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

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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-pro-moting 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 CD11chiMHCIIhiCD3CD49bCD19FcRI DC via PI3K–Akt–NF-B 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 CD8 DC, whereas nonlethal Plasmodium yoelii induced IL-4 by both CD8 and CD8 DC. In both P. berghei ANKA- and P. yoelii-infected mice, IL-4 – expressing CD8 DC did not express IL-12, but a distinct CD8 DC subset expressed IL-12. In P. berghei ANKA infection, CD8 DC expressed IL-12 but not IL-4, whereas in P. yoelii infection, CD8 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-B signaling, revealing signaling and molecular mechanisms that initiate and promote Th2 development.

Original languageEnglish (US)
Pages (from-to)10425-10434
Number of pages10
JournalJournal of Biological Chemistry
Volume293
Issue number27
DOIs
StatePublished - Jan 1 2018

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Interleukin-4
Dendritic Cells
Malaria
Interleukin-12
Proteins
Plasmodium yoelii
Plasmodium berghei
T-cells
Cytokines
Parasites
T-Lymphocytes
Plasmodium falciparum
Infection
Anti-Inflammatory Agents

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

@article{46f493f5f1264d2b9551fb7b1d636c53,
title = "A malaria protein factor induces IL-4 production by dendritic cells via PI3K–Akt–NF-B signaling independent of MyD88/ TRIF and promotes Th2 response",
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-pro-moting 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 CD11chiMHCIIhiCD3CD49bCD19FcRI DC via PI3K–Akt–NF-B 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 CD8 DC, whereas nonlethal Plasmodium yoelii induced IL-4 by both CD8 and CD8 DC. In both P. berghei ANKA- and P. yoelii-infected mice, IL-4 – expressing CD8 DC did not express IL-12, but a distinct CD8 DC subset expressed IL-12. In P. berghei ANKA infection, CD8 DC expressed IL-12 but not IL-4, whereas in P. yoelii infection, CD8 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-B signaling, revealing signaling and molecular mechanisms that initiate and promote Th2 development.",
author = "Xianzhu Wu and Gowda, {Nagaraj M.} and Yuka Imamura and Channe Gowda",
year = "2018",
month = "1",
day = "1",
doi = "10.1074/jbc.AC118.001720",
language = "English (US)",
volume = "293",
pages = "10425--10434",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "27",

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TY - JOUR

T1 - A malaria protein factor induces IL-4 production by dendritic cells via PI3K–Akt–NF-B signaling independent of MyD88/ TRIF and promotes Th2 response

AU - Wu, Xianzhu

AU - Gowda, Nagaraj M.

AU - Imamura, Yuka

AU - Gowda, Channe

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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-pro-moting 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 CD11chiMHCIIhiCD3CD49bCD19FcRI DC via PI3K–Akt–NF-B 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 CD8 DC, whereas nonlethal Plasmodium yoelii induced IL-4 by both CD8 and CD8 DC. In both P. berghei ANKA- and P. yoelii-infected mice, IL-4 – expressing CD8 DC did not express IL-12, but a distinct CD8 DC subset expressed IL-12. In P. berghei ANKA infection, CD8 DC expressed IL-12 but not IL-4, whereas in P. yoelii infection, CD8 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-B signaling, revealing signaling and molecular mechanisms that initiate and promote Th2 development.

AB - 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-pro-moting 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 CD11chiMHCIIhiCD3CD49bCD19FcRI DC via PI3K–Akt–NF-B 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 CD8 DC, whereas nonlethal Plasmodium yoelii induced IL-4 by both CD8 and CD8 DC. In both P. berghei ANKA- and P. yoelii-infected mice, IL-4 – expressing CD8 DC did not express IL-12, but a distinct CD8 DC subset expressed IL-12. In P. berghei ANKA infection, CD8 DC expressed IL-12 but not IL-4, whereas in P. yoelii infection, CD8 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-B signaling, revealing signaling and molecular mechanisms that initiate and promote Th2 development.

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U2 - 10.1074/jbc.AC118.001720

DO - 10.1074/jbc.AC118.001720

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JO - Journal of Biological Chemistry

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