Thrombin induces Sp1-mediated antiviral effects in cytomegalovirus-infected human retinal pigment epithelial cells

Scholz, Martin; Vogel, Jens‐Uwe; Höver, Gerold; Prösch, Susanna; Kotchetkov, Rouslan; Činátl, Jaroslav; Koch, Frank; Činátl, Jindřich

doi:10.1007/s00430-003-0194-x

Cited by 9 publications

(11 citation statements)

References 48 publications

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“…Levels of phosphorylated Sp1 in cytoplasmic cell lysates were elevated after 5A-APC treatment of N2a-SOD1 G85R cells ( Figure 5, E and F), consistent with an earlier report suggesting that PAR1 signaling results in SP1 phosphorylation, preventing its nuclear translocation or retention (38). Increased Sp1 phosphorylation was inhibited both by the PI3K inhibitor LY294002 and by PAR1 and PAR3 antibodies.…”

Section: Figuresupporting

confidence: 91%

“…(C) Scanning densitometry of SOD1 G93A and mSOD1 bands in B, relative to β-actin. n = 3-5. after PAR1 activation (38). We used 3-color confocal microscopy to simultaneously localize Sp1 and the neuronal microtubule-associated protein MAP2 in N2a-SOD1 G85R cells, and found that almost all of these cells normally expressed nuclear Sp1 ( Figure 5A).…”

Section: Figurementioning

confidence: 98%

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Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells

Zhong¹,

Ilieva²,

Hallagan³

et al. 2009

J. Clin. Invest.

135

192

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Activated protein C (APC) is a signaling protease with anticoagulant activity. Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival. A proteolytically inactive form of APC with reduced anticoagulant activity provided no benefit. APC crossed the blood-spinal cord barrier in mice via endothelial protein C receptor. When administered after disease onset, APC eliminated leakage of hemoglobin-derived products across the blood-spinal cord barrier and delayed microglial activation. In microvessels, motor neurons, and microglial cells from SOD1-mutant mice and in cultured neuronal cells, APC transcriptionally downregulated SOD1. Inhibition of SOD1 synthesis in neuronal cells by APC required protease-activated receptor-1 (PAR1) and PAR3, which inhibited nuclear transport of the Sp1 transcription factor. Diminished mutant SOD1 synthesis by selective gene excision within endothelial cells did not alter disease progression, which suggests that diminished mutant SOD1 synthesis in other cells, including motor neurons and microglia, caused the APCmediated slowing of disease. The delayed disease progression in mice after APC administration suggests that this approach may be of benefit to patients with familial, and possibly sporadic, ALS.

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Section: Figuresupporting

confidence: 91%

Section: Figurementioning

confidence: 98%

Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells

Zhong¹,

Ilieva²,

Hallagan³

et al. 2009

J. Clin. Invest.

135

192

View full text Add to dashboard Cite

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“…The results are in agreement with previous studies that described expression of PAR1 and -3 in cultured RPE cells. 30 The data indicate that RPE cells express mRNA for various factors that are involved in the generation of thrombin from prothrombin, as well as for thrombin receptors.…”

Section: Expression Of Thrombin Receptorsmentioning

confidence: 96%

Effects of Thrombin on RPE Cells Are Mediated by Transactivation of Growth Factor Receptors

Hollborn

Petto

Steffen

et al. 2009

Invest. Ophthalmol. Vis. Sci.

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“…This was Wrst described in recipients of virus containing fresh-blood units ("transfusion mononucleosis"). In humans suVering from pathologically acquired immune deWciency syndrome (AIDS) or therapeutically acquired immunodeWciency (immunosuppressive treatment of transplant recipients), a wide spectrum of partially life-threatening inXammatory diseases are associated with HCMV, aVecting all visceral organs (gastroenteritis, colitis, hepatitis, nephritis), the lungs (interstitial pneumonia), and the central nervous system (CNS: encephalitis, chorioretinitis) [8][9][10][11]. Since HCMV reveals a distinct endothelial cell tropism, it has been associated with atherosclerosis and acute transplant rejection.…”

Section: Introductionmentioning

confidence: 99%

Epidemiology of Human Cytomegalovirus (HCMV) in an urban region of Germany: what has changed?

Lübeck

Doerr

Rabenau

2009

Med Microbiol Immunol

Self Cite

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Since the dynamics of transmission of human cytomegalovirus (HCMV) have not been clarified yet, we assessed a possible change in HCMV seroprevalence in Frankfurt am Main, Germany during the past twenty years and tried to detect variables with an impact on epidemiology. Between 1/1/1988 and 10/15/2008, a total of 54443 serum samples were collected for routine diagnostics and analyzed using Enzygnost Anti HCMV-IgG enzyme immunoassay (Siemens/Dade Behring, Marburg, Germany). Two decades, 1/1/1988-12/31/1997 and 1/1/1998-10/15/2008, and several groups (type of health insurance, gender, age, HIV-status) were evaluated to assess changes in seroprevalence. Regarding both decades, the overall age-adjusted prevalence of HIV-negative patients dropped from 63.70% (confidence interval (CI) 95% 63.15-64.25) to 57.25% (CI 95% 56.57-57.93; P < 0.0001). Private health insurance (PHI) patients showed significant lower HCMV seroprevalences than members of obligatory health insurances (OHI) in both decades (1988-1997: PHI = 55.79%, OHI = 64.27%; P < 0.0001; 1998-1908: PHI = 47.02%, OHI = 58.74%; P < 0.0001). Furthermore, comparing the two decades, there was generally a gender-specific statistically significant decrease in HCMV seroprevalence for males (63.54-55.54%) and females (63.83-58.73%) as well as for members of PHI and OHI (PHI males: 57.59% to 47.19%, PHI females 54.10-46.80%; OHI males: 64.00-57.06%, OHI females 64.50-60.11%). Also, while female HIV-positive patients showed significant difference in HCMV seroprevalence between the two decades (83.17 and 87.80%, P = 0.023), there was no significant difference in male patients with HIV (88.76 and 87.32% in the first and second decade, respectively (P = 0.196). The cumulative HCMV prevalence of all HIV-negative patients tested in the past 20 years demonstrates a biphasic, age-related rise of HCMV seroprevalence throughout all age-groups. The seroprevalence of HCMV has declined between 1988-1997 and 1998-2008 in Frankfurt am Main, Germany. The decline varied between different age-groups. HCMV prevalence correlates with the type of health insurance, gender, age, and HIV-status.

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Thrombin induces Sp1-mediated antiviral effects in cytomegalovirus-infected human retinal pigment epithelial cells

Cited by 9 publications

References 48 publications

Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells

Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells

Effects of Thrombin on RPE Cells Are Mediated by Transactivation of Growth Factor Receptors

Epidemiology of Human Cytomegalovirus (HCMV) in an urban region of Germany: what has changed?

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