The cytokine TNF can trigger highly proinflammatory RIPK1-dependent cell death. Here, we show that the two adapter proteins, TANK and AZI2, suppress TNF-induced cell death by regulating the activation of TBK1 kinase. Mice lacking either TANK or AZI2 do not show an overt phenotype. Conversely, animals deficient in both adapters are born in a sub-Mendelian ratio and suffer from severe multi-organ inflammation, excessive antibody production, male sterility, and early mortality, which can be rescued by TNFR1 deficiency and significantly improved by expressing a kinase-dead form of RIPK1. Mechanistically, TANK and AZI2 both recruit TBK1 to the TNF receptor signaling complex, but with distinct kinetics due to interaction with different complex components. While TANK binds directly to the adapter NEMO, AZI2 is recruited later via deubiquitinase A20. In summary, our data show that TANK and AZI2 cooperatively sustain TBK1 activity during different stages of TNF receptor assembly to protect against autoinflammation.

• MeSH
• adaptorové proteiny signální transdukční * metabolismus   genetika   MeSH
• buněčná smrt MeSH
• endopeptidasy MeSH
• intracelulární signální peptidy a proteiny metabolismus   genetika   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši knockoutované * MeSH
• myši MeSH
• protein-serin-threoninkinasy * metabolismus   genetika   MeSH
• receptory TNF - typ I * metabolismus   genetika   MeSH
• serin-threoninkinasy interagující s receptory * metabolismus   genetika   MeSH
• signální transdukce MeSH
• TNF-alfa * metabolismus   MeSH
• TNFAIP3 metabolismus   genetika   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its regulatory adapter molecule iRhom2 for bacterial uptake by phagocytes. Inhibition of metalloproteinase activity led to increased phagocytosis of pHrodo labelled Gram-negative and -positive bacteria (E. coli and S. aureus, respectively) by human and murine monocytic cell lines or primary phagocytes. Bone marrow-derived macrophages showed enhanced uptake of heat-inactivated and living E. coli when they lacked either ADAM17 or iRhom2 but not upon ADAM10-deficiency. In monocytic THP-1 cells, corresponding short hairpin RNA (shRNA)-mediated knockdown confirmed that ADAM17, but not ADAM10, promoted phagocytosis of E. coli. The augmented bacterial uptake occurred in a cell autonomous manner and was accompanied by increased release of the chemokine CXCL8, less TNFα release and only minimal changes in the surface expression of the receptors TNFR1, TLR6 and CD36. Inhibition experiments indicated that the enhanced bacterial phagocytosis after ADAM17 knockdown was partially dependent on TNFα-activity but not on CXCL8. This novel role of ADAM17 in bacterial uptake needs to be considered in the development of ADAM17 inhibitors as therapeutics.

• MeSH
• antigeny CD36 genetika   metabolismus   MeSH
• Escherichia coli patogenita   MeSH
• fagocytóza MeSH
• fagocyty metabolismus   mikrobiologie   MeSH
• interleukin-8 metabolismus   MeSH
• intracelulární signální peptidy a proteiny genetika   metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• myši MeSH
• protein ADAM17 genetika   metabolismus   MeSH
• RAW 264.7 buňky MeSH
• receptory TNF - typ I genetika   metabolismus   MeSH
• Staphylococcus aureus patogenita   MeSH
• THP-1 buňky MeSH
• toll-like receptor 6 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The linear-ubiquitin chain assembly complex (LUBAC) modulates signalling via various immune receptors. In tumour necrosis factor (TNF) signalling, linear (also known as M1) ubiquitin enables full gene activation and prevents cell death. However, the mechanisms underlying cell death prevention remain ill-defined. Here, we show that LUBAC activity enables TBK1 and IKKε recruitment to and activation at the TNF receptor 1 signalling complex (TNFR1-SC). While exerting only limited effects on TNF-induced gene activation, TBK1 and IKKε are essential to prevent TNF-induced cell death. Mechanistically, TBK1 and IKKε phosphorylate the kinase RIPK1 in the TNFR1-SC, thereby preventing RIPK1-dependent cell death. This activity is essential in vivo, as it prevents TNF-induced lethal shock. Strikingly, NEMO (also known as IKKγ), which mostly, but not exclusively, binds the TNFR1-SC via M1 ubiquitin, mediates the recruitment of the adaptors TANK and NAP1 (also known as AZI2). TANK is constitutively associated with both TBK1 and IKKε, while NAP1 is associated with TBK1. We discovered a previously unrecognized cell death checkpoint that is mediated by TBK1 and IKKε, and uncovered an essential survival function for NEMO, whereby it enables the recruitment and activation of these non-canonical IKKs to prevent TNF-induced cell death.

