Background and aims Glucocorticoid-induced Leucine Zipper (GILZ) is a GC-inducible gene with multiple immune-regulatory functions, and GILZ deficiency in mice results in the development of a lupus-like phenotype. In Systemic Lupus Erythematosus (SLE), plasmacytoid dendritic cells (pDCs) are major producers of Type 1 interferons (IFN) in response to nucleic acid-containing immune complexes. GILZ inhibits activation of B cells, T cells and other myeloid cells and we studied whether GILZ regulates interferon secretion by pDC.
Methods We conducted a study of GILZ expression in human peripheral blood mononuclear cells in-vitro and in-vitro study in GILZ KO mouse model to analyse the regulatory function of GILZ.
Results Our data suggests that loss of GILZ up-regulates type 1 IFN production by pDC in response to TLR7 and TLR9 stimulation. Basal GILZ expression was lower in pDCs than in other myeloid cell types and the relative deficiency of GILZ expression in pDC may predispose these cells to rapid activation and interferon production in SLE. Moreover, GILZ appears to be rapidly downregulated by type 1 interferons and in SLE patients, the level of GILZ, normalised by prednisolone dose, negatively correlated with SLEDAI. Thus, downregulation of GILZ by type I interferon may allow heightened interferon release by pDC, and this mechanism potentially leads to amplification of inflammation and cyclical disease flare-ups in lupus patients.
Conclusions Restoration of GILZ may be a potential therapeutic strategy that could reduce the GC dependence in SLE, a strategy that is appealing since GILZ has thus far not recapitulated any of the metabolic effects of GC.
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