Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: The requirement of extracellular signal-regulated kinase, p38, c-Jun N-terminal kinase and NF-κB pathways for the expression of proinflammatory cytokines and nitric oxide

The glycosylphosphatidylinositol (GPI) anchors of Plasmodium falciparum have been proposed to be the major factors that contribute to malaria pathogenesis by eliciting the production of proinflammatory cytokines and nitric oxide by the host innate immune system. In this study we demonstrate that the parasite GPIs can effectively induce the production of TNF-α at 5-20 nM concentrations in interferon-γ-primed monocytes and macrophages. The potency of the parasite GPIs activity is physiologically relevant to their ability to contribute to severe malaria pathogenesis. More importantly, we investigated the requirement of the extracellular signal-regulated kinase (ERK)-, c-Jun N-terminal kinase (JNK)-, p38-, and NF-κB-signaling pathways that are activated in response to P. falciparum GPIs through toll-like receptor-mediated recognition (Krishnegowda, G., Hajjar, A. M., Zhu J. Z., Douglass, E. J., Uematsu, S., Akira, S., Wood, A. S., and Gowda, D. C. (2005) J. Biol. Chem. 280, 8606-8616) for the proinflammatory responses by macrophages. The data conclusively show that the production of TNF-α, interleukin (IL)-12, IL-6, and nitric oxide by macrophages stimulated with parasite GPIs is critically dependent on the NF-κB and JNK pathways. NF-κB1 is essential for IL-6 and IL-12 production but not for TNF-α and nitric oxide, whereas NF-κB/c-Rel appears to be important for all four proinflammatory mediators. JNK1 and JNK2 are functionally redundant for the expression of TNF-α, IL-6, and nitric oxide, whereas JNK2 but not JNK1 is essential for IL-12 production. The ERK signaling pathway is not involved in TNF-α and nitric oxide production, but, interestingly, negatively regulates the expression of IL-6 and IL-12. Furthermore, p38 is critical for the production of IL-6 and IL-12 but is only marginally required for the production of TNF-α and nitric oxide. Thus, our data define the differential requirement of the downstream signaling molecules for the production of key proinflammatory cytokines and nitric oxide by macrophages in response to P. falciparum GPI stimuli. The data have important implications for the development of therapeutics for malaria treatment.