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Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06 Podcast
The cardiovascular hormone ANP interferes with LPS-induced early inflammatory pathways in vitro and in vivo

The cardiovascular hormone ANP interferes with LPS-induced early inflammatory pathways in vitro and in vivo

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06 vor 20 Jahren

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Altogether, we have proven that ANP mediated effects are diverse
yet similar in different organs derived from endotoxemic mice and
in isolated blood leukocytes. These ANP mediated interactions are
proceeding at the onset of LPS-induced inflammation and sepsis.
Primarily, we can clearly demonstrate that ANP preconditioning in
endotoxemic mice yields TNF-alpha m-RNA reduction, determined in
the spleen as well as in the liver. As investigated in whole liver
tissue, ANP preconditioning mediates its beneficial effects by
reducing LPS-induced transcription factor NF-kappaB activation.
This reduction is caused by decreased phosphorylation of the
NF-kappaB inhibitory factor IkappaBalpha, proximately leading to
impaired degradation of IkappaBalpha protein. Thus, enhanced
IkappaBalpha protein level in the cytosol prevent NF-kappaB
translocation into the nucleus, and subsequently transcription
factor activity and gene expression. These effects might be caused
by or lead to the reduction in TNF-alpha gene expression, finally
preventing liver failure. Secondly, besides the transcriptional
regulation of TNF-aplha gene expression determined in spleen and
liver tissue, we focused on ANP mediated effects in LPS stimulated
murine and human blood derived leukocytes. Following LPS
stimulation, we observed reduced total TNF-alpha protein levels as
well as decreased TNF-alpha amounts on the cell-surface in ANP
preconditioned blood leukocytes, respectively monocytes and
neutrophils. These initial investigations indicate that the reduced
TNF-alpha protein levels in leukocytes might either be evoked by
interference of ANP in transcriptional or posttranscriptional
processes. Eventually, due to its effects on key events of cell
activation, such as the reduction of LPS-induced TNF-alpha
expression, ANP may represent a promising beneficial autocrine
substance in modulating early inflammatory signaling pathways.