Regulation of leukocyte-endothelial interactions by glucocorticoids.
Glucocorticoids (GCs) are steroid molecules endowed with powerful anti-inflammatory and immunosuppressive properties. Traditionally, the anti-inflammatory action of GC has been largely ascribed to the synthesis of lipocortin-1 (now know as annexin I), while the immunosuppressive effect has been linked to the inhibition of several immune functions and the synthesis of important cytokines and chemokines. In addition to these modes of action, there is a mounting body of evidence suggesting that GCs can also inhibit cell adhesion events, which also play a crucial role in the inflammatory/ immune response. The mechanisms by which GCs modulate cell adhesion are complex and multifactorial. It is now clear that GCs can directly regulate cell adhesion molecule (CAM) gene transactivation through the classical glucocorticoid receptor (GR) pathways. These involve interference with activation/ transcription factors such as AP-1 and NF-kappaB, as well as binding of the GC-GR complex to specific DNA sequences, called glucocorticoid response element "GRE," with ensuing CAM gene inhibition. In addition to these "genomic" mechanisms, there is increasing recognition of alternative modalities of action of GC that are independent from modulating gene expression and for this reason defined as "non-genomic." These are characterized by a rapid response (seconds/minutes) and insensitivity to inhibitors of gene transcription and protein synthesis. The non-genomic effects could be due to direct physicochemical interactions with cell membrane constituents including ion channels and membrane associated proteins. This would lead to inhibition of intracellular signaling pathways involved in CAM activation and cytoskeleton reorganization essential for cell adhesion and locomotion.
Pitzalis
Costantino
C
Rheumatology Unit, Thomas Guy House, Guy's Hospital, London, UK. costantino.pitzalis@kcl.ac.uk
Pipitone
Nicolo
N
Perretti
Mauro
M
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D008954:Models, Biological; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D005938:Glucocorticoids; D016023:Integrins; D011965:Receptors, Glucocorticoid; D016201:Receptors, Lymphocyte Homing; D013755:Tetradecanoylphorbol Acetate