Activation of NF-kB mediates ICAM-1 induction in respiratory cells exposed to an adenovirus-derived vector

Melotti, Paola; Nicolis, Elena; Tamanini, Anna; Rolfini, Rossella; Pavirani, Andréa; Cabrini, Giulio

doi:10.1038/sj.gt.3301533

Cited by 70 publications

(53 citation statements)

References 43 publications

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“…NF-B activation upregulates the expression of a number of chemokines, cytokines, and cell adhesion molecules that have been implicated in the fibrotic changes of renal obstruction (34,41,46). In addition, specific NF-B inhibition with a proteosome inhibitor has been shown to attenuate obstruction-induced renal fibrosis (53).…”

Section: F456 Induction Of Fibrosis and Inflammation By Parp1mentioning

confidence: 99%

Loss of poly(ADP-ribose) polymerase 1 attenuates renal fibrosis and inflammation during unilateral ureteral obstruction

Kim¹,

Padanilam

2011

American Journal of Physiology-Renal Physiology

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Poly(ADP-ribose) polymerase 1 (PARP1) contributes to necrotic cell death and inflammation in several disease models; however, the role of PARP1 in fibrogenesis remains to be defined. Here, we tested whether PARP1 was involved in the pathogenesis of renal fibrosis using the unilateral ureteral obstruction (UUO) mouse model. UUO was performed by ligation of the left ureter near the renal pelvis in Parp1-knockout (KO) and wild-type (WT) male mice. After 10 days of UUO, renal PARP1 expression and activation were strongly increased by 6- and 13-fold, respectively. Interstitial fibrosis induced by UUO was significantly attenuated in Parp1-KO kidneys compared with that in WT kidneys at 10 days, but not at 3 days, based on collagen deposition, α-smooth muscle actin (α-SMA), and fibronectin expression. Intriguingly, the UUO kidneys in Parp1-KO mice showed a dramatic decrease in infiltration of neutrophil and reduction in expression of proinflammatory proteins including intercellular adhesion molecule-1, tumor necrosis factor-α, inducible nitric oxide synthase, and toll-like receptor 4 as well as phosphorylation of nuclear factor-κB p65, but not transforming growth factor-β1 (TGF-β1) at both 3 and 10 days. Pharmacological inhibition of PARP1 in rat renal interstitial fibroblast (NRK-49F) cell line or genetic ablation in primary mouse embryonic fibroblast cells did not affect TGF-β1-induced de novo α-SMA expression. Parp1 deficiency significantly attenuated UUO-induced histological damage in the kidney tubular cells, but not apoptosis. These data suggest that PARP1 induces necrotic cell death and contributes to inflammatory signaling pathways that trigger fibrogenesis in obstructive nephropathy.

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Section: F456 Induction Of Fibrosis and Inflammation By Parp1mentioning

confidence: 99%

Loss of poly(ADP-ribose) polymerase 1 attenuates renal fibrosis and inflammation during unilateral ureteral obstruction

Kim¹,

Padanilam

2011

American Journal of Physiology-Renal Physiology

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“…The role of NFjB nuclear translocation in mediating viral recognition and immune responses has been shown during vesicular stomatitis virus infection 41 and for adenovirus-derived vector (Ad.CFTR) infection of the lung carcinoma cells. 42 Other viruses shown to activate NFjB, include HIV-1, HTLV-1, HBV, HCV, EBV and influenza virus. 43 The TLR signaling leads to activation of NFkB and following cytokine and chemokine production like TNF-a, IL-6 and IL-12.…”

Section: Discussionmentioning

confidence: 99%

Activation of the human immune system via toll‐like receptors by the oncolytic parvovirus H‐1

Sieben

Schäfer-Keller

Dinsart

et al. 2012

Intl Journal of Cancer

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This study aimed to investigate the function of toll-like receptors (TLRs) during oncolytic parvovirus H-1 (H-1PV)-induced human immune responses. First, the role of TLRs in the activation of the NFjB transcription factor was characterized; second, the immunologic effects of H-1PV-induced tumor cell lysates (TCL) on human antitumor immune responses were evaluated. A human ex vivo model was used to study immune responses with dendritic cells (DCs). Human embryonic kidney cells (HEK293) transfected to stably express TLRs were used as potential human DC equivalents to further investigate the role of specific TLRs during immune activation. TLR3 and TLR9 were activated by H-1PV infection, which correlated with NFjB translocation to the nucleus and a reduced cytoplasmic IjB expression. Using a TLR-signaling reporter plasmid (pNiFty-Luc), NFjB activity was increased following H-1PV infection. In addition, human DCs coincubated with H-1PV-induced TCL demonstrated increased TLR3 and TLR9 expression. These data suggest that H-1PV-induced TCL stimulate human DCs at least in part through TLR-dependent signaling pathways. Thus, DC maturation occurred through exposure to H-1PV-induced TCL through TLR-signaling leading to NFjB-dependent activation of the adaptive immune system as indicated by the increased expression of CD86, TLR3 and TLR9. Furthermore, the transcription of various cytokines indicates the activation of immune response, therefore the production of the proinflammatory cytokine TNF-a was determined. Here, H-1PV-induced TCL significantly enhanced the TNF-a level by DCs after coculture. H-1PV oncolytic virotherapy enhances immune priming by different effects on DCs and generates antitumor immunity. These findings potentially offer a new approach to tumor therapy.

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“…For example, both the NF-kB and MAP kinase pathways are reported to be activated by adenovirus infection of respiratory epithelium, endothelial cells, hepatocytes and antigen-presenting cells. [6][7][8][9][10] To date, there are no reports regarding these effects in human cancer cells. Since such pathways play a central role in the regulation of apoptosis and in inflammatory and immune responses, these events may have a significant influence upon the efficacy and toxicity of adenovirus cancer gene therapy.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of NF-κB enhances the cytotoxicity of virus-directed enzyme prodrug therapy and oncolytic adenovirus cancer gene therapy

et al. 2005

Gene Ther

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Virus-directed enzyme prodrug therapy utilizing the bacterial enzyme nitroreductase delivered by a replication-defective adenovirus vector to activate the prodrug CB1954 is a promising strategy currently undergoing clinical trials in patients with a range of cancers. Similarly, selectively replicating oncolytic adenoviruses are entering clinical trials. An understanding of interactions between vector and target cell are critical to the development of these strategies. We demonstrate that adenovirus vectors activate cellular pathways that promote cell survival in an NF-kB-dependent manner, and consequently have a negative effect on the efficacy of cell killing induced by cancer gene therapy strategies. This provides a potential therapeutic target to enhance the cytotoxicity of these approaches.

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Activation of NF-kB mediates ICAM-1 induction in respiratory cells exposed to an adenovirus-derived vector

Cited by 70 publications

References 43 publications

Loss of poly(ADP-ribose) polymerase 1 attenuates renal fibrosis and inflammation during unilateral ureteral obstruction

Loss of poly(ADP-ribose) polymerase 1 attenuates renal fibrosis and inflammation during unilateral ureteral obstruction

Activation of the human immune system via toll‐like receptors by the oncolytic parvovirus H‐1

Inhibition of NF-κB enhances the cytotoxicity of virus-directed enzyme prodrug therapy and oncolytic adenovirus cancer gene therapy

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