Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


GILZ Is a Novel Regulatory Protein in RA

Beaulieu1,  Elaine, Ngo1,  Devi, Cheng1,  Qiang, Santos1,  Leilani, Smith2,  Malcolm, Leech1,  Michelle, Morand1,  Eric F.

Monash University, Clayton, Australia
Repatriation General Hospital, Adelaide, Australia

Purpose:

Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid (GC)-induced transcription factor with recently described inhibitory effects on T cell and macrophage function via binding to NFkB and AP-1. Its expression and function have not previously been reported in RA. We herein report GILZ expression in human RA, and novel regulatory functions in FLS and human endothelial cells.

Methods:

GILZ was detected in synovial sections from normal and RA subjects, and in cultured RA FLS and umbilical vein endothelial cells (HUVEC), using immunohistochemistry, qPCR and immunoblotting. The effects of GILZ overexpression on RA FLS and HUVEC cytokines and chemokines were examined, and GILZ effects on whole blood leukocyte adhesion and rolling interactions with HUVEC were examined in a flow chamber.

Results:

GILZ was detected in normal synovium in lining and sublining layers. Compared to normal synovium, synovial sublining and endothelial GILZ were significantly increased in active RA. In RA FLS, the GC dexamethasone (Dex) potently and highly significantly upregulated GILZ mRNA and protein, with up to a 150-fold increase in mRNA within 4 hours which was GC receptor-dependent. In contrast, TNF and LPS significantly inhibited both endogenous and Dex-induced RA FLS GILZ expression. RA FLS release of the pro-inflammatory cytokines IL-6 and IL-8 was inhibited by GILZ without affecting proliferation. Unexpectedly, GILZ was also expressed in synovial endothelial cells and cultured HUVEC. HUVEC GILZ was significantly increased by Dex and inhibited by TNF. TNF also induced leukocyte rolling and adhesion interactions with HUVEC, which were in turn inhibited by restoration of GILZ. This was not due to an effect of GILZ on HUVEC release of the chemokines IL-8, RANTES, IP-10 and MCP-1.

Conclusion:

We report the first expression and functional data regarding GILZ in human RA and human endothelial cells. GILZ expression in RA FLS is exquisitely sensitive to induction by GC, and its expression inhibits FLS cytokines. GILZ is expressed in vascular endothelial cells, where it inhibits leukocyte–endothelial interactions. These findings identify GILZ as a novel regulatory protein in RA.

To cite this abstract, please use the following information:
Beaulieu, Elaine, Ngo, Devi, Cheng, Qiang, Santos, Leilani, Smith, Malcolm, Leech, Michelle, et al; GILZ Is a Novel Regulatory Protein in RA [abstract]. Arthritis Rheum 2009;60 Suppl 10 :32
DOI: 10.1002/art.25115

Abstract Supplement

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2009 ACR/ARHP