genomewide characterization of host-pathogen interactions by ...

Maren Depke
Discussion and Conclusions
balance in severely ill patients (Demling 2007). Finally, amplified protein breakdown with a loss of
more than 40 % of lean body mass leads to irreversible cell damage (Beale et al. 1999, Demling
2007).
In conclusion, the physiological measurements and hepatic gene expression profiling
demonstrated that highly demanding psychological stress in the absence of injury or infection is
able to induce a severe hypermetabolic syndrome in mice. Such overwhelming wasting condition
can reduce the individual’s resistance to further stressful stimuli such as injury or infection.
The same data set of hepatic gene expression was used to gain deeper insight into hepatic
immune regulatory and cell cycle processes of BALB/c mice, which develop systemic
immunodeficiency with a reduced antibacterial defense after repeated stress exposure (Kiank et
al. 2006, 2007a,b). This second part of the results has been published by Depke et al. in 2009.
Already a single acute stress exposure drastically altered the expression of immune response
and of apoptosis related genes. An activation of immunosuppressive mechanisms in the liver was
measured in both acutely and chronically stressed mice including increased expression of
Tsc22d3 (GILZ, glucocorticoid-induced leucine zipper) and Fkbp5, which both are inducible by
high glucocorticoid levels (Ayroldi et al. 2007, Berrebi et al. 2003, D'Adamio et al. 1997,
Mittelstadt/Ashwell 2001). Tsc22d3 inhibits the expression of CD80 and CD86 co-stimulatory
molecules or toll-like receptor 2 and reduces the production of proinflammatory mediators
(Berrebi et al. 2003, Cohen et al. 2006). Fkbp5, an immunophilin family member, inhibits
calcineurin signaling in lymphocytes and modifies glucocorticoid signaling by binding heat shock
proteins of steroid receptors (Baughman et al. 1995, Sinars et al. 2003). Other B and T
lymphocyte signaling molecules such as protein kinase C ν (Prkcn), or several GTPases showed
altered hepatic mRNA expression in both acutely and chronically stressed mice, respectively.
Importantly, the down-regulation of several IFN-γ inducible genes after acute stress was
amplified by repeated stress exposure. Some of the interferon-inducible mRNA transcripts like
Igtp and Stat1, which were repressed in the liver of chronically stressed mice, encode for host
proteins of well characterized antimicrobial activity (Döffinger et al. 2002, Johnson/Scott 2007,
Martens et al. 2004). Diminished expression of IFN-γ inducible GTPases was shown to be related
to a reduced defense against Listeria monocytogenes and Mycobacterium avium infection
(Martens et al. 2004). Stat1 is important for IFN-γ, IL-6, IL-10, and IL-12 signaling and for
maintaining MHC- and co-stimulatory molecule expression in dendritic cells, which all are
important for the antibacterial response (Döffinger et al. 2002, Johnson/Scott 2007). In line with
this, chronically stressed animals showed a repression of the Stat1 gene and reduced expression
of MHC-molecules along with a heightened susceptibility to bacterial infections (Kiank et al. 2006,
2007b) and an increased spreading of translocated commensals into liver and lung, which went
along with a reduced ex vivo inducibility of IFN-γ (Kiank et al. 2008).
Besides the reduced expression of cellular signaling molecules, genes associated with immune
cell migration and tissue invasion were differentially expressed. These included T cell
chemoattractive peptides such as Cxcl11 and Cxcl12 and neutrophil chemoattractive Cxcl1
(Ghosh et al. 2006, Helbig et al. 2004, Wiekowski et al. 2001) and an increased expression of cell
adhesion molecules such as Vcam-1 in the liver homogenate after both acute and chronic stress.
Arhgap5 was selectively induced after repeated stress exposure (Cook-Mills 2002, Haddad/Harb
2005, Kim et al. 2006, Petri/Bixel 2006) while the expression of several claudins, which are tight
junction proteins that regulate paracellular permeability (Amasheh et al. 2002), was significantly
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