genomewide characterization of host-pathogen interactions by ...

Maren Depke
Discussion and Conclusions
However, tissue protective mechanisms seem to be active in the liver of chronically stressed
mice as well. These include an increased expression of Alas1, which functions as an oxygen
radical scavenger (Kaliman et al. 2005), and of glutaredoxin and glutathione S-transferase alpha
that are ubiquitous proteins with redox-active cysteine-groups (Garg/Aggarwal 2002,
Haddad/Harb 2005, Jurado et al. 2003). Increased expression of these anti-oxidant enzymes may
compensate and protect from further oxidative stress-induced damage. Therefore, long lasting
increased glucocorticoid levels, which are highly potent mediators of inducing apoptotic
processes, are proposed to be the main mediators of hepatic cell death in chronically stressed
animals (Ayroldi et al. 2007, Herold et al. 2006), but this remains to be elucidated.
The liver has an extraordinary ability to regenerate or heal itself by replacing or repairing
injured tissue (Fausto et al. 2006, Klein et al. 2005, Riehle et al. 2008). Hepatic gene expression
profiling after acute and chronic stress included increased hepatic expression of protein tyrosine
phosphatase 4a1, which initiates the liver regeneration response, and of IL-6 receptor whose
ligation was shown to be protective during liver injury (Fausto et al. 2006, Klein et al. 2005, Riehle
et al. 2008). Thus, acute stress-induced up-regulation of genes coding for tissue destructive
mechanisms associated with oxidative stress were counter-regulated by increased expression of
anti-oxidative and tissue regenerative genes which may have protected mice from more severe
damage of hepatic tissue during chronic psychological stress.
In summary, the data show that already acute stress exposure induces hepatic mRNA
expression of several LPS and glucocorticoid-sensitive immune response genes as well as of
apoptosis-related markers. Besides increased oxidative stress, this does not cause measurable
immune alterations or cell death immediately after stress exposure. However, when stress is
repeated and becomes chronic, reduced antigen presentation and altered gene expression of
cellular signaling molecules of immune cells along with an ongoing expression of apoptosisrelated
molecules may contribute to biologically relevant immunosuppression which was
demonstrated by a reduced ability of stressed mice to clear bacterial infections from the liver.
Moreover, the induction of cell protective and liver regenerative genes in hepatic tissue of
chronically stressed mice give strong evidence that counter-regulatory mechanisms are activated
to prevent further hepatocyte damage in these animals.
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