The Interplay between the Glucocorticoid Receptor and Nuclear Factor-κB or Activator Protein-1: Molecular Mechanisms for Gene Repression

Abstract

The inflammatory response is a highly regulated physiological process that is critically important for homeostasis. A precise physiological control of inflammation allows a timely reaction to invading pathogens or to other insults without causing overreaction liable to damage the host. The cellular signaling pathways identified as important regulators of inflammation are the signal transduction cascades mediated by the nuclear factor-kappaB and the activator protein-1, which can both be modulated by glucocorticoids. Their use in the clinic includes treatment of rheumatoid arthritis, asthma, allograft rejection, and allergic skin diseases. Although glucocorticoids have been widely used since the late 1940s, the molecular mechanisms responsible for their antiinflammatory activity are still under investigation. The various molecular pathways proposed so far are discussed in more detail.

Mental Performance in Old Age Dependent on Cortisol and Genetic Variance in the Mineralocorticoid and Glucocorticoid Receptors

“…However, the multivariate analysis did not add any extra information. The cortisol signaling cascade is complex and involves numerous chaperones, accessory proteins, co-regulators and interacting transcription factors that permit differentiation between the MR-and GR-mediated actions (De Bosscher et al, 2003;Pascual-Le Tallec and Lombes, 2005). For instance, recently it was found that increase in recurrence of depressive episodes is associated with a variant in a gene (FKBP5) that regulates GR activity (Binder et al, 2004).…”

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…The transcription factor AP-1 mediates gene regulation in response to a broad range of physiological and pathological stimuli, including cytokines, growth factors, ROS, infection and other stress signals as well as oncogenic stimuli [353,385,[389][390][391][392][393][394]. In addition, steroid producing tissues are thought to require AP-1 for the regulation of steroidogenesis [387,[385][386][387][388][389][390][391][392][393][394][395][396][397][398][399][400].…”

“…In addition, steroid producing tissues are thought to require AP-1 for the regulation of steroidogenesis [387,[385][386][387][388][389][390][391][392][393][394][395][396][397][398][399][400]. AP-1 transcription factors are homo-and hetero-dimers of Jun (c-Jun, JunB and JunD), Fos (c-Fos, FosB, FosB splice variants FosB2 and DeltaFosB2 and Fra-1 and Fra-2) Jun dimerization partner (JDP1 and JDP2) and the closely related activating transcription factor (ATFa, ATF2, LRF1/ATF3, B-ATF) family of proteins characterized by basic region and leucine-zipper domains [353,385,[389][390][391][392][393][394]. In addition, some of the Maf proteins (vMaf, c-Maf and Nrl) can heterodimerize with c-Junior c-Fos, whereas other Maf related proteins, including MafB, MafF, MafG and MafK, heterodimerize with c-Fos but not with cJun.…”

“…AP-1 activity is regulated at various levels, including transcriptional and post-transcriptional mechanisms leading to increased AP-1 expression and post-translational modifications, such as phosphorylation, post-translational processing and turnover or pre-existing or newly synthesized AP-1 subunits and oxidation/reduction, altering DNA binding affinity and transactivation potential [390,[392][393][394][401][402][403][404][405]. Since DNA binding affinity and transactivation potential are different for the various proteins, AP-1 activity is also determined by its composition [390,393,403,405].…”

Association of NFKB1 −94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease

“…26 Therefore, the treatment of Graves' ophthalmopathy with glucocorticoids is predominantly directed against the NF-kB signaling pathway. 27,28 To analyze further the effect of NFKB1 vs other environmental and demographic factors on the development of eye symptoms, we applied multiple logistic regression analysis. In both cohorts the NFKB1 polymorphism increased the risk of developing eye disease.…”