Toxic epidermal necrolysis (TEN) represents a rare drug-induced autoimmune reaction with delayed-type hypersensitivity that initiates the process of developing massive keratinocyte apoptosis, dominantly in the dermoepidermal junction. Although the etiopathophysiology has not yet been fully elucidated, the binding of Fas ligand (FasL, CD95L) to the Fas receptor (CD95) was shown to play a key role in the induction of apoptosis in this syndrome. The knowledge of the role of immunoglobulin G (IgG) in inhibition of Fas-mediated apoptosis contributed to the introduction of i.v. Ig (IVIg) in the therapy of TEN patients. Despite great enthusiasm for this therapy at the end of the 1990s, subsequent studies in various populations and meta-analyses could not unequivocally confirm the efficacy of the IVIg-based treatment concept. Today, therefore, we are faced with the dilemmas of how to adjust therapy of TEN patients most effectively, which patients could benefit from IVIg therapy and what dose of the preparation should be administrated. The ground-breaking question is: do the host genetic profiles influence the responsiveness and side-effects of IVIg therapy in TEN patients? Based on recent pharmacological, immunological and genetic findings, we suggest that the variability of IVIg therapy outcomes in TEN patients may be related to functional variants in Fas, FasL and Fc-γ receptor genes. This novel concept could lead to improved quality of care for patients with TEN, facilitating personalized therapy to reduce mortality.
Elimination of the interdigital web is considered to be the classical model for assessing apoptosis. So far, most of the molecules described in the process have been connected to the intrinsic (mitochondrial) pathway. The extrinsic (receptor mediated) apoptotic pathway has been rather neglected, although it is important in development, immunomodulation and cancer therapy. This work aimed to investigate factors of the extrinsic apoptotic machinery during interdigital regression with a focus on three crucial initiators: Fas, Fas ligand and caspase-8. Immunofluorescent analysis of mouse forelimb histological sections revealed abundant expression of these molecules prior to digit separation. Subsequent PCR Array analyses indicated the expression of several markers engaged in the extrinsic pathway. Between embryonic days 11 and 13, statistically significant increases in the expression of Fas and caspase-8 were observed, along with other molecules involved in the extrinsic apoptotic pathway such as Dapk1, Traf3, Tnsf12, Tnfrsf1A and Ripk1. These results demonstrate for the first time the presence of extrinsic apoptotic components in mouse limb development and indicate novel candidates in the molecular network accompanying the regression of interdigital tissue during digitalisation.
- MeSH
- antigeny CD95 analýza genetika metabolismus MeSH
- apoptóza * MeSH
- kaspasa 8 analýza genetika metabolismus MeSH
- ligand Fas nedostatek genetika metabolismus MeSH
- mitochondrie metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- přední končetina cytologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články 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
- MeSH
- antigeny CD95 fyziologie genetika krevní zásobení MeSH
- apoptóza genetika účinky záření MeSH
- buněčné linie MeSH
- finanční podpora výzkumu jako téma MeSH
- lidé MeSH
- nádorový supresorový protein p53 antagonisté a inhibitory fyziologie genetika MeSH
- nádory prsu genetika metabolismus MeSH
- upregulace fyziologie účinky záření MeSH
- Check Tag
- lidé MeSH
