Type I interferon (IFN) is essential for host defenses against viruses; however, dysregulated IFN signaling is causally linked to autoimmunity, particularly systemic lupus erythematosus. Autoimmune disease treatments rely on glucocorticoids (GCs), which act via the GC receptor (GR) to repress proinflammatory cytokine gene transcription. Conversely, cytokine signaling through cognate Jak/STAT pathways is reportedly unaffected or even stimulated by GR. Unexpectedly, we found that GR dramatically inhibited IFN-stimulated gene (ISG) expression in macrophages. The target of inhibition, the heterotrimeric STAT1-STAT2-IRF9 (ISGF3) transcription complex, utilized the GR cofactor GRIP1/TIF2 as a coactivator. Consequently, GRIP1 knockdown, genetic ablation, or depletion by GC-activated GR attenuated ISGF3 promoter occupancy, preinitiation complex assembly, and ISG expression. Furthermore, this regulatory loop was restricted to cell types such as macrophages expressing the GRIP1 protein at extremely low levels, and pharmacological disruption of the GR-GRIP1 interaction or transient introduction of GRIP1 restored RNA polymerase recruitment to target ISGs and the subsequent IFN response. Thus, type I IFN is a cytokine uniquely controlled by GR at the levels of not only production but also signaling through antagonism with the ISGF3 effector function, revealing a novel facet of the immunosuppressive properties of GCs.

Inhibition of cytokine gene expression by the hormone-activated glucocorticoid receptor (GR) is the key component of the antiinflammatory actions of glucocorticoids, yet the underlying molecular mechanisms remain obscure. Here we report that glucocorticoid repression of cytokine genes in primary macrophages is mediated by GR-interacting protein (GRIP)1, a transcriptional coregulator of the p160 family, which is recruited to the p65-occupied genomic NFκB-binding sites in conjunction with liganded GR. We created a mouse strain enabling a conditional hematopoietic cell-restricted deletion of GRIP1 in adult animals. In this model, GRIP1 depletion in macrophages attenuated in a dose-dependent manner repression of NFκB target genes by GR irrespective of the upstream Toll-like receptor pathway responsible for their activation. Furthermore, genome-wide transcriptome analysis revealed a broad derepression of lipopolysaccharide (LPS)-induced glucocorticoid-sensitive targets in GRIP1-depleted macrophages without affecting their activation by LPS. Consistently, conditional GRIP1-deficient mice were sensitized, relative to the wild type, to a systemic inflammatory challenge developing characteristic signs of LPS-induced shock. Thus, by serving as a GR corepressor, GRIP1 facilitates the anti-inflammatory effects of glucocorticoids in vivo.inflammation | macrophage transcriptome | transcriptional regulation | coactivators | corepressors

For decades, natural and synthetic glucocorticoids (GC) have been among the most commonly prescribed classes of immunomodulatory drugs. Their unsurpassed immunosuppressive and antiinflammatory activity along with cost-effectiveness makes these compounds a treatment of choice for the majority of autoimmune and inflammatory diseases, despite serious side effects that frequently accompany GC therapy. The activated GC receptor (GR) that conveys the signaling information of these steroid ligands to the transcriptional machinery engages a number of pathways to ultimately suppress autoimmune responses. Of those, GR-mediated apoptosis of numerous cell types of hematopoietic origin and suppression of proinflammatory cytokine gene expression have been described as the primary mechanisms responsible for the antiinflammatory actions of GC. However, along with the ever-increasing appreciation of the complex functions of the immune system in health and disease, we are beginning to recognize new facets of GR actions in immune cells. Here, we give a brief overview of the extensive literature on the antiinflammatory activities of GC and discuss in greater detail the unexpected pathways, factors, and mechanisms that have recently begun to emerge as novel targets for GC-mediated immunosuppression.