title: Corticosteroids inhibit lymphocyte binding to endothelium and intercellular adhesion: an additional mechanism for their anti-inflammatory and immunosuppressive effect.
abstract: Glucocorticosteroids (GCS) are potent anti-inflammatory and immunosuppressive agents widely used in the treatment of many medical conditions, but their mechanism of action is not yet fully understood. Some of the anti-inflammatory effects of GCS have been attributed to the synthesis of lipocortins, whereas the immunosuppressive effects are thought to be mediated through the inhibition of several immune functions through a down-regulation of cytokine gene expression. Another important mechanism of action of GCS may relate to their ability to interfere with the phenomena of adhesion and migration of inflammatory cells. In this study, the direct effects of GCS on lymphocyte adhesion capacity in vitro were investigated. We demonstrate that GCS inhibit lymphocyte adhesion to endothelium through the down-modulation of lymphocyte adhesion molecules. We also provide evidence that GCS inhibit cell aggregate