genomewide characterization of host-pathogen interactions by ...

Maren Depke
Discussion and Conclusions
reduced. Thus, data from the murine psychological stress model indicate that leukocyte
migration associated molecules were increasingly transcribed already after acute stress.
However, leukocyte infiltration into hepatic tissue was not measurable at this particular moment
immediately after a single stress exposure but this may be due to the point in time of data
acquisition which was chosen. Other authors showed leukocyte recruitment into the liver 3−6 h
after hepatic ischemia/reperfusion (Zwacka et al. 1997) or 2−4 h after initiation of an acute phase
response (APR) following brain injury (Campbell et al. 2003). Therefore, one can propose that cell
recruitment into the liver may be detectable in the next few hours after termination of acute
stress, which remains to be elucidated in further experiments, and later manifests during
repeated stress exposure as shown by the data of chronically stressed mice.
An invasion of inflammatory cells such as neutrophils and macrophages into tissue is often
associated with increased release of proinflammatory cytokines, which in turn enhance
catabolism and stimulate the hypothalamus-pituitary-adrenal axis (Bartolomucci 2007, Herold et
al. 2006, Lundberg 2005). Although increased expression of cytokine genes in the liver was not
shown, plasma glucocorticoids levels were increased after both acute and chronic psychological
stress exposure causing up-regulation of glucocorticoid-inducible genes, such as acute phase
proteins (Kiank et al. 2006, Depke et al. 2008). In line with these data after chronic stress, Yoo
and Desiderio found increased expression of several APR markers, including C-reactive protein
(CRP), serum amyloid A proteins, lipocalins or orsomucoid at 3 h, 6 h and 12 h after low-dose
bolus application of LPS (Yoo/Desiderio 2003), which can serve as a model of minute bacterial
translocation. Acute phase proteins (APPs) have several immune and metabolic regulatory
functions such as enhancing the antimicrobial response: CRP can opsonize microorganisms and
activate the complement system (Casey et al. 2008, Mold/Du Clos 2006), apolipoproteins, or
lipocalin 2 regulate the cholesterol transport, endotoxin scavenging, and free radical production
(Levels et al. 2003, Roudkenar et al. 2007, Tseng et al. 2004, Wurfel et al. 1994). In contrast, other
APPs such as haptoglobin, which were found to be induced after repeated stress, have strong
anti-inflammatory effects (Tseng et al. 2004) and therewith may contribute to the reduced
antibacterial defense of chronically stressed mice, which even suffered from long-lasting bacterial
infiltration into liver and lung (Kiank et al. 2008). Along with the increased expression of APR
genes, high expression levels of cytochrome P450 enzymes were detected which normally are
suppressed during an APR (Siewert et al. 2000). This can be explained by findings of others who
showed that hepatic levels of P450 enzymes increased during fasting and then became resistant
to the suppression during inflammatory states (Iber et al. 2001, Morgan 2001). Therefore, the
increased cytochrome expression in the chronic stress model may be a part of the hypercatabolic
stress response that overcomes an inflammation-induced repression of P450 enzyme expression.
An activation of cytochromes enhances the generation of reactive oxygen species (ROS) (Morgan
2001, Zangar et al. 2004). Oxidative stress, in turn, can cause lipid peroxidation or increase
protein carbonyl content (Ermak/Davies 2001, Garg/Aggarwal 2002, Ott et al. 2007, Zangar et al.
2004), which was also observed in plasma and liver after acute stress exposure in this study.
Carbonylated proteins are likely non-functional and prone to degradation. Oxidant-induced
damage in hepatic tissue of acutely stressed mice is supported by the finding that several cell
cycle and cell death associated genes such as Cdkn1a, Gadd45b, Gadd45g or Fkbp5 were already
induced immediately after acute stress – a moment when detection of cellular apoptosis is
probably too early – and remained highly expressed after repeated stress when increased
hepatocyte apoptosis was measured.
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