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J Biol Chem. 2018 Jul 6;293(27):10425-10434. doi: 10.1074/jbc.AC118.001720. Epub 2018 Apr 17.

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.

Author information

1
From the Department of Biochemistry and Molecular Biology and.
2
the Department of Pharmacology and the Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
3
From the Department of Biochemistry and Molecular Biology and gowda@psu.edu.

Abstract

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.

KEYWORDS:

IL-4 production; PI3K-Akt-NF-kB; Toll-like receptor (TLR); dendritic cell; interleukin; malaria; protein complex; protein factor; signaling; signaling mechanism

PMID:
29666186
PMCID:
PMC6036203
[Available on 2019-07-06]
DOI:
10.1074/jbc.AC118.001720

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