title: Mechanisms of the anti-inflammatory effects of glucocorticoids: genomic and nongenomic interference with MAPK signaling pathways.
abstract: Glucocorticoids (GCs) are steroid hormones produced by the adrenal gland and regulated by the hypothalamus-pituitary-adrenal axis. GCs mediate effects that mostly result in transcriptional regulation of glucocorticoid receptor target genes. Mitogen-activated protein kinases (MAPKs) comprise a family of signaling proteins that convert extracellular stimuli into the activation of intracellular transduction pathways via phosphorylation of a cascade of substrates. They modulate a variety of physiological cell processes, such as proliferation, apoptosis, and development. However, when MAPKs are improperly activated by proinflammatory and/or extracellular stress stimuli, they contribute to the regulation of proinflammatory transcription factors, thus perpetuating activation of the inflammatory cascade. One of the mechanisms by which GCs exert their anti-inflammatory effects is negative interference with MAPK signaling pathways. Several functional interactions between GCs and MAPK signaling have been discovered and studied. Some of these interactions involve the GC-mediated up-regulation of proteins that in turn interfere with the activation of MAPK, such as glucocorticoid-induced-leucine zipper, MAPK phosphatase-1, and annexin-1. Other mechanisms include activated GR directly interacting with components of the MAPK pathway and negatively regulating their activation. The multiple interactions between GCs and MAPK pathways and their potential biological relevance in mediating the anti-inflammatory effects of GCs are reviewed.
authors.affiliation: Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Perugia, Via del Giochetto, 06122 Perugia, Italy. ayroldi@unipg.it
authors.forename: Emira
authors.initials: E
authors.lastname: Ayroldi
authors.forename: Lorenza
authors.initials: L
authors.lastname: Cannarile
authors.forename: Graziella
authors.initials: G
authors.lastname: Migliorati
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
authors.forename: Domenico V
authors.initials: DV
authors.lastname: Delfino
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D020928:Mitogen-Activated Protein Kinases