Format

Send to

Choose Destination
J Steroid Biochem Mol Biol. 2019 Dec;195:105485. doi: 10.1016/j.jsbmb.2019.105485. Epub 2019 Sep 24.

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.

Author information

1
University Medical Center Göttingen, Institute for Cellular and Molecular Immunology, Humboldtallee 34, 37073 Göttingen, Germany.
2
Max Planck Institute for Molecular Genetics, Ihnestraße 63, 14195 Berlin, Germany.
3
University Medical Center Göttingen, Institute for Pathology, Robert-Koch-Straße 40, 37075 Göttingen, Germany.
4
University Medical Center Göttingen, Institute for Neuroimmunology and Multiple Sclerosis Research, von-Siebold-Straße 3a, 37075 Göttingen, Germany.
5
German Primate Center, Leibniz Institute for Primate Research, Primate Genetics Laboratory, Kellnerweg 4, 37077 Göttingen, Germany.
6
University Medical Center Göttingen, Institute for Cellular and Molecular Immunology, Humboldtallee 34, 37073 Göttingen, Germany. Electronic address: hreichardt@med.uni-goettingen.de.

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.

KEYWORDS:

Gene expression; Glucocorticoids; GvHD; RNAseq; T cells

PMID:
31561002
DOI:
10.1016/j.jsbmb.2019.105485
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center