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Antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of IL-10 production in monocytes.


ABSTRACT:

Background

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.

Principle finding

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)-3? inactivation in a PKA/PI3K/PKB-regulated manner, and inhibition of GSK-3? 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-3?/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.

Significance

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-3?/CREB pathway, and both of which impact viral replication.

SUBMITTER: Tsai TT 

PROVIDER: S-EPMC4239119 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Publications

Antibody-dependent enhancement infection facilitates dengue virus-regulated signaling of IL-10 production in monocytes.

Tsai Tsung-Ting TT   Chuang Yi-Jui YJ   Lin Yee-Shin YS   Chang Chih-Peng CP   Wan Shu-Wen SW   Lin Sheng-Hsiang SH   Chen Chia-Ling CL   Lin Chiou-Feng CF  

PLoS neglected tropical diseases 20141120 11


<h4>Background</h4>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.<h4>Principle finding</h4>We found that DENV infection and/or attachment was sufficient to induce increased expression of IL-10 and its downstream regulator suppressor of cytokine  ...[more]

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