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Analysis and comparison of the glycoproteomic phenotype of TLR4- and TLR2-induced tolerance in human monocytes
Endotoxin tolerance of human monocytes contributes to sepsis-induced immunosuppression, a leading cause of sepsis-related deaths worldwide. Although several studies already demonstrated distinct alterations of cytokine expression, phagocytotic capability and expression changes of particular receptor- and glycoproteins to be linked with the tolerant state in human monocytes, no study investigated changes of the whole glycoproteome on a global level. Due to the fact that most membrane-bound receptors are glycosylated, the characterization of the tolerant monocyte cell state by glycoproteomics using tandem mass spectrometry (LC-MS/MS) might reveal new and useful markers to distinguish tolerant from naϊve cells and can provide possible new targets for improving immune-modulatory therapies. In this doctoral thesis, (a) PAMPs binding to cell surface-expressed pattern recognition receptors (PRRs) (TLR4 agonist LPS, TLR2/1 agonist Pam3CSK and TLR2/6 agonist MALP2), (b) PAMPs binding to intracellular PRR (NOD- like receptor (NLR) ligands 1 and 2; iE-DAP and MDP) and (c) the alarmin S100A12, signaling via the receptor for advanced glycation endproducts (RAGE) and TLR4, were examined for their capability to induce the monocyte tolerant state. Qualitative and quantitative analysis of glycoprotein expression changes in purified monocytes of three different peripheral blood donors were assessed with and without LPS-, Pam3CSK- and MALP2-stimulation and analyzed in the naϊve and tolerant state. Tolerance was measured by restimulation with LPS of monocytes that were prestimulated with adjusted concentrations of either LPS, Pam3CSK or MALP2. Prestimulation with all three PRR agonists led to highly decreased expression of the pro-inflammatory cytokines TNF-α and IL-6, which is consistent with the cells entering a tolerant state. NLR ligands iE-DAP and MDP induced only weak pro-inflammatory responses in human monocytes and none of the NLR ligands demonstrated a reduction of TNF-α expression in subsequent LPS challenges. ...
Analysis and comparison of the glycoproteomic phenotype of TLR4- and TLR2-induced tolerance in human monocytes
Endotoxin tolerance of human monocytes contributes to sepsis-induced immunosuppression, a leading cause of sepsis-related deaths worldwide. Although several studies already demonstrated distinct alterations of cytokine expression, phagocytotic capability and expression changes of particular receptor- and glycoproteins to be linked with the tolerant state in human monocytes, no study investigated changes of the whole glycoproteome on a global level. Due to the fact that most membrane-bound receptors are glycosylated, the characterization of the tolerant monocyte cell state by glycoproteomics using tandem mass spectrometry (LC-MS/MS) might reveal new and useful markers to distinguish tolerant from naϊve cells and can provide possible new targets for improving immune-modulatory therapies. In this doctoral thesis, (a) PAMPs binding to cell surface-expressed pattern recognition receptors (PRRs) (TLR4 agonist LPS, TLR2/1 agonist Pam3CSK and TLR2/6 agonist MALP2), (b) PAMPs binding to intracellular PRR (NOD- like receptor (NLR) ligands 1 and 2; iE-DAP and MDP) and (c) the alarmin S100A12, signaling via the receptor for advanced glycation endproducts (RAGE) and TLR4, were examined for their capability to induce the monocyte tolerant state. Qualitative and quantitative analysis of glycoprotein expression changes in purified monocytes of three different peripheral blood donors were assessed with and without LPS-, Pam3CSK- and MALP2-stimulation and analyzed in the naϊve and tolerant state. Tolerance was measured by restimulation with LPS of monocytes that were prestimulated with adjusted concentrations of either LPS, Pam3CSK or MALP2. Prestimulation with all three PRR agonists led to highly decreased expression of the pro-inflammatory cytokines TNF-α and IL-6, which is consistent with the cells entering a tolerant state. NLR ligands iE-DAP and MDP induced only weak pro-inflammatory responses in human monocytes and none of the NLR ligands demonstrated a reduction of TNF-α expression in subsequent LPS challenges. ...
Analysis and comparison of the glycoproteomic phenotype of TLR4- and TLR2-induced tolerance in human monocytes
Behnert, Andrea (author) / Slevogt, Hortense / Lepenies, Bernd / König, Rainer
2018-01-01
Theses
Electronic Resource
English
Monoclonal Antibody Reactive with Human Monocytes
| British Library Online Contents | 1992
Influence of NPT 15392 on activity of human monocytes
| Elsevier | 1985