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Title: The role of the mitogen-activated protein kinases (MAPKs) in endotoxin tolerance
Authors: VOSSIUS, Sofie
Advisors: RAHMOUNI, S.
Issue Date: 2007
Publisher: tUL
Abstract: The innate immune response uses pattern recognition receptors, such as TLRs, to recognize highly conserved structures on pathogens. Stimulation of these TLRs induces several signal transduction pathways like NF- B and MAPK signaling pathways. Activation of these pathways is important to induce the production of pro-inflammatory cytokines and helps to induce the adaptive immune response. In human, there are three well known MAPKs pathways: ERK1/2, p38 and JNK1/2. They become activated upon phosphorylation on their threonine and tyrosine residues. Termination of these pathways is important to prevent overproduction of pro-inflammatory cytokines which can cause septic shock and even death. MAPK phosphatases (MKPs) are responsible for dephosphorylating and thereby inactivating MAPKs. However, pretreatment with LPS for example, can render immune cells tolerant to a second exposure with the same endotoxin. This phenomenon is known as endotoxin tolerance and has also been observed in septic shock patients. Tolerant cells fail to produce proinflammatory cytokines to eliminate the pathogen which caused the endotoxin stimulus; this makes patients more susceptible to a secondary infection which has severe detrimental effects. To investigate the molecular mechanisms of endotoxin tolerance and more precisely the role of the MAPKs and MKPs, we started setting up a murine and human in vitro LPS tolerance model using murine macrophages (RAW 264.7) and human monocyte-derived dendritic cells (DCs). The cells were stimulated once for the control condition or twice to induce the tolerance state as was reported in the literature. TNF- cytokine production profile was used as readout because it is well known that tolerant cells fail to produce this cytokine. Indeed, we observed dramatic decreases of TNF- secretion when the macrophage or DCs were challenged twice with LPS but not when these cells were activated once. In the tolerant cells, a lower ERK1/2 and p38 phosphorylation was observed compared to non tolerant cells. As previously reported in the literature, we also observed a stabilization of IkB upon two successive stimulations with LPS while a nice degradation of this protein was induced 30 min after a single LPS stimulation. Finally, we were able to downregulate by almost 50% MKP-1 after transfection with specific siRNA against MKP-1 in RAW 264.7 cells. However, we were not able to conclude if MKP-1 is involved in the LPS-induced tolerance in RAW 264.7 macrophages.
Notes: Master in de Biomedische wetenschappen - Klinische en moleculaire wetenschappen
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Category: T2
Type: Theses and Dissertations
Appears in Collections:Master theses

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