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Disruption of JNK2 Decreases the Cytokine Response to Plasmodium falciparum Glycosylphosphatidylinositol In Vitro and Confers Protection in a Cerebral Malaria Model¹

Ziyue Lu^*, Lena Serghides, Samir N. Patel, Norbert Degousee, Barry B. Rubin, Gowdahali Krishnegowda, D. Channe Gowda, Michael Karin^¶ and Kevin C. Kain^2,*,,||

^* Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University Health Network-Toronto General Hospital, Toronto, Canada; Faculty of Medicine, University of Toronto, Toronto, Canada; Division of Vascular Surgery, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Canada; Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033; ^¶ Department of Pharmacology, School of Medicine, University of California, San Diego, CA 92093; and ^|| McLaughlin-Rotman Centre, McLaughlin Centre for Molecular Medicine, University Health Network, and University of Toronto, Toronto, Canada

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- 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- 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- in vivo and exhibited significantly higher survival rates when challenged with Plasmodium berghei ANKA. These results provide direct evidence that pfGPI induces TNF- secretion through activation of MAPK pathways, including JNK2. These results suggest that JNK2 is a potential target for therapeutic interventions in severe malaria.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Canadian Institutes for Health Research Team Grant in Malaria (to K.C.K.), Operating Grant MT-13721 (to K.C.K.), Operating Grant 53297 (to B.B.R.), Genome Canada (to K.C.K.), Canadian Genetics Disease Network (to K.C.K.), Physicians’ Services Incorporated (to K.C.K.), and Canadian Institutes for Health Research Canada Research Chair (to K.C.K.).

² Address correspondence and reprint requests to Dr. Kevin C. Kain, University Health Network-Toronto General Hospital, EN 13-214, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. E-mail address: kevin.kain{at}uhn.on.ca

³ Abbreviations used in this paper: ms, monocytes/macrophages; pfGPI, Plasmodium falciparum GPI; ATF-2, activating transcription factor-2; PD98059, 2'-amino-3'-methoxyflavone; SB203580, 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole; SP600125, 1,9-pyrazoloanthrone; MAPKK, MAPK kinase; WT, wild type.

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