genomewide characterization of host-pathogen interactions by ...

LBP [ng/ml]
CPR [ng/ml]
Maren Depke
Results
Liver Gene Expression Pattern in a Mouse Psychological Stress Model
revealed the following five prime targets: “PXR/RXR activation” (p = 4.04E−06), “Glucocorticoid
Receptor Signaling” (p = 4.26E−05), “LPS/IL-1 Mediated Inhibition of RXR function”
(p = 6.44E−05), “IGF-1 Signaling” (p = 7.29E−05), and “Hepatic Fibrosis/Hepatic Stellate Cell
Activation” (p = 2.96E−04). An IPA driven analysis of the consequences of chronic stress exposure
in turn uncovered a prime influence onto the following five canonical pathways, which partially
overlapped with those influenced by acute stress in hepatic tissue: “LPS/IL-1-Mediated Inhibition
of RXR Function” (p = 4.38E−06), “PXR/RXR activation” (p = 5.41E−06), “Acute Phase Response
Signaling” (p = 2.48E−05), “Antigen Presentation Pathway” (p = 1.78E−04), and “Glucocorticoid
Receptor Signaling” (p = 4.24E−04).
Already after acute stress, many genes which are associated with immune activation were
induced (e. g. Egfr, Fgf1, Jun, Irf2, Lgals4, Lipg, Map3k5). Several of these markers such as Il1r1,
Il6ra, Cxcl1, Lpin1, Tnfrsf1b, or Vcam1 were highly expressed in hepatic tissue also after repeated
stress exposure when compared with non-stressed controls. Interestingly, IPA revealed a high
mRNA expression of acute phase response (APR) genes immediately after acute stress exposure
(canonical pathway affected at rank 8 after acute stress: “Acute Phase Response Signaling” with
p = 8.7E−04), which was even further increased after the ninth stress session (Canonical pathway
“Acute phase response”; Table R.1.2). To validate the biological relevance of an increased APR,
LPS-binding protein (LBP) and C-reactive protein (CRP) concentrations were determined in
plasma. Acutely stressed mice did not show any significantly increased concentration of these
APR proteins after 2 h stress exposure whereas LBP and CRP levels were significantly enhanced in
the plasma of chronically stressed mice (Fig. R.1.6).
Fig. R.1.6: Acute phase proteins in the
plasma after acute and chronic stress and
in control mice.
Plasma level of (A) LPS-binding protein
(LBP) and (B) C-reactive protein (CRP) of
acutely stressed mice (grey box plot),
chronically stressed animals (black box
plot), and of non-stressed controls.
n = 12 mice/group;
summarized from two independent
experiments with comparable results.
** p < 0.01, *** p < 0.001 by one-way
ANOVA and Bonferroni multiple
comparison test.
A
750 *** **
500
250
0
B
500
400
300
200
100
0
***
Moreover, gene expression patterns contained several hints for the induction of immune
suppressive pathways which included an up-regulation of Tsc22d3 (GILZ, glucocorticoid-induced
leucine zipper) or Fkbp5 in both acutely and chronically stressed mice and reduced expression of
interferon gamma inducible target genes such as Ifi47, Iigp1, Stat1, and Socs2 selectively after
chronic stress compared with acutely stressed mice and non-stressed controls. Importantly,
chronically stressed mice showed a reduced hepatic transcription of antigen presentation
pathway molecules such as CD74 antigen (Ia antigen-associated invariant chain) and the
histocompatibility class II antigens H2-Aa and H2-Ea. An overlay of the gene expression data to
the pre-defined IPA-canonical pathway “Antigen Presentation Pathway” depicts that chronic
stress-induced repression especially affected genes of the MHC class II signaling pathway
(Fig. R.1.7) which may significantly reduce the capacity to mount an antibacterial response.
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