Disruption of JNK2 decreases the cytokine response to Plasmodium falciparum glycosylphosphatidylinositol in vitro and confers protection in a cerebral malaria model

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

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)6344-6352
Number of pages9
JournalJournal of Immunology
Volume177
Issue number9
DOIs
StatePublished - Nov 1 2006

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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