Mechanism of LPS-induced sFlt-1 Expression in Macrophage
Date Issued
2008
Date
2008
Author(s)
Lee, Ming-Cheng
Abstract
Upon pathogen infection, the activated monocytes or macrophages secret a variety of cytokines to orchestrate a complicated immune response in the host. However, overwhelming systemic inflammation may result in septic diseases which cause organ dysfunction and eventually lead to death. Nearly one million cases of severe sepsis are diagnosed and cost approximately ten billion US dollars each year in the United States. Development of effective therapies for septic diseases is a high priority task. Our previous studies found that LPS treatment could induce sFlt-1 secretion in macrophage and exogenous sFlt-1 treatment could decrease the mortality in LPS-induced septic mouse model. However, the molecular mechanism of LPS-induced sFlt-1 expression is still not understood. In this thesis, we found that in the murine RAW264.7 cells, as well as in primary human monocytes/macrophages, pretreatment with a general PKC inhibitor GF109203X or with a novel PKCδ inhibitor rottlerin or overexpression of a kinase-inactive form of PKCδ (K376R) eliminated LPS-induced sFlt-1 expression and augmented LPS-induced VEGF expression at both the protein and the transcription levels. These data suggest that PKCδ signaling is involved in LPS-induced sFlt-1expression and serves as a negative mediator in LPS-induced VEGF expression in macrophages.tatin, an inhibitor of HMG-CoA reductase, exert pleiotropic effects independent of cholesterol reduction. It is noted that the mortality and morbidity of sepsis patients treated with statin are reduced. However, the molecular mechanism of anti-inflammatory effect for this drug is not fully understood. In this thesis, we demonstrated that simvastatin enhanced both LPS-induced sFlt-1 mRNA and protein expressions in murine RAW 264.7 macrophages. Co-treatment with mevalonate or its metabolites geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP), blocked the effect of simvastatin. These data suggested that protein geranylgeranylation may play a crucial role in the regulation of sFlt-1 in response to LPS. We also found that simvastatin pretreatment prolonged ERK1/2 phosphorylation in response to LPS stimulation. Furthermore, blockage of ERK signaling by U0126 inhibited sFlt-1 secretion in response co-treatment of LPS and simvastatin. Our results indicate that both PKCδ activation and mevalonate pathway play important roles in LPS-induced sFlt-1 expression in murine RAW 264.7 macrophages.
Subjects
sepsis
soluble Flt-1
VEGF
Protein kinase C
Statin
SDGs
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