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 Collagen-Induced Arthritis
Ngo1, Devi, Beaulieu1, Elaine, Apparailly2, Florence, Courties2, Gabriel, Escriou3, Virginie, Scherman4, Daniel, Jorgensen2, Christian
Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid (GC)-induced transcription factor that is reported to bind to NFkB and AP-1, inhibiting T cell and macrophage function. Its expression and function in animal models of RA have not previously been reported. We herein report GILZ expression in murine collagen-induced arthritis (CIA), and describe the function of endogenous GILZ for the first time in vivo.
GILZ was detected in mouse paw, synovium, spleen, and macrophages using immunohistochemistry, qPCR and immunoblotting. CIA was induced in DBA/1 mice and GILZ expression was silenced in vivo using cationic liposome-encapsulated (lipoplexed) GILZ siRNA.
In murine CIA synovium, GILZ was detected in synovial lining and endothelial cells. The GC dexamethasone (0.25 mg/kg) significantly inhibited clinical expression of CIA, accompanied by significantly increased GILZ expression in synovium, peritoneal macrophages and spleen cells. Intravenous (IV) injection of red fluorescent siRNA lipoplexes resulted in lipofection of 20% of circulating monocytes within 4hrs. Compared to control (non-targeting) siRNA, IV administration of GILZ siRNA lipoplexes significantly inhibited GILZ protein expression in vivo. To determine the function of constitutive GILZ expression in the regulation of arthritis, GILZ was silenced in vivo in mice developing CIA. GILZ silencing resulted in marked and significant exacerbation of CIA clinical score compared to control (non-targeting) siRNA, associated with increased synovial expression of IL-1 and TNF but without affecting anti-type II collagen autoantibodies.
These findings demonstrate that GILZ acts as an endogenous inhibitor of inflammation and cytokine production in CIA. GILZ induction during GC inhibition of murine CIA suggests that GILZ may contribute to the therapeutic effects of GC in this model and in RA. This suggests that modulation of GILZ in human RA could be a promising therapeutic approach.
To cite this abstract, please use the following information:
Ngo, Devi, Beaulieu, Elaine, Apparailly, Florence, Courties, Gabriel, Escriou, Virginie, Scherman, Daniel, et al; GILZ Is a Novel Regulatory Protein in Collagen-Induced Arthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :15