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Maren Depke Results Liver Gene Expression Pattern in a Mouse Psychological Stress Model Table R.1.2: Tabular overview of stress-regulated hepatic genes, which are included in Ingenuity Pathway Analysis’ (IPA, Ingenuity Systems, www.ingenuity.com) canonical pathway „Acute Phase Response Signaling“. information on canonical pathway „Acute Phase Response Signaling“ in IPA information on stress regulated hepatic genes cellular location and Function plasma membrane receptor cytoplasm / signal transduction nucleus / transcription regulator affected genes of acute phase response name in canonical pathway (IPA) a members in IPA, if group of more than one gene gene name (NetAffx) gene title (NetAffx) probe set ID fold change b in chronic stress in acute stress IL1R1 IL-1R, Il1r1 interleukin 1 receptor, type I 1448950_at 4.4 4.0 IL-1R/TLR IL-6R Il6ra interleukin 6 receptor, alpha 1452416_at 3.3 5.5 TNFR NGFR, TNFRSF1A, TNFRSF1B, TNFRSF11B Tnfrsf1b tumor necrosis factor receptor superfamily, member 1b 1418099_at 2.4 3.4 ASK1 Map3k5 (LOC 675366) mitogen activated protein kinase kinase kinase 5 /// similar to mitogen activated protein kinase kinase kinase 5 mitogen activated protein kinase 3 ERK1/2 MAPK1, MAPK3 Mapk3 GCR* Nr3c1 nuclear receptor subfamily 3, group C, member 1 IκBα* BCL3, Nfkbia nuclear factor of kappa light NFKBIA, chain gene enhancer in B-cells NFKBIB, inhibitor, alpha NFKBIE SOCS* SOCS1, SOCS2, SOCS3, SOCS4, SOCS5, SOCS6 Socs2 suppressor of cytokine signaling 2 1421340_at 2.5 1427060_at -1.6 1460303_at -1.5 1448306_at 1.8 2.0 1449109_at -2.4 c-FOS Fos FBJ osteosarcoma oncogene 1423100_at 2.5 c-JUN Jun Jun oncogene 1448694_at 1417409_at 1.7 2.0 GCR* Nr3c1 nuclear receptor subfamily 3, 1460303_at -1.5 group C, member 1 NF-IL6 Cebpb CCAAT/enhancer binding protein (C/EBP), beta 1418901_at 1427844_a_at 3.3 4.0 5.1 6.9 CRP Crp C-reactive protein, pentraxinrelated 1421946_at 1.6 IκBα* BCL3, Nfkbia nuclear factor of kappa light 1448306_at 1.8 2.0 NFKBIA, chain gene enhancer in B-cells NFKBIB, inhibitor, alpha NFKBIE ORM ORM1, Orm2 orosomucoid 2 1420438_at 3.3 SAA SOCS* ORM2 SAA1, SAA2, SAA4 SOCS1, SOCS2, SOCS3, SOCS4, SOCS5, SOCS6 Saa1 serum amyloid A 1 1419075_s_at 1450788_at 23.7 27.9 Saa2 serum amyloid A 2 1449326_x_at 30.5 Saa4 serum amyloid A 4 1419318_at 1419319_at 2.6 2.6 Socs2 suppressor of cytokine signaling 1449109_at -2.4 2 a Some genes and their products marked by * belong to more than one group of the first column. b Fold change values are only given if the gene was considered as regulated in acute or chronic stress experiments. 2.2 2.5 70
Maren Depke Results Liver Gene Expression Pattern in a Mouse Psychological Stress Model Fig. R.1.7: Hepatic repression of antigen presentation related genes after chronic stress. Canonical “Antigen Presentation Pathway” of Ingenuity Pathway Analysis (adapted from IPA, Ingenuity Systems, www.ingenuity.com) displaying genes specifically repressed during chronic but not during acute stress. Repression of gene expression is indicated in green. The following genes are affected: H2- Aa and H2-Ea (MHC-IIα); Cd74 (CLIP); Psmb9 (LMP2). The blue circle indicates gene repression for H2-Ab1 (MHC-IIβ), which did not pass the regulation criteria because of low expression level. Increased leukocyte trafficking into the liver of chronically stressed mice Immediately after acute stress, several markers of leukocyte migration were differentially regulated in hepatic tissue compared with non-stressed controls. This set included lymphocyte chemoattractive molecules such as Cxcl11 and Cxl12, which were repressed, or neutrophils attractive Cxcl1, which was highly expressed after acute but also after chronic stress exposure. An induction of Vcam1 after acute and chronic stress and of Arhgap5 selectively after repeated stress as well as the repression of Bcar3 in the liver after acute stress exposure indicated that the extravasation of leukocytes was facilitated. Additionally, mRNA profiling uncovered a repression of genes whose products are involved in maintaining the endothelial barrier function such as claudin 1 (Cldn1), selectively after acute stress, or claudin 2 and 3 after both acute and chronic stress. To investigate whether these changes in gene expression also caused physiological changes in leukocyte composition of the liver, immunofluorescence staining was performed which revealed that no changes of immune cell numbers in the liver were detectable immediately after a single acute stress session by staining leukocytes with anti-CD45 antibodies (data not shown). However, in the periportal areas of chronically stressed animals there were increased numbers of CD45-positive cells, which supports the data of the gene expression profiling that indicated stress-induced leukocyte migration (data not shown). Increased oxidative stress in the liver after acute psychological stress exposure is counterregulated after repeated stress Inflammatory responses are associated with increased generation of reactive oxygen and nitrogen species. Gene expression profiling gave hints for increased oxidative stress in the liver of acutely and chronically stressed mice. Alas1 or As3mt, which are important for the regulation of the oxidative state, were differentially regulated after acute and chronic stress. The redox 71
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G E N O M E W I D E C H A R A C T E
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Maren Depke C O N T E N T S GENOMEW
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Maren Depke Z U S A M M E N F A S S
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Maren Depke Zusammenfassung der Dis
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Maren Depke S U M M A R Y O F D I S
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Maren Depke Summary of Dissertation
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Maren Depke I N T R O D U C T I O N
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Maren Depke Introduction Besides op
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Maren Depke Introduction Extracellu
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Maren Depke Results Host Cell Gene
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Maren Depke Results Pathogen Gene E
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Maren Depke D I S C U S S I O N A N
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Maren Depke Discussion and Conclusi
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Maren Depke References Athanasopoul
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Maren Depke References Byrne GI, Le
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Maren Depke References Demling R. T
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Maren Depke References Foss GS, Pry
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Maren Depke References Hagopian K,
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Maren Depke References Jin T, Bokar
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Maren Depke References Kwan T, Liu
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Maren Depke References Luster AD, U
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Maren Depke References Namiki S, Na
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Maren Depke References Puccetti P.
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Maren Depke References Siewert E, B
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Maren Depke A F F I D A V I T / E R
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Maren Depke Acknowledgments Kidney
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