genomewide characterization of host-pathogen interactions by ...

Maren Depke
Results
Kidney Gene Expression Pattern in an in vivo Infection Model
The canonical pathway “TREM1 Signaling” (p = 8.15E−13; ratio = 23/69) slightly overlaps with
the pathway “IL-6 Signaling” as branches of signal transduction also lead to IL-6 and TNFα
transcription via STAT3 and NFκB (all induced after infection). Also TLR4 is included because after
activation, the receptor can associate with TREM1, activate the kinase IRAK1 and finally the
NFκB-mediated transcription. The increased Trem1 itself, a receptor whose ligand is still
unknown and which is expressed by neutrophils, monocytes and macrophages, and the increased
adapter molecule DAP12 (Tyrobp) are the beginning of a proinflammatory reaction chain that
includes AKT/PKB (Rac2, induced), PLCγ and NTAL (Plcg2 and Lat2, induced by trend). TREM1
signaling not only influences transcription of proinflammatory cytokines (MCP-1/Ccl2, TNFα,
MCP-3/Ccl7, IL-6, MIP-1α/Ccl3), but also the translocation of cytokines from cytoplasm to the
extracellular space (MCP-1/Ccl2, TNFα, IL-6, IL-1β). DAP12 positively influences the activation of
IL-1β by CASP1 (both induced) in the pathway of NLR (intracellular NACHT-LRR receptors)
recognizing intracellular bacteria.
Furthermore, DAP12 leads to the transcription of cell adhesion molecules (CD11c/Itgax,
CD49e/Itga5) and the co-stimulatory proteins CD54/Icam1 and CD86 (all induced). Genes coding
for cell surface proteins CD32/Fcgr2b and CD40, which are additionally regulated via DAP12, were
increased by trend.
Opposed to these proinflammatory signaling pathways, the “IL-10 Signaling” pathway
(p = 1.99E−15; ratio = 27/70; Fig. R.2.11) is an example for a mechanism aiming to limit and
terminate the cellular inflammatory response in addition to regulating growth and differentiation
of different immune cells. Here, the IL-10 receptor α-chain (Il10ra) was induced after infection.
Induced Stat3 is part of the signaling cascade like in IL-6 signaling but SOCS3, suppressor of
cytokine signaling, was additionally increased. This gene is itself transcriptionally regulated at the
end of the IL-10 signaling pathway. Furthermore, Ccr1, Ccr5, Arg2, Il4ra, and Hmox1 were
induced genes responding to IL-10. IL-6 signals are also mediated via STAT3, and the cytokine IL-6
was induced contrarily to IL-10, which was not regulated. Therefore, the IL-10 pathway might not
be activated yet, but just prepared for a later phase of anti-inflammatory reactions.
Fig. R.2.11:
IL-10 Signaling (modified from IPA, www.ingenuity.com).
Red color indicates increase of expression. More intense shade of color is
used for higher absolute fold change values.
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