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  Glucocorticoid resistance of allogeneic T cells alters the gene expression profile in the inflamed small intestine of mice suffering from acute graft-versus-host disease

Li, H., Kaiser, T. K., Borschiwer, M., Bohnenberger, H., Reichardt, S. D., Luhder, F., et al. (2019). Glucocorticoid resistance of allogeneic T cells alters the gene expression profile in the inflamed small intestine of mice suffering from acute graft-versus-host disease. Journal of Steroid Biochemistry and Molecular Biology, 195: 105485. doi:10.1016/j.jsbmb.2019.105485.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-91F0-7 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-91F1-6
Genre: Journal Article

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Li, H., Author
Kaiser, T. K., Author
Borschiwer, M.1, Author              
Bohnenberger, H., Author
Reichardt, S. D., Author
Luhder, F., Author
Walter, L., Author
Dressel, R., Author
Meijsing, Sebastiaan1, Author              
Reichardt, H. M., Author
Affiliations:
1Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479641              

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Free keywords: *Gene expression *Glucocorticoids *GvHD *RNAseq *T cells
 Abstract: Glucocorticoids (GCs) play an important role in controlling acute graft-versus-host disease (aGvHD), a frequent complication of allogeneic hematopoietic stem cell transplantation. The anti-inflammatory activity of GCs is mainly ascribed to the modulation of T cells and macrophages, for which reason a genetically induced GC resistance of either of these cell types causes aggravated aGvHD. Since only a few genes are currently known that are differentially regulated under these conditions, we analyzed the expression of 54 candidate genes in the inflamed small intestine of mice suffering from aGvHD when either allogeneic T cells or host myeloid cells were GC resistant using a microfluidic dynamic array platform for high-throughput quantitative PCR. The majority of genes categorized as cytokines (e.g. Il2, Il6), chemokines (e.g. Ccl2, Cxcl1), cell surface receptors (e.g. Fasl, Ctla4) and intracellular molecules (e.g. Dusp1, Arg1) were upregulated in mice transplanted with GC resistant allogeneic T cells. Moreover, the expression of several genes linked to energy metabolism (e.g. Glut1) was altered. Surprisingly, mice harboring GC resistant myeloid cells showed almost no changes in gene expression despite their fatal disease course after aGvHD induction. To identify additional genes in the inflamed small intestine that were affected by a GC resistance of allogeneic T cells, we performed an RNAseq analysis, which uncovered more than 500 differentially expressed transcripts (e.g. Cxcr6, Glut3, Otc, Aoc1, Il1r1, Sphk1) that were enriched for biological processes associated with inflammation and tissue disassembly. The changes in gene expression could be confirmed during full-blown disease but hardly any of them in the preclinical phase using high-throughput quantitative PCR. Further analysis of some of these genes revealed a highly selective expression pattern in T cells, intestinal epithelial cells and macrophages, which correlated with their regulation during disease progression. Collectively, we identified an altered gene expression profile caused by GC resistance of transplanted allogeneic T cells, which could help to define new targets for aGvHD therapy.

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Language(s): eng - English
 Dates: 2019-09-24
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.jsbmb.2019.105485
ISSN: 1879-1220 (Electronic)0960-0760 (Print)
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Title: Journal of Steroid Biochemistry and Molecular Biology
  Other : J. Steroid Biochem. Mol. Biol.
Source Genre: Journal
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Publ. Info: Oxford : Pergamon
Pages: - Volume / Issue: 195 Sequence Number: 105485 Start / End Page: - Identifier: ISSN: 0960-0760
CoNE: https://pure.mpg.de/cone/journals/resource/954927548271