Document Type

Article

Publication Date

9-7-2012

Identifier

DOI: 10.1371/journal.pone.0044500; PMCID: PMC3436894

Abstract

Using TLR pathways, primary human cytomegalovirus (HCMV) induces innate responses including the production of inflammatory cytokines. Mounting evidence suggests that LPS recognition by TLR4/MD2/CD14 results in differential utilization of TIRAP-TRAF6 and TRAM-TRIF signaling, thereby leading to transcriptional activation of various cytokine genes. However, relative roles of the TLR4/MD2/CD14 complex and its adaptor proteins TIRAP and TRAM involved in regulating monocyte responses to HCMV are incomplete. Here, we provided evidence supporting the notion that the TLR4/MD2/CD14 complex contributes notably to HCMV-induced signaling and subsequent cytokine production in monocytes. In particular, induction of both IL-6 and IL-8 is associated with elevated TIRAP and reduced TRAM mRNA expression. The latter may serve in a compensatory pathway that yields a robust IFN response when TIRAP signaling is blocked in monocytes incubated with Toledo strain HCMV. Inhibitory studies using antisense oligonucleotides or neutralizing antibodies indicate that IL-6 induction by TLR4/MD2 complex is important for the activation of endogenous CD14 which later acts in concert or synergy with TLR4/MD2 as a factor resulting in IL-8 gene expression. We further show that exogenous recombinant CD14 can potentiate innate immune response via TLR4-dependent and possibly via TLR9-dependent pathways to promote enhanced expression/production of IL-8 and IFN-β, respectively.

Journal Title

PLoS One

Volume

7

Issue

9

First Page

44500

Last Page

44500

MeSH Keywords

Adaptor Proteins, Signal Transducing; Cell Line; Cytomegalovirus; Humans; Interferon-beta; Interleukin-8; Membrane Glycoproteins; Monocytes; Receptors, Interleukin-1; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Keywords

Adaptor Proteins, Signal Transducing; Cell Line; Cytomegalovirus; Humans; Interferon-beta; Interleukin-8; Membrane Glycoproteins; Monocytes; Receptors, Interleukin-1; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Comments

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publisher's Link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044500

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