GILZ overexpression inhibits endothelial cell adhesive function through regulation of NF-{K}B and MAPK activity

Qiang Cheng, Huapeng Fan, Devi Ngo, Elaine Vicky Beaulieu, Sun Kwong Patrick Leung, Camden Yeung-Wah Lo, Rosemary Burgess, Yvonne van der Zwan, Stefan White, Levon Michael Khachigian, Michael John Hickey, Eric Francis Morand

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Glucocorticoid-induced leucine zipper (GILZ) is an anti-inflammatory protein first identified in T lymphocytes. We recently observed that GILZ is highly expressed in synovial endothelial cells in rheumatoid arthritis. However, the function of GILZ in endothelial cells is unknown. To investigate the actions of GILZ in this cell type, we induced GILZ expression in HUVECs via transient transfection. GILZ overexpression significantly reduced the capacity of TNF-stimulated HUVECs to support leukocyte rolling, adhesion, and transmigration. These effects were associated with decreased expression of E-selectin, ICAM-1, CCL2, CXCL8, and IL-6. Experiments in a human microvascular endothelial cell line demonstrated that TNF-inducible NF-?B activity was significantly inhibited by overexpression of GILZ. Exogenous GILZ inhibited TNF-induced NF-?B p65 DNA binding, although this occurred in the absence of an effect on p65 nuclear translocation, indicating that the mechanism of action of exogenous GILZ in endothelial cells differs from that reported in other cell types. GILZ overexpression also inhibited TNF-induced activation of p38, ERK, and JNK MAPKs, as well as increased expression of the MAPK inhibitory phosphatase, MKP-1. In contrast, silencing endogenous GILZ in glucocorticoid-treated HUVECs did not alter their capacity to support leukocyte interactions. These data demonstrate that exogenous GILZ exerts inhibitory effects on endothelial cell adhesive function via a novel pathway involving modulation of NF-?B p65 DNA binding and MAPK activity. Induction of GILZ expression in endothelial cells may represent a novel therapeutic modality with the potential to inhibit inflammatory leukocyte recruitment.
Original languageEnglish
Pages (from-to)424 - 433
Number of pages10
JournalJournal of Immunology
Volume191
Issue number1
DOIs
Publication statusPublished - 2013

Cite this

Cheng, Qiang ; Fan, Huapeng ; Ngo, Devi ; Beaulieu, Elaine Vicky ; Leung, Sun Kwong Patrick ; Lo, Camden Yeung-Wah ; Burgess, Rosemary ; van der Zwan, Yvonne ; White, Stefan ; Khachigian, Levon Michael ; Hickey, Michael John ; Morand, Eric Francis. / GILZ overexpression inhibits endothelial cell adhesive function through regulation of NF-{K}B and MAPK activity. In: Journal of Immunology. 2013 ; Vol. 191, No. 1. pp. 424 - 433.
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title = "GILZ overexpression inhibits endothelial cell adhesive function through regulation of NF-{K}B and MAPK activity",
abstract = "Glucocorticoid-induced leucine zipper (GILZ) is an anti-inflammatory protein first identified in T lymphocytes. We recently observed that GILZ is highly expressed in synovial endothelial cells in rheumatoid arthritis. However, the function of GILZ in endothelial cells is unknown. To investigate the actions of GILZ in this cell type, we induced GILZ expression in HUVECs via transient transfection. GILZ overexpression significantly reduced the capacity of TNF-stimulated HUVECs to support leukocyte rolling, adhesion, and transmigration. These effects were associated with decreased expression of E-selectin, ICAM-1, CCL2, CXCL8, and IL-6. Experiments in a human microvascular endothelial cell line demonstrated that TNF-inducible NF-?B activity was significantly inhibited by overexpression of GILZ. Exogenous GILZ inhibited TNF-induced NF-?B p65 DNA binding, although this occurred in the absence of an effect on p65 nuclear translocation, indicating that the mechanism of action of exogenous GILZ in endothelial cells differs from that reported in other cell types. GILZ overexpression also inhibited TNF-induced activation of p38, ERK, and JNK MAPKs, as well as increased expression of the MAPK inhibitory phosphatase, MKP-1. In contrast, silencing endogenous GILZ in glucocorticoid-treated HUVECs did not alter their capacity to support leukocyte interactions. These data demonstrate that exogenous GILZ exerts inhibitory effects on endothelial cell adhesive function via a novel pathway involving modulation of NF-?B p65 DNA binding and MAPK activity. Induction of GILZ expression in endothelial cells may represent a novel therapeutic modality with the potential to inhibit inflammatory leukocyte recruitment.",
author = "Qiang Cheng and Huapeng Fan and Devi Ngo and Beaulieu, {Elaine Vicky} and Leung, {Sun Kwong Patrick} and Lo, {Camden Yeung-Wah} and Rosemary Burgess and {van der Zwan}, Yvonne and Stefan White and Khachigian, {Levon Michael} and Hickey, {Michael John} and Morand, {Eric Francis}",
year = "2013",
doi = "10.4049/jimmunol.1202662",
language = "English",
volume = "191",
pages = "424 -- 433",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "1",

