Title

Blockade of Lyn kinase upregulates both canonical and non-canonical TLR-3 pathways in THP-1 monocytes exposed to human cytomegalovirus.

Document Type

Article

Publication Date

2011

Identifier

DOI: 10.4149/av_2011_03_243

Abstract

Regulation of monocyte response to human cytomegalovirus (HCMV) occurs via activation of receptors that elicit innate antiviral effects and later T-cell responses. Our previous data (Yew et al.., 2010) demonstrated that human monocyte scavenger receptor A type 1 (SR-A1) are required for sensing of HCMV by endosomal toll-like receptors (TLRs)-3 and -9, which in turn induce critical pro-inflammatory cytokines. However, it remains unclear which subcellular molecules associated with SR-A1 lead to downstream activation of TLR-3 and/or TLR-9 signaling pathways. Herein we report that Lyn kinase, associated physically and functionally with SR-A for low density lipoprotein (LDL) recognition, acts as a key SR-A1-induced kinase that plays a critical role in TLR-3/9 signal transduction upon HCMV exposure to THP-1 monocytes. We found that disruption of the SR-A1 signal transduction through molecular inhibition by Lyn kinase oligonucleotides not only blocks the activation of downstream TLR-9 pathway but also alters the downstream TLR-3 pathway. In particular, Lyn kinase oligonucleotides resulted in decreased expression of TLR-9-induced tumor necrosis factor alpha (TNF-α) but strongly upregulated canonical TLR-3-induced interferon beta (IFN-β) and non-canonical TLR-3-induced NF-κB-dependent p35 (35kDa) subunit of interleukin 12 (IL-12p35) gene transcription. Thus, the observed shift away from TNF-α to robust IFN-β and IL-12p35 induction may offer opportunities for therapeutic interventions.

Journal Title

Acta virologica. English ed

Volume

55

Issue

3

First Page

243

Last Page

253

MeSH Keywords

Cell Line; Cytomegalovirus; Humans; Interferon-beta; Interleukin-12; Monocytes; NF-kappa B; Signal Transduction; Toll-Like Receptor 3; Toll-Like Receptor 9; Tumor Necrosis Factor-alpha; Up-Regulation; src-Family Kinases

Keywords

Cell Line; Cytomegalovirus; Humans; Interferon-beta; Interleukin-12; Monocytes; NF-kappa B; Signal Transduction; Toll-Like Receptor 3; Toll-Like Receptor 9; Tumor Necrosis Factor-alpha; Up-Regulation; src-Family Kinases

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