK pathways, including JNK2. These results suggest that JNK2 is a potential target for therapeutic interventions in severe malaria.
Lu
Ziyue
Z
Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University Health Network-Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada.
Serghides
Lena
L
Patel
Samir N
SN
Degousee
Norbert
N
Rubin
Barry B
BB
Krishnegowda
Gowdahali
G
Gowda
D Channe
DC
Karin
Michael
M
Kain
Kevin C
KC
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D017261:Glycosylphosphatidylinositols / Q000276:immunology* / Q000494:pharmacology; D016779:Malaria, Cerebral / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D016778:Malaria, Falciparum / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008817:Mice, Mutant Strains; D048056:Mitogen-Activated Protein Kinase 9 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000276:immunology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016207:Cytokines; D017261:Glycosylphosphatidylinositols; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D048056:Mitogen-Activated Protein Kinase 9