• MeSH
• buněčná smrt účinky léků   MeSH
• buňky A549 MeSH
• fosforylace účinky léků   MeSH
• HeLa buňky MeSH
• kinasa I-kappa B metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• myši knockoutované MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• receptory TNF - typ I metabolismus   MeSH
• serin-threoninkinasy interagující s receptory metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• TNF-alfa farmakologie   MeSH
• ubikvitinace účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Death ligands and their tumor necrosis factor receptor (TNFR) family receptors are the best-characterized and most efficient inducers of apoptotic signaling in somatic cells. In this study, we analyzed whether these prototypic activators of apoptosis are also expressed and able to be activated in human pluripotent stem cells. We examined human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC) and found that both cell types express primarily TNF-related apoptosis-inducing ligand (TRAIL) receptors and TNFR1, but very low levels of Fas/CD95. We also found that although hESC and hiPSC contain all the proteins required for efficient induction and progression of extrinsic apoptotic signaling, they are resistant to TRAIL-induced apoptosis. However, both hESC and hiPSC can be sensitized to TRAIL-induced apoptosis by co-treatment with protein synthesis inhibitors such as the anti-leukemia drug homoharringtonine (HHT). HHT treatment led to suppression of cellular FLICE inhibitory protein (cFLIP) and Mcl-1 expression and, in combination with TRAIL, enhanced processing of caspase-8 and full activation of caspase-3. cFLIP likely represents an important regulatory node, as its shRNA-mediated down-regulation significantly sensitized hESC to TRAIL-induced apoptosis. Thus, we provide the first evidence that, irrespective of their origin, human pluripotent stem cells express canonical components of the extrinsic apoptotic system and on stress can activate death receptor-mediated apoptosis.

• MeSH
• antigeny CD95 genetika   metabolismus   MeSH
• apoptóza účinky léků   MeSH
• buněčná diferenciace MeSH
• embryonální kmenové buňky cytologie   účinky léků   metabolismus   MeSH
• FLIP (buněčný) antagonisté a inhibitory   genetika   metabolismus   MeSH
• harringtoniny farmakologie   MeSH
• inhibitory syntézy proteinů farmakologie   MeSH
• kaspasa 3 genetika   metabolismus   MeSH
• kaspasa 8 genetika   metabolismus   MeSH
• lidé MeSH
• malá interferující RNA genetika   metabolismus   MeSH
• pluripotentní kmenové buňky cytologie   účinky léků   metabolismus   MeSH
• proliferace buněk MeSH
• protein MCL-1 genetika   metabolismus   MeSH
• protein TRAIL genetika   metabolismus   farmakologie   MeSH
• receptory TNF - typ I genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• signální transdukce MeSH
• synergismus léků MeSH
• TRAIL receptory genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The most frequent cause of ischaemic heart disease is coronary arteriosclerosis. This study was aimed at assessing gene expression of TNFA and its two receptors (TNFR1, TNFR2), as well as determining coronary artery calcium score (CACS) in the context of occurrence of classical risk factors in patients with subclinical atherosclerosis of coronary vessels. The study involved 47 subjects with complaints of chest pain and suspicion of acute coronary syndrome or stable coronary disease. Additionally, CACS was assessed by 64-slice computerized tomography. QRT-PCR molecular studies were performed using RNA isolated from peripheral blood mononuclear cells. Preliminary results of molecular studies on patients with subclinical coronary atherosclerosis revealed a significantly lower numbers of TNFR1 and TNFR2 gene copies as compared with healthy subjects. In addition, it can be demonstrated that among classical risk factors hypertension is of substantial importance in the progression of coronary arteries' calcification, and that in the examined group CACS increases together with the rising number of classical risk factors involved. No correlation was observed, however, between expression of TNFA, TNFR1 and TNFR2 genes and the value of CACS. Conclusions: 1. The occurrence of hypertension facilitates initiation and progression of arteriosclerotic lesions in blood vessels including the coronary ones; the raised number of circulatory disease classical risk factors involved correlates with elevated calcification of coronary arteries as shown by 64-slice computerized tomography scans. 2. Significantly decreased numbers of TNFR1 and TNFR2 gene copies observed in the investigated group may play a significant role in initiation and progression of arteriosclerosis.

• MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• genetická transkripce * MeSH
• koronární cévy metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci koronárních tepen genetika   MeSH
• receptory TNF - typ I genetika   metabolismus   MeSH
• receptory TNF - typ II genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• rizikové faktory MeSH
• senioři MeSH
• TNF-alfa genetika   MeSH
• vápník metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• Crohnova nemoc * diagnóza   farmakoterapie   MeSH
• dospělí MeSH
• latentní tuberkulóza * imunologie   patofyziologie   MeSH
• lidé MeSH
• monoklonální protilátky * farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• Mycobacterium tuberculosis * imunologie   patogenita   růst a vývoj   MeSH
• receptory TNF - typ I * účinky léků   MeSH
• TNF-alfa * antagonisté a inhibitory   fyziologie   MeSH
• tuberkulóza gastrointestinální * diagnóza   etiologie   farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• imunoglobulin G terapeutické užití   MeSH
• lidé MeSH
• nádory epidemiologie   klasifikace   MeSH
• receptory TNF - typ I terapeutické užití   MeSH
• rekombinantní fúzní proteiny terapeutické užití   MeSH
• revmatoidní artritida farmakoterapie   MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• multicentrická studie MeSH

