title: Cell matrix contact modifies endothelial major histocompatibility complex class II expression in high-glucose environment.
abstract: Atherosclerosis is a chronic inflammatory disease. Cardiovascular risk factors such as hyperglycemia, hyperlipidemia, and arterial hypertension induce endothelial dysfunction with alterations in endothelial biosecretion and immune behavior. The aim of this study is to elucidate whether glucose-induced modifications of endothelial biosecretory and immune functions are regulated by interactions of endothelial cells (ECs) with their extracellular matrix [ECs plated on polystyrene-coated tissue culture plates (TC-EC) vs. ECs embedded within three-dimensional (3-D) collagen-based matrixes (3D-EC)]. In the absence of glucose, IFN-γ-induced phosphorylation of JAK and STAT proteins and human leukocyte antigen (HLA)-DR expression were lower in 3D-EC compared with TC-EC. Inversely, the expression of suppressor of cytokine signaling proteins (SOCS)-1 and -3 were significantly higher in naïve 3D-EC compared with naïve TC-EC. IFN-γ-induced upregulation of SOCS proteins was further amplified by the 3-D environment. Glucose significantly augmented IFN-γ-dependent signaling pathways in TC-EC. IFN-γ-induced phosphorylation of JAK and STAT proteins as well as HLA-DR expression by ECs in low- and high-glucose medium was significantly lower in 3-D than in two-dimensional environment. Glucose increased SOCS expression in TC-EC and 3D-EC to the same extent, such that expression levels in 3D-EC exceeded SOCS-1 and -3 expression in TC-EC by 1.6-2.5-fold. In conclusion, low- and high-glucose concentrations amplify IFN-γ-induced signaling pathways in TC-EC. Increased SOCS expression raises the threshold for IFN-γ to induce HLA-DR expression in a 3-D environment. This immunoprotective effect is maintained even in states of experimental hyperglycemia.
authors.affiliation: Department of Internal Medicine/Cardiology, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Nickmann
authors.forename: Michael
authors.initials: M
authors.lastname: Saemisch
authors.forename: Ute
authors.initials: U
authors.lastname: Wilbert-Lampen
authors.forename: Thomas
authors.initials: T
authors.lastname: Nickel
authors.forename: Elazer R
authors.initials: ER
authors.lastname: Edelman
authors.forename: Heiko
authors.initials: H
authors.lastname: Methe
mesh_terms: D049109:Cell Proliferation; D021982:Cell-Matrix Junctions / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D024141:Collagen Type IV / Q000378:metabolism*; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D005781:Gelatin Sponge, Absorbable; D005947:Glucose / Q000378:metabolism*; D006684:HLA-DR Antigens / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D008213:Lymphocyte Activation; D010766:Phosphorylation; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D024141:Collagen Type IV; D006684:HLA-DR Antigens; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D050791:STAT Transcription Factors; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; D053612:Janus Kinases; D005947:Glucose
keywords: ECM; diabetes; endothelial cell; immunomodulation
references.citation: Am J Nephrol. 2010;31(5):380-8
references.pmid: 20299783
references.citation: Life Sci. 2001 Jan 5;68(7):727-37
references.pmid: 11205865
references.citation: Cardiovasc Diabetol. 2005 Aug 09;4:12
references.pmid: 16086844
references.citation: Diabetes Care. 2011 Jun;34(6):1249-57
references.pmid: 21617109
references.citation: Hypertension. 1992 Aug;20(2):253-63
references.pmid: 1639468
references.citation: Nat Rev Immunol. 2007 Oct;7(10):803-15
references.pmid: 17893694
references.citation: Biomaterials. 2013 Jan;34(3):677-84
references.pmid: 23102623
references.citation: Int J Biochem Cell Biol. 1997 May;29(5):721-5
references.pmid: 9251239
references.citation: Eur J Pharmacol. 1992 May 14;215(2-3):329-31
references.pmid: 1396999
references.citation: Mol Cell Biochem. 2009 Feb;322(1-2):161-9
references.pmid: 18998200
references.citation: J Clin Invest. 1992 Dec;90(6):2548-54
references.pmid: 1469103
references.citation: Thromb Haemost. 2007 Aug;98(2):278-82
references.pmid: 17721607
references.citation: Semin Immunol. 2008 Apr;20(2):117-22
references.pmid: 18243732
references.citation: J Ocul Pharmacol Ther. 2011 Feb;27(1):7-15
references.pmid: 21091050
references.citation: Cell Signal. 2011 Jan;23(1):125-34
references.pmid: 20816750
references.citation: Lymphology. 2007 Sep;40(3):102-13
references.pmid: 18062611
references.citation: Diabetes. 1994 Jun;43(6):836-41
references.pmid: 8194672
references.citation: Vasc Cell. 2011 May 02;3(1):10
references.pmid: 21535874
references.citation: Circulation. 2005 Aug 30;112(9 Suppl):I89-95
references.pmid: 16159871
references.citation: J Biol Chem. 2007 May 11;282(19):14635-44
references.pmid: 17327226
references.citation: Microbes Infect. 2004 Nov;6(13):1219-25
references.pmid: 15488742
references.citation: Diabetologia. 1992 Aug;35(8):771-6
references.pmid: 1511805
references.citation: N Engl J Med. 1989 Apr 20;320(16):1025-30
references.pmid: 2927481
references.citation: Curr Eye Res. 2011 Aug;36(8):747-53
references.pmid: 21780924
references.citation: Biochem J. 2009 Mar 1;418(2):325-36
references.pmid: 18821851
references.citation: Transplant Proc. 2006 Dec;38(10):3293-9
references.pmid: 17175253
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8130-4
references.pmid: 7667257
references.citation: J Vasc Surg. 2009 Dec;50(6):1359-68.e1
references.pmid: 19958986
references.citation: Cell Transplant. 2009;18(3):261-73
references.pmid: 19558775
references.citation: Clin Sci (Lond). 2005 Aug;109(2):143-59
references.pmid: 16033329
references.citation: Br J Pharmacol. 1997 Jul;121(5):972-6
references.pmid: 9222555
references.citation: Physiol Res. 2004;53(1):77-82
references.pmid: 14984317
references.citation: Nat Rev Immunol. 2007 Sep;7(9):678-89
references.pmid: 17717539
references.citation: Diabetologia. 1995 Apr;38(4):430-6
references.pmid: 7796983
references.citation: J R Soc Interface. 2006 Oct 22;3(10):589-601
references.pmid: 16971328
references.citation: Biomaterials. 2009 Sep;30(25):4094-103
references.pmid: 19481080
references.citation: Diabetes Care. 2003 Jul;26(7):2165-73
references.pmid: 12832330
references.citation: Eur J Immunol. 2007 Jul;37(7):1773-84
references.pmid: 17559179
references.citation: Cell Signal. 2010 May;22(5):791-800
references.pmid: 20067833
references.citation: J Cell Physiol. 2008 Oct;217(1):86-92
references.pmid: 18446810
references.citation: FEBS Lett. 2008 Oct 15;582(23-24):3484-8
references.pmid: 18801363