Background/Purpose: Glucocorticoids (GC) are broadly used in the treatment of inflammatory diseases, including systemic lupus erythematosus (SLE). Despite their widespread use, most SLE patients do not reach a state of low disease activity on GC treatment. Currently it is not completely understood what factors play a role in the response to this treatment. It is thought that many anti-inflammatory effects of GC are mediated through upregulation of glucocorticoid-induced leucine zipper (GILZ). GILZ expression is decreased in the blood of SLE patients compared to healthy controls. Interestingly, we have previously shown that this is inversely correlated with the interferon (IFN) signature induced by type I IFN, including IFNα and IFNβ. Given the important role of type I IFN in SLE pathogenesis, we studied whether IFNα could suppress GILZ and thereby reduce the effectiveness of GC.

Methods: Human peripheral blood mononuclear cells (PBMC) were isolated from healthy individuals and treated with 1000 IU IFNα2a, 100 nM dexamethasone (DEX) or both, with or without the Jak1/Tyk2 inhibitor tosylate salt (TS). GILZ expression in these cultures was analysed using RT-PCR. STAT1 binding sites were analyzed from public datasets and using chromatin immunoprecipitation followed by RT-PCR. Public datasets were also used to study the effect of IFNα and the interplay between GC and IFNα on GILZ expression in SLE patients.

Results: IFNα treatment reduces the expression of GILZ in human PBMC in a dose- and time-dependent manner. Interestingly, it also reduces the DEX-induced upregulation of GILZ. This corresponds to data in SLE patients, where GC treatment is less effective at inducing GILZ in patients with a high IFN score than in patients with a low IFN score. Mechanistically, we found that IFNα2a reduces GILZ expression via the Jak1/Tyk2 signalling pathway, as treatment with the specific inhibitor TS reversed the effects of IFNα2a. In public datasets, and then confirmed via ChIP, we subsequently found that the transcription factor STAT1, downstream of Jak1/Tyk2, has multiple DNA binding sites surrounding the GILZ locus. These STAT1 binding sites coincide with binding sites of the glucocorticoid receptor (GR), which may explain the mechanism by which IFNα2a reduces the DEX-induced GILZ upregulation.

Conclusion: In human PBMC, IFNα2a reduces GILZ expression and the DEX-induced upregulation of GILZ via the Jak1/Tyk2 signalling pathway and direct DNA binding of STAT1 to the GILZ locus. These data reveal a potential mechanism by which type I IFN suppress the effectivity of GC, which could be targeted to improve therapeutic efficacy in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-interferon-inhibits-glucocorticoid-induced-leucine-zipper-gilz-expression-and-upregulation-by-glucocorticoids/