• MeSH
• imunoglobulin G terapeutické užití   MeSH
• lidé MeSH
• monoklonální protilátky terapeutické užití   MeSH
• placebo terapeutické užití   MeSH
• psoriatická artritida farmakoterapie   MeSH
• receptory TNF - typ I terapeutické užití   účinky léků   MeSH
• rekombinantní fúzní proteiny terapeutické užití   MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• randomizované kontrolované studie MeSH

BACKGROUND: The fine balance in cellular life and death is affected by a number of tightly regulated, direct signals that can help to turn the balance either in favor of or against the ultimate fate. Among the most prominent players in the field of the extracellular signals leading to cell death, preferentially through induction of apoptosis belong several receptors from so-called Death Receptors group of the Tumour Necrosis Factors Receptors (TNFR) family. METHODS AND RESULTS: Over 15 years of the research on activation and regulation of the most prominent member of this group - receptors for the ligands TRAIL, FasL and TNFalpha brought not only a detail (and still refining) mechanism of these receptors activation and downstream signaling, but also connected them with the ultimate apoptotic gatekeeper - mitochondria. Mitochondria are, in addition to their essential role as the energy factories also repositories of a cavalry of apoptosis-inducing as well as regulatory proteins. However, in addition to the pro-death signaling, these receptors were also shown under certain circumstances to activate an opposite, pro-proliferative signaling as well as to participate in pro-inflammatory responses. CONCLUSIONS: Thus despite the concerned effort of a number of groups and thousands of published papers, novel roles for the intriguing group of these receptors and their ligands and fine tuning of their signaling still await to be uncovered. This cut-through review will be mainly focused on the prominent death-inducing members of this group - TNFR1, Fas/CD95 and TRAIL receptors.

• MeSH
• antigeny CD95 metabolismus   MeSH
• financování organizované MeSH
• lidé MeSH
• receptory domény smrti metabolismus   MeSH
• receptory TNF - typ I metabolismus   MeSH
• receptory TNF metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• TRAIL receptory metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

Biologická terapie představuje v gastroenterologii významnou součást standardní terapie idiopatických střevních zánětů, kolorektálního karcinomu a uplatňuje se také v léčbě po transplantaci jater. U idiopatických střevních zánětů v současné době lze použít v léčbě Crohnovy nemoci infliximab či adalimumab, při onemocnění ulcerózní kolitidou pouze infliximab. Terapie je soustředěna do center biologické léčby, která garantují správnost indikace a realizaci léčby. Současné indikace umožňují použití biologické terapie u idiopatických střevních zánětů po vyčerpání možností konvenční léčby kortikosteroidy a/nebo imunosupresivy. V terapii kolorektálního karcinomu se ukazují výhodné kombinace bevacizumabu a cetuximabu s konvenční chemoterapií, jejíž účinek potencuje. Použití biologické terapie v hepatologii je již na hranicích transplantologické problematiky, do jejíž kompetence patří také její indikace.

In gastroenterology, biological therapy represents a significant component in the standard treatment for both idiopathic inflammatory bowel disease and colorectal cancer and is also employed following liver transplantation. Currently, the management of idiopathic inflammatory bowel diseases involves the use of infliximab or adalimumab to treat Crohn‘ s disease and the use of infliximab alone to treat ulcerative colitis. Therapy is restricted to biological therapy centres which guarantee correct indication and implementation of treatment. Current indications make possible the use of biological therapy in idiopathic inflammatory bowel diseases once conventional treatment options using corticosteroids and/or immunosuppressives have failed. The combination of bevacizumab and cetuximab with conventional chemotherapy the effect of which is thus potentiated has been shown beneficial in the treatment of colorectal cancer. The use of biological therapy in hepatology is rather an issue for transplantology which is also responsible for its indications.

• MeSH
• biologická terapie metody   škodlivé účinky   MeSH
• Crohnova nemoc farmakoterapie   MeSH
• idiopatické střevní záněty farmakoterapie   MeSH
• imunoglobuliny - Fab fragmenty škodlivé účinky   terapeutické užití   MeSH
• kolorektální nádory farmakoterapie   MeSH
• lidé MeSH
• monoklonální protilátky terapeutické užití   MeSH
• nádory chemicky indukované   MeSH
• neutropenie chemicky indukované   MeSH
• receptory TNF - typ I škodlivé účinky   terapeutické užití   MeSH
• rekombinantní proteiny škodlivé účinky   terapeutické užití   MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• tvorba protilátek účinky léků   MeSH
• ulcerózní kolitida farmakoterapie   MeSH
• Check Tag
• lidé MeSH