TIMP3 checks inflammation

Black, Roy A.

doi:10.1038/ng0904-934

Cited by 76 publications

(60 citation statements)

References 15 publications

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“…Timp3 was upregulated at all three time points investigated. It is located in the extracellular matrix and can control levels of TNF-a by inhibition of the TNF-a-converting enzyme (TACE) (Black, 2004).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of host responses in mouse lungs following aerosol infection with type A Francisella tularensis

Andersson

Hartmanová

KuoLee

et al. 2006

Journal of Medical Microbiology

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Tularaemia caused by inhalation of type A Francisella tularensis bacteria is one of the most aggressive infectious diseases known, but the reasons for the very rapid spread of the organism from the lungs to internal organs and the ensuing mortality are unknown. The present study used the mouse model to examine in detail the host immune response in the lung. After an aerosol challenge with 20 c.f.u. of the type A strain FSC033, all mice developed clinical signs of severe disease, showed weight loss by day 4 of infection and died the next day. Histopathological findings in the lung revealed acute inflammation and intense vasculitis and perivasculitis on day 4. Gene transcriptional changes in the mouse lung samples were examined on days 1, 2 and 4 of infection using a cDNA microarray with 20 600 mouse clones representing 18 500 genes. In total, 424 genes were found to be differentially expressed, some of which were both up-and downregulated at different time points, 192 of which were upregulated and 234 of which were downregulated for at least one time point. A high percentage of selected genes identified by the microarray analysis were confirmed to be differentially regulated by quantitative real-time PCR. Categorization of the differentially expressed genes showed that those preferentially involved in host immune responses were activated extensively on day 4 but hardly or not at all on days 1 and 2. Further analysis revealed that several of the genes upregulated on day 4 are known to depend on gamma interferon or tumour necrosis factor alpha for their regulation. In keeping with this finding, tumour necrosis factor alpha and gamma interferon levels were found to be increased significantly in bronchoalveolar lavage on day 4.

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Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of host responses in mouse lungs following aerosol infection with type A Francisella tularensis

Andersson

Hartmanová

KuoLee

et al. 2006

Journal of Medical Microbiology

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“…Studies reported that elevated cell and cytokine-mediated markers of inflammation, including C-reactive protein (CRP), fibrinogen and various cytokines are associated with periodontal disease (Black 2004). The same pro-inflammatory markers in periodontal disease have also been linked with atherothrombogenesis (Danesh et al 2000).…”

Section: The Link To Systemic Conditionsmentioning

confidence: 99%

Infection and inflammatory mechanisms

Dyke

Winkelhoff

2013

Journal of Periodontology

147

123

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This introductory article examines the potential mechanisms that may play a role in the associations between periodontitis and the systemic conditions being considered in the EFP/AAP Workshop in Segovia, Spain. Three basic mechanisms have been postulated to play a role in these interactions; metastatic infections, inflammation and inflammatory injury, and adaptive immunity. The potential role of each alone and together is considered in in vitro and animal studies and in human studies when available. This is not a systematic or critical review, but rather an overview of the field to set the stage for the critical reviews in each of the working groups.

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“…In addition to TNF and its receptors, EGFR ligands (HB-EGF, TGF-α, amphiregulin) are critical substrates of ADAM17, which is inhibited by TIMP3 (18,36,37). Adam17 -/-mice phenocopy Egfr -/-mice, and hepatic deletion of Egfr results in failed liver regeneration, indicating its requirement as a mitogenic stimulus for hepatocyte division (38).…”

Section: Tnfr1 Shedding Dampens Jnk Phosphorylation and Nf-κb Activatmentioning

confidence: 99%

Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice

et al. 2010

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The cell death receptor Fas plays a role in the establishment of fulminant hepatitis, a major cause of druginduced liver failure. Fas activation elicits extrinsic apoptotic and hepatoprotective signals; however, the mechanisms by which these signals are integrated during disease are unknown. Tissue inhibitor of metalloproteinases 3 (TIMP3) controls the critical sheddase a disintegrin and metalloproteinase 17 (ADAM17) and may dictate stress signaling. Using mice and cells lacking TIMP3, ADAM17, and ADAM17-regulated cell surface molecules, we have found that ADAM17-mediated ectodomain shedding of TNF receptors and EGF family ligands controls activation of multiple signaling cascades in Fas-induced hepatitis. We demonstrated that TNF signaling promoted hepatotoxicity, while excessive TNF receptor 1 (TNFR1) shedding in Timp3 -/-mice was protective. Compound Timp3 -/-Tnf -/-and Timp3 -/-Tnfr1 -/-knockout conferred complete resistance to Fas-induced toxicity. Loss of Timp3 enhanced metalloproteinase-dependent EGFR signaling due to increased release of the EGFR ligands TGF-α, amphiregulin, and HB-EGF, while depletion of shed amphiregulin resensitized Timp3 -/-hepatocytes to apoptosis. Finally, adenoviral delivery of Adam17 prevented acetaminophen-induced liver failure in a clinically relevant model of Fas-dependent fulminant hepatitis. These findings demonstrate that TIMP3 and ADAM17 cooperatively dictate cytokine signaling during death receptor activation and indicate that regulated metalloproteinase activity integrates survival and death signals during acute hepatotoxic stress.

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TIMP3 checks inflammation

Cited by 76 publications

References 15 publications

Transcriptional profiling of host responses in mouse lungs following aerosol infection with type A Francisella tularensis

Transcriptional profiling of host responses in mouse lungs following aerosol infection with type A Francisella tularensis

Infection and inflammatory mechanisms

Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice

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