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Rogatsky I.,Hospital for Special Surgery Research Division | Rogatsky I.,The New School | Adelman K.,U.S. National Institutes of Health
Molecular Cell | Year: 2014

In cells of the immune system, inflammatory stimuli trigger highly coordinated cascades of gene activation that are precisely calibrated to the nature and strength of the stimulus. Herein, we describe the forces that control inflammatory gene transcription and highlight that many critical determinants of responsiveness are established prior to challenge. We discuss key steps in the transcription cycle that are regulated during gene activation and the importance of the underlying enhancer landscape. Further, we illustrate how the diversity in regulatory strategies employed at inflammatory genes provides novel opportunities for therapeutic intervention. © 2014 Elsevier Inc.

Flammer J.R.,The New School | Flammer J.R.,Hospital for Special Surgery Research Division | Dobrovolna J.,Hospital for Special Surgery Research Division | Kennedy M.A.,Hospital for Special Surgery Research Division | And 6 more authors.
Molecular and Cellular Biology | Year: 2010

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. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

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