TY - JOUR
T1 - GILZ regulates type I interferon release and sequesters STAT1
AU - Nataraja, Champa
AU - Flynn, Jacqueline
AU - Dankers, Wendy
AU - Northcott, Melissa
AU - Zhu, Wendy
AU - Sherlock, Rochelle
AU - Bennett, Taylah J
AU - Russ, Brendan E
AU - Miceli, Iolanda
AU - Pervin, Mehnaz
AU - D'Cruz, Akshay
AU - Harris, James
AU - Morand, Eric F
AU - Jones, Sarah A
N1 - Copyright © 2022. Published by Elsevier Ltd.
PY - 2022/7
Y1 - 2022/7
N2 - Glucocorticoids remain a mainstay of modern medicine due to their ability to broadly suppress immune activation. However, they cause severe adverse effects that warrant urgent development of a safer alternative. The glucocorticoid-induced leucine zipper (GILZ) gene, TSC22D3, is one of the most highly upregulated genes in response to glucocorticoid treatment, and reduced GILZ mRNA and protein levels are associated with increased severity of inflammation in systemic lupus erythematosus (SLE), Ulcerative Colitis, Psoriasis, and other autoimmune/autoinflammatory diseases. Here, we demonstrate that low GILZ permits expression of a type I interferon (IFN) signature, which is exacerbated in response to TLR7 and TLR9 stimulation. Conversely, overexpression of GILZ prevents IFN-stimulated gene (ISG) up-regulation in response to IFNα. Moreover, GILZ directly binds STAT1 and prevents its nuclear translocation, thereby negatively regulating IFN-induced gene expression and the auto-amplification loop of the IFN response. Thus, GILZ powerfully regulates both the expression and action of type I IFN, suggesting restoration of GILZ as an attractive therapeutic strategy for reducing reliance on glucocorticoids.
AB - Glucocorticoids remain a mainstay of modern medicine due to their ability to broadly suppress immune activation. However, they cause severe adverse effects that warrant urgent development of a safer alternative. The glucocorticoid-induced leucine zipper (GILZ) gene, TSC22D3, is one of the most highly upregulated genes in response to glucocorticoid treatment, and reduced GILZ mRNA and protein levels are associated with increased severity of inflammation in systemic lupus erythematosus (SLE), Ulcerative Colitis, Psoriasis, and other autoimmune/autoinflammatory diseases. Here, we demonstrate that low GILZ permits expression of a type I interferon (IFN) signature, which is exacerbated in response to TLR7 and TLR9 stimulation. Conversely, overexpression of GILZ prevents IFN-stimulated gene (ISG) up-regulation in response to IFNα. Moreover, GILZ directly binds STAT1 and prevents its nuclear translocation, thereby negatively regulating IFN-induced gene expression and the auto-amplification loop of the IFN response. Thus, GILZ powerfully regulates both the expression and action of type I IFN, suggesting restoration of GILZ as an attractive therapeutic strategy for reducing reliance on glucocorticoids.
KW - Gene Expression Regulation
KW - Glucocorticoids/metabolism
KW - Humans
KW - Interferon Type I/genetics
KW - Lupus Erythematosus, Systemic/metabolism
KW - Psoriasis
KW - STAT1 Transcription Factor/genetics
U2 - https://doi.org/10.1016/j.jaut.2022.102858
DO - https://doi.org/10.1016/j.jaut.2022.102858
M3 - Article
C2 - 35810690
SN - 0896-8411
VL - 131
SP - 102858
JO - Journal of autoimmunity
JF - Journal of autoimmunity
ER -