}

Cheng, Q, Fan, H, Ngo, D, Beaulieu, EV, Leung, SKP, Lo, CY-W, Burgess, R, van der Zwan, Y, White, S, Khachigian, LM, Hickey, MJ & Morand, EF 2013, 'GILZ overexpression inhibits endothelial cell adhesive function through regulation of NF-{K}B and MAPK activity' Journal of Immunology, vol. 191, no. 1, pp. 424 - 433. https://doi.org/10.4049/jimmunol.1202662

GILZ overexpression inhibits endothelial cell adhesive function through regulation of NF-{K}B and MAPK activity. / Cheng, Qiang; Fan, Huapeng; Ngo, Devi; Beaulieu, Elaine Vicky; Leung, Sun Kwong Patrick; Lo, Camden Yeung-Wah; Burgess, Rosemary; van der Zwan, Yvonne; White, Stefan; Khachigian, Levon Michael; Hickey, Michael John; Morand, Eric Francis.

In: Journal of Immunology, Vol. 191, No. 1, 2013, p. 424 - 433.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - GILZ overexpression inhibits endothelial cell adhesive function through regulation of NF-{K}B and MAPK activity

AU - Cheng, Qiang

AU - Fan, Huapeng

AU - Ngo, Devi

AU - Beaulieu, Elaine Vicky

AU - Leung, Sun Kwong Patrick

AU - Lo, Camden Yeung-Wah

AU - Burgess, Rosemary

AU - van der Zwan, Yvonne

AU - White, Stefan

AU - Khachigian, Levon Michael

AU - Hickey, Michael John

AU - Morand, Eric Francis

PY - 2013

Y1 - 2013

N2 - Glucocorticoid-induced leucine zipper (GILZ) is an anti-inflammatory protein first identified in T lymphocytes. We recently observed that GILZ is highly expressed in synovial endothelial cells in rheumatoid arthritis. However, the function of GILZ in endothelial cells is unknown. To investigate the actions of GILZ in this cell type, we induced GILZ expression in HUVECs via transient transfection. GILZ overexpression significantly reduced the capacity of TNF-stimulated HUVECs to support leukocyte rolling, adhesion, and transmigration. These effects were associated with decreased expression of E-selectin, ICAM-1, CCL2, CXCL8, and IL-6. Experiments in a human microvascular endothelial cell line demonstrated that TNF-inducible NF-?B activity was significantly inhibited by overexpression of GILZ. Exogenous GILZ inhibited TNF-induced NF-?B p65 DNA binding, although this occurred in the absence of an effect on p65 nuclear translocation, indicating that the mechanism of action of exogenous GILZ in endothelial cells differs from that reported in other cell types. GILZ overexpression also inhibited TNF-induced activation of p38, ERK, and JNK MAPKs, as well as increased expression of the MAPK inhibitory phosphatase, MKP-1. In contrast, silencing endogenous GILZ in glucocorticoid-treated HUVECs did not alter their capacity to support leukocyte interactions. These data demonstrate that exogenous GILZ exerts inhibitory effects on endothelial cell adhesive function via a novel pathway involving modulation of NF-?B p65 DNA binding and MAPK activity. Induction of GILZ expression in endothelial cells may represent a novel therapeutic modality with the potential to inhibit inflammatory leukocyte recruitment.

AB - Glucocorticoid-induced leucine zipper (GILZ) is an anti-inflammatory protein first identified in T lymphocytes. We recently observed that GILZ is highly expressed in synovial endothelial cells in rheumatoid arthritis. However, the function of GILZ in endothelial cells is unknown. To investigate the actions of GILZ in this cell type, we induced GILZ expression in HUVECs via transient transfection. GILZ overexpression significantly reduced the capacity of TNF-stimulated HUVECs to support leukocyte rolling, adhesion, and transmigration. These effects were associated with decreased expression of E-selectin, ICAM-1, CCL2, CXCL8, and IL-6. Experiments in a human microvascular endothelial cell line demonstrated that TNF-inducible NF-?B activity was significantly inhibited by overexpression of GILZ. Exogenous GILZ inhibited TNF-induced NF-?B p65 DNA binding, although this occurred in the absence of an effect on p65 nuclear translocation, indicating that the mechanism of action of exogenous GILZ in endothelial cells differs from that reported in other cell types. GILZ overexpression also inhibited TNF-induced activation of p38, ERK, and JNK MAPKs, as well as increased expression of the MAPK inhibitory phosphatase, MKP-1. In contrast, silencing endogenous GILZ in glucocorticoid-treated HUVECs did not alter their capacity to support leukocyte interactions. These data demonstrate that exogenous GILZ exerts inhibitory effects on endothelial cell adhesive function via a novel pathway involving modulation of NF-?B p65 DNA binding and MAPK activity. Induction of GILZ expression in endothelial cells may represent a novel therapeutic modality with the potential to inhibit inflammatory leukocyte recruitment.

UR - http://www.jimmunol.org/content/191/1/424.full.pdf

U2 - 10.4049/jimmunol.1202662

DO - 10.4049/jimmunol.1202662

M3 - Article

VL - 191

SP - 424

EP - 433

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

ER -