title: Blockade of Lyn kinase upregulates both canonical and non-canonical TLR-3 pathways in THP-1 monocytes exposed to human cytomegalovirus.
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.
authors: Children's Mercy Hospitals, Kansas City, MO, USA.
authors: K H
authors: KH
authors: Yew
authors: C J
authors: CJ
authors: Harrison
mesh_terms: D002460:Cell Line; D003587:Cytomegalovirus / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism* / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; C495344:TLR3 protein, human; C495371:TLR9 protein, human; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D016899:Interferon-beta; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases