Functional and Transcriptomic Characterization of Peritoneal Immune-Modulation by Addition of Alanyl-Glutamine to Dialysis Fluid

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Abstract

Peritonitis remains a major cause of morbidity and mortality during chronic peritoneal dialysis (PD). Glucose-based PD fluids reduce immunological defenses in the peritoneal cavity. Low concentrations of peritoneal extracellular glutamine during PD may contribute to this immune deficit. For these reasons we have developed a clinical assay to measure the function of the immune-competent cells in PD effluent from PD patients. We then applied this assay to test the impact on peritoneal immune-competence of PD fluid supplementation with alanyl-glutamine (AlaGln) in 6 patients in an open-label, randomized, crossover pilot trial (EudraCT 2012-004004-36), and related the functional results to transcriptome changes in PD effluent cells. Ex-vivo stimulation of PD effluent peritoneal cells increased release of interleukin (IL) 6 and tumor necrosis factor (TNF) α. Both IL-6 and TNF-α were lower at 1 h than at 4 h of the peritoneal equilibration test but the reductions in cytokine release were attenuated in AlaGln-supplemented samples. AlaGln-supplemented samples exhibited priming of IL-6-related pathways and downregulation of TNF-α upstream elements. Results from measurement of cytokine release and transcriptome analysis in this pilot clinical study support the conclusion that suppression of PD effluent cell immune function in human subjects by standard PD fluid is attenuated by AlaGln supplementation.

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Most cited references 35

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Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice.

Hui-Chen Hsu, PingAr Yang, John Wang … (2008)

Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4+ T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.

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Molecular mechanisms of glutamine action.

Donald Sellitti, J Procopio, P Newsholme … (2005)

Glutamine is the most abundant free amino acid in the body and is known to play a regulatory role in several cell specific processes including metabolism (e.g., oxidative fuel, gluconeogenic precursor, and lipogenic precursor), cell integrity (apoptosis, cell proliferation), protein synthesis, and degradation, contractile protein mass, redox potential, respiratory burst, insulin resistance, insulin secretion, and extracellular matrix (ECM) synthesis. Glutamine has been shown to regulate the expression of many genes related to metabolism, signal transduction, cell defense and repair, and to activate intracellular signaling pathways. Thus, the function of glutamine goes beyond that of a simple metabolic fuel or protein precursor as previously assumed. In this review, we have attempted to identify some of the common mechanisms underlying the regulation of glutamine dependent cellular functions. (c) 2005 Wiley-Liss, Inc.

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Monocytes, Peripheral Blood Mononuclear Cells, and THP-1 Cells Exhibit Different Cytokine Expression Patterns following Stimulation with Lipopolysaccharide

Anita Schildberger, Eva Rossmanith, Tanja Eichhorn … (2013)

THP-1 cells are widely applied to mimic monocytes in cell culture models. In this study, we compared the cytokine release from THP-1, peripheral blood mononuclear cells (PBMC), monocytes, or whole blood after stimulation with lipopolysaccharide (LPS) and investigated the consequences of different cytokine profiles on human umbilical vein endothelial cell (HUVEC) activation. While Pseudomonas aeruginosa-stimulated (10 ng/mL) THP-1 secreted similar amounts of tumor necrosis factor alpha (TNF- α ) as monocytes and PBMC, they produced lower amounts of interleukin(IL)-8 and no IL-6 and IL-10. Whole blood required a higher concentration of Pseudomonas aeruginosa (1000 ng/mL) to induce cytokine release than isolated monocytes or PBMC (10 ng/mL). HUVEC secreted more IL-6 and IL-8 after stimulation with conditioned medium derived from whole blood than from THP-1, despite equal concentrations of TNF- α in both media. Specific adsorption of TNF- α or selective cytokine adsorption from the conditioned media prior to HUVEC stimulation significantly reduced HUVEC activation. Our findings show that THP-1 differ from monocytes, PBMC, and whole blood with respect to cytokine release after stimulation with LPS. Additionally, we could demonstrate that adsorption of inflammatory mediators results in reduced endothelial activation, which supports the concept of extracorporeal mediator modulation as supportive therapy for sepsis.

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Author and article information

Contributors

Klaus Kratochwill:

ORCID: http://orcid.org/0000-0003-0803-614X

klaus.kratochwill@meduniwien.ac.at

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 24 July 2017

Publication date PMC-release: 24 July 2017

Publication date Collection: 2017

Volume: 7

Electronic Location Identifier: 6229

Affiliations

[1 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, , Medical University of Vienna, Department of Pediatrics and Adolescent Medicine, ; Vienna, Austria

[2 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, , Medical University of Vienna, Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, ; Vienna, Austria

[3 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, , Medical University of Vienna, Center for Medical Statistics, Informatics, and Intelligent Systems, ; Vienna, Austria

[4 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, , Medical University of Vienna, Department of Surgery, Research Laboratories & Core Facility Flow Cytometry, ; Vienna, Austria

[5 ]ISNI 0000 0000 9011 8547, GRID grid.239395.7, Division of Interdisciplinary Medicine, , Beth Israel Deaconess Medical Center, ; Boston, MA USA

[6 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Medicine, , Harvard Medical School, ; Boston, MA USA

[7 ]ISNI 0000 0000 9011 8547, GRID grid.239395.7, Division of Nephrology and Center for Vascular Biology Research, , Beth Israel Deaconess Medical Center, ; Boston, MA USA

[8 ]Medical University of Vienna, Department of Medicine III, Division of Nephrology and Dialysis, Vienna, Austria

Author information

Klaus Kratochwill http://orcid.org/0000-0003-0803-614X

Article

Publisher ID: 5872

DOI: 10.1038/s41598-017-05872-2

PMC ID: 5524796

SO-VID: 5cc1a6c5-23f5-4c49-a079-13232bf3b784

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 16 February 2017

Date accepted : 5 June 2017

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Most cited references 35

Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice.

Molecular mechanisms of glutamine action.

Monocytes, Peripheral Blood Mononuclear Cells, and THP-1 Cells Exhibit Different Cytokine Expression Patterns following Stimulation with Lipopolysaccharide

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