RESUMEN
Signaling via death receptor family members such as TNF-R1 mediates pleiotropic biological outcomes ranging from inflammation and proliferation to cell death. Pro-survival signaling is mediated via TNF-R1 complex I at the cellular plasma membrane. Cell death induction requires complex IIa/b or necrosome formation, which occurs in the cytoplasm. In many cell types, full apoptotic or necroptotic cell death induction requires the internalization of TNF-R1 and receptosome formation to properly relay the signal inside the cell. We interrogated the role of the enzyme A disintegrin and metalloprotease 17 (ADAM17)/TACE (TNF-α converting enzyme) in death receptor signaling in human hematopoietic cells, using pharmacological inhibition and genetic ablation. We show that in U937 and Jurkat cells the absence of ADAM17 does not abrogate, but rather increases TNF mediated cell death. Likewise, cell death triggered via DR3 is enhanced in U937 cells lacking ADAM17. We identified ADAM17 as the key molecule that fine-tunes death receptor signaling. A better understanding of cell fate decisions made via the receptors of the TNF-R1 superfamily may enable us, in the future, to more efficiently treat infectious and inflammatory diseases or cancer.
Asunto(s)
Proteína ADAM17/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Proteína ADAM17/antagonistas & inhibidores , Proteína ADAM17/deficiencia , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Muerte Celular , Supervivencia Celular , Endocitosis , Humanos , Células Jurkat , Células MCF-7 , Modelos Biológicos , FN-kappa B/metabolismo , Miembro 25 de Receptores de Factores de Necrosis Tumoral/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/farmacología , Células U937RESUMEN
BACKGROUND: Data of critically ill COVID-19 patients are being evaluated worldwide, not only to understand the various aspects of the disease and to refine treatment strategies but also to improve clinical decision-making. For clinical decision-making in particular, prognostic factors of a lethal course of the disease would be highly relevant. METHODS: In this retrospective cohort study, we analyzed the first 59 adult critically ill Covid-19 patients treated in one of the intensive care units of the University Medical Center Regensburg, Germany. Using uni- and multivariable regression models, we extracted a set of parameters that allowed for prognosing in-hospital mortality. RESULTS: Within the cohort, 19 patients died (mortality 32.2%). Blood pH value, mean arterial pressure, base excess, troponin, and procalcitonin were identified as highly significant prognostic factors of in-hospital mortality. However, no significant differences were found for other parameters expected to be relevant prognostic factors, like low arterial partial pressure of oxygen or high lactate levels. In the multivariable logistic regression analysis, the pH value and the mean arterial pressure turned out to be the most influential prognostic factors for a lethal course.