DNA containing CpG motifs induces angiogenesis

Zheng, Min; Klinman, Dennis M.; Gieryńska, Małgorzata; Rouse, Barry T.

doi:10.1073/pnas.132605599

Cited by 87 publications

(65 citation statements)

References 31 publications

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“…The heat-stable TLR9-dependent stimulus is most likely viral DNA. Indeed, high concentrations of isolated HSV DNA have been shown to be stimulatory (17,30). The TLR9-independent mechanism of HSV-1 recognition is not fully elucidated, but two different mechanisms could be envisaged.…”

Section: Discussionmentioning

confidence: 99%

Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways

Hochrein

Schlatter

O’Keeffe

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

398

332

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Type I IFN production in response to the DNA virus herpes simplex virus type-1 (HSV-1) is essential in controlling viral replication. We investigated whether plasmacytoid dendritic cells (pDC) were the major tissue source of IFN-␣, and whether the production of IFN-␣ in response to HSV-1 depended on Toll-like receptor 9 (TLR9). Total spleen cells or bone marrow (BM) cells, or fractions thereof, including highly purified pDC, from WT, TLR9, and MyD88 knockout mice were stimulated with known ligands for TLR9 or active HSV-1. pDC freshly isolated from both spleen and BM were the major source of IFN-␣ in response to oligodeoxynucleotides containing CpG motifs, but in response to HSV-1 the majority of IFN-␣ was produced by other cell types. Moreover, IFN-␣ production by non-pDC was independent of TLR9. The tissue source determined whether pDC responded to HSV-1 in a strictly TLR9-dependent fashion. Freshly isolated BM pDC or pDC derived from culture of BM precursors with FMS-like tyrosine kinase-3 ligand, produced IFN-␣ in the absence of functional TLR9, whereas spleen pDC did not. Heat treatment of HSV-1 abolished maturation and IFN-␣ production from all TLR9-deficient DC but not WT DC. Thus pDC and non-pDC produce IFN-␣ in response to HSV-1 via both TLR9-independent and -dependent pathways.

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Section: Discussionmentioning

confidence: 99%

Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways

Hochrein

Schlatter

O’Keeffe

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

398

332

View full text Add to dashboard Cite

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“…Additionally, patients with XLA are known to be susceptible to herpes viruses such as HHV-6, varicella-zoster, herpes simplex, and cytomegalovirus (29). Herpes viruses have been shown to contain unmethylated CpG motifs (30), and according to one study carried out on 96 XLA patients, herpes simplex virus infections represented 37% of all viral infections (31,32). An impairment in TLR9 signaling due to the defect in Btk may help explain this susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Signaling by Toll-like Receptors 8 and 9 Requires Bruton's Tyrosine Kinase

Doyle

Jefferies

Feighery

et al. 2007

Journal of Biological Chemistry

116

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Toll-like receptors (TLRs) are a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. TLR7 and TLR8 sense single-stranded RNA from viruses or host ribonucleoproteins and synthetic imidazoquinolines such as R848, whereas TLR9 senses unmethylated CpG motifs in viral and bacterial DNA and in host DNA. Here we report the endogenous interaction between Brutons's tyrosine kinase (Btk) and human TLR8 and TLR9 in the monocytic cell line THP1. We also show that R848, single-stranded RNA, and CpGB-DNA activate Btk in THP1 cells as shown by phosphorylation of the tyrosine 223 residue of Btk and also by increased autokinase activity. We demonstrate that Btk is required for NF B activation, participating in the pathway to increased phosphorylation of p65 on serine 536 activated by TLR8 and TLR9. Finally we demonstrate that peripheral blood mononuclear cells from patients with X-linked agammaglobulinaemia (XLA) that have dysfunctional Btk are impaired in the induction of interleukin-6 by CpGB-DNA. This study therefore establishes Btk as a key signaling molecule that interacts with and acts downstream of TLR8 and TLR9. Lack of functioning Btk in XLA patients downstream of TLR8 and TLR9 might explain the susceptibility of XLA patients to viral infections.

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“…30 The mechanisms underlying the enhanced inflammation are not precisely known, but preclinical data regarding herpetic stromal keratitis in wild-type HSV 1 infection revealed that angiogenesis may be induced by paracrine effects resulting from release of VP22 or the CpG motifs in the DNA of HSV 1, which are required for viral replication. [57][58][59][60] Most of these stimuli, especially the CpG motif, potently stimulate secretion of vascular endothelial growth factor (VEGF) A. [58][59][60][61] In addition, antiangiogenic molecules such as thrombospondin 1 and 2 are reduced in wild-type HSV 1 infection.…”

Section: X400 X400mentioning

confidence: 99%

“…[57][58][59][60] Most of these stimuli, especially the CpG motif, potently stimulate secretion of vascular endothelial growth factor (VEGF) A. [58][59][60][61] In addition, antiangiogenic molecules such as thrombospondin 1 and 2 are reduced in wild-type HSV 1 infection. 59 Many studies have shown that VEGF A is upregulated in HSV 1 infections; [62][63][64] thus, VEGF A may be the factor underlying the angiogenesis seen in our study.…”

Section: X400 X400mentioning

confidence: 99%

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

et al. 2011

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Oncolytic viruses are a promising method of cancer therapy, even for advanced malignancies. HF10, a spontaneously mutated herpes simplex type 1, is a potent oncolytic agent. The interaction of oncolytic herpes viruses with the tumor microenvironment has not been well characterized. We injected HF10 into tumors of patients with recurrent breast carcinoma, and sought to determine its effects on the tumor microenvironment. Six patients with recurrent breast cancer were recruited to the study. Tumors were divided into two groups: saline-injected (control) and HF10-injected (treatment). We investigated several parameters including neovascularization (CD31) and tumor lymphocyte infiltration (CD8, CD4), determined by immunohistochemistry, and apoptosis, determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Median apoptotic cell count was lower in the treatment group (P ¼ 0.016). Angiogenesis was significantly higher in treatment group (P ¼ 0.032). Count of CD8-positive lymphocytes infiltrating the tumors was higher in the treatment group (P ¼ 0.008). We were unable to determine CD4-positive lymphocyte infiltration. An effective oncolytic viral agent must replicate efficiently in tumor cells, leading to higher viral counts, in order to aid viral penetration. HF10 seems to meet this criterion; furthermore, it induces potent antitumor immunity. The increase in angiogenesis may be due to either viral replication or the inflammatory response.

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DNA containing CpG motifs induces angiogenesis

Cited by 87 publications

References 31 publications

Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways

Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways

Signaling by Toll-like Receptors 8 and 9 Requires Bruton's Tyrosine Kinase

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

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