Antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of IL-10 production in monocytes.
Interleukin (IL)-10 levels are increased in dengue virus (DENV)-infected patients with severe disorders. A hypothetical intrinsic pathway has been proposed for the IL-10 response during antibody-dependent enhancement (ADE) of DENV infection; however, the mechanisms of IL-10 regulation remain unclear...
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doaj-731cc867bdd44cb9ac864bdaad4e0ddf2020-11-25T01:55:03ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352014-11-01811e332010.1371/journal.pntd.0003320Antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of IL-10 production in monocytes.Tsung-Ting TsaiYi-Jui ChuangYee-Shin LinChih-Peng ChangShu-Wen WanSheng-Hsiang LinChia-Ling ChenChiou-Feng LinInterleukin (IL)-10 levels are increased in dengue virus (DENV)-infected patients with severe disorders. A hypothetical intrinsic pathway has been proposed for the IL-10 response during antibody-dependent enhancement (ADE) of DENV infection; however, the mechanisms of IL-10 regulation remain unclear.We found that DENV infection and/or attachment was sufficient to induce increased expression of IL-10 and its downstream regulator suppressor of cytokine signaling 3 in human monocytic THP-1 cells and human peripheral blood monocytes. IL-10 production was controlled by activation of cyclic adenosine monophosphate response element-binding (CREB), primarily through protein kinase A (PKA)- and phosphoinositide 3-kinase (PI3K)/PKB-regulated pathways, with PKA activation acting upstream of PI3K/PKB. DENV infection also caused glycogen synthase kinase (GSK)-3β inactivation in a PKA/PI3K/PKB-regulated manner, and inhibition of GSK-3β significantly increased DENV-induced IL-10 production following CREB activation. Pharmacological inhibition of spleen tyrosine kinase (Syk) activity significantly decreased DENV-induced IL-10 production, whereas silencing Syk-associated C-type lectin domain family 5 member A caused a partial inhibition. ADE of DENV infection greatly increased IL-10 expression by enhancing Syk-regulated PI3K/PKB/GSK-3β/CREB signaling. We also found that viral load, but not serotype, affected the IL-10 response. Finally, modulation of IL-10 expression could affect DENV replication.These results demonstrate that, in monocytes, IL-10 production is regulated by ADE through both an extrinsic and an intrinsic pathway, all involving a Syk-regulated PI3K/PKB/GSK-3β/CREB pathway, and both of which impact viral replication.http://europepmc.org/articles/PMC4239119?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tsung-Ting Tsai Yi-Jui Chuang Yee-Shin Lin Chih-Peng Chang Shu-Wen Wan Sheng-Hsiang Lin Chia-Ling Chen Chiou-Feng Lin |
spellingShingle |
Tsung-Ting Tsai Yi-Jui Chuang Yee-Shin Lin Chih-Peng Chang Shu-Wen Wan Sheng-Hsiang Lin Chia-Ling Chen Chiou-Feng Lin Antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of IL-10 production in monocytes. PLoS Neglected Tropical Diseases |
author_facet |
Tsung-Ting Tsai Yi-Jui Chuang Yee-Shin Lin Chih-Peng Chang Shu-Wen Wan Sheng-Hsiang Lin Chia-Ling Chen Chiou-Feng Lin |
author_sort |
Tsung-Ting Tsai |
title |
Antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of IL-10 production in monocytes. |
title_short |
Antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of IL-10 production in monocytes. |
title_full |
Antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of IL-10 production in monocytes. |
title_fullStr |
Antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of IL-10 production in monocytes. |
title_full_unstemmed |
Antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of IL-10 production in monocytes. |
title_sort |
antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of il-10 production in monocytes. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Neglected Tropical Diseases |
issn |
1935-2727 1935-2735 |
publishDate |
2014-11-01 |
description |
Interleukin (IL)-10 levels are increased in dengue virus (DENV)-infected patients with severe disorders. A hypothetical intrinsic pathway has been proposed for the IL-10 response during antibody-dependent enhancement (ADE) of DENV infection; however, the mechanisms of IL-10 regulation remain unclear.We found that DENV infection and/or attachment was sufficient to induce increased expression of IL-10 and its downstream regulator suppressor of cytokine signaling 3 in human monocytic THP-1 cells and human peripheral blood monocytes. IL-10 production was controlled by activation of cyclic adenosine monophosphate response element-binding (CREB), primarily through protein kinase A (PKA)- and phosphoinositide 3-kinase (PI3K)/PKB-regulated pathways, with PKA activation acting upstream of PI3K/PKB. DENV infection also caused glycogen synthase kinase (GSK)-3β inactivation in a PKA/PI3K/PKB-regulated manner, and inhibition of GSK-3β significantly increased DENV-induced IL-10 production following CREB activation. Pharmacological inhibition of spleen tyrosine kinase (Syk) activity significantly decreased DENV-induced IL-10 production, whereas silencing Syk-associated C-type lectin domain family 5 member A caused a partial inhibition. ADE of DENV infection greatly increased IL-10 expression by enhancing Syk-regulated PI3K/PKB/GSK-3β/CREB signaling. We also found that viral load, but not serotype, affected the IL-10 response. Finally, modulation of IL-10 expression could affect DENV replication.These results demonstrate that, in monocytes, IL-10 production is regulated by ADE through both an extrinsic and an intrinsic pathway, all involving a Syk-regulated PI3K/PKB/GSK-3β/CREB pathway, and both of which impact viral replication. |
url |
http://europepmc.org/articles/PMC4239119?pdf=render |
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