Lipopolysaccharide- and p38 MAPK-mediated signaling of the Heme oxygenase-1 (HO-1) gene in macrophages
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Monocytes or macrophages are crucial regulators of inflammation. Intracellular signaling in macrophages is tightly regulated to ensure that they do not undergo excessive activation, which may lead to chronic inflammation accompanied with potential damage to the host tissue. Induction of HO-1 in macrophages has been shown to have potent immunomodulatory properties.In this thesis two different signalling mechanisms are described which lead to the induction of HO-1 in macrophages. In the first part the signalling pathway leading to the induction of HO-1 via toll-like receptor (TLR)4 by the classical pro-inflammatory stimulus lipopolysaccharide (LPS) is described. The second part of this thesis deals with the induction of HO-1 caused by the inhibition of the mitogen activated protein kinase (MAPK) p38.Induction of HO-1 by LPS in macrophages has been described earlier, but the exact regulatory mechanisms of this pathway are not well understood. In this thesis it is shown that Bruton s tyrosine kinase (Btk) mediates the LPS-induction of HO-1. LPS-dependent induction of HO-1 was blocked in macrophages treated with the Btk inhibitor, LFM-A13 or in Btk alveolar macrophages. Promoter studies and quantitative real time PCR studies revealed a transcriptional regulatory mechanism. Btk was shown to mediate the production of ROS and activation of the transcription factor Nrf2.p38 MAPK inhibition is shown to increase the expression of HO-1. This was rather surprising, because activation of p38 MAPK has earlier been shown to mediate HO-1 induction caused by various stimuli. This increase in HO-1 expression was also observed in p38mouse embryonic fibroblasts. Further analysis revealed that p38 inhibition leads to an increased production of reactive oxygen species (ROS) and activation of Nrf2. Furthermore, ERK MAPK was also shown to be involved in this pathway.Taken together, this thesis demonstrates that signaling to HO-1 in macrophages is primarily mediated by the transcription factor Nrf2. Further studies to unravel the regulation of this gene may help to develop novel strategies for clinical intervention in inflammatory disorders.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler