A malaria protein factor induces IL-4 production by dendritic cells via PI3K–Akt–NF-κB signaling independent of MyD88/TRIF and promotes Th2 response

• Published in: The Journal of biological chemistry 2018-07, Vol.293 (27), p.10425-10434
• Main Authors: Wu, Xianzhu, Gowda, Nagaraj M., Kawasawa, Yuka I., Gowda, D. Channe
• Format: Article
• Language: English
• Subjects: Accelerated Communications; Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; Animals; Cytokines - metabolism; dendritic cell; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - parasitology; IL-4 production; interleukin; Interleukin-4 - metabolism; Interleukin-4 - physiology; malaria; Malaria - immunology; Malaria - metabolism; Malaria - parasitology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; PI3K-Akt-NF-kB; Plasmodium yoelii - immunology; protein complex; protein factor, dendritic cell; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Signal Transduction; signaling; signaling mechanism; Th1 Cells - immunology; Th1 Cells - metabolism; Th1 Cells - parasitology; Th2 Cells - immunology; Th2 Cells - metabolism; Th2 Cells - parasitology; Toll-like receptor (TLR); Toll-Like Receptor 2 - physiology; Toll-Like Receptor 4 - physiology; Toll-Like Receptor 9 - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.AC118.001720

Dendritic cells (DC) and cytokines produced by DC play crucial roles in inducing and regulating pro-/anti-inflammatory and Th1/Th2 responses. DC are known to produce a Th1-promoting cytokine, interleukin (IL)-12, in response to malaria and other pathogenic infections, but it is thought that DC do not produce Th2-promoting cytokine, IL-4. Here, we show that a protein factor of malaria parasites induces IL-4 responses by CD11chiMHCIIhiCD3ϵ−CD49b−CD19−FcϵRI− DC via PI3K–Akt–NF-κB signaling independent of TLR-MyD88/TRIF. Malaria parasite–activated DC induced IL-4 responses by T cells both in vitro and in vivo, favoring Th2, and il-4–deficient DC were unable to induce IL-4 expression by T cells. Interestingly, lethal parasites, Plasmodium falciparum and Plasmodium berghei ANKA, induced IL-4 response primarily by CD8α− DC, whereas nonlethal Plasmodium yoelii induced IL-4 by both CD8α+ and CD8α− DC. In both P. berghei ANKA- and P. yoelii-infected mice, IL-4–expressing CD8α− DC did not express IL-12, but a distinct CD8α− DC subset expressed IL-12. In P. berghei ANKA infection, CD8α+ DC expressed IL-12 but not IL-4, whereas in P. yoelii infection, CD8α+ DC expressed IL-4 but not IL-12. These differential IL-4 and IL-12 responses by DC subsets may contribute to different Th1/Th2 development and clinical outcomes in lethal and nonlethal malaria. Our results for the first time demonstrate that a malaria protein factor induces IL-4 production by DC via PI3K–Akt–NF-κB signaling, revealing signaling and molecular mechanisms that initiate and promote Th2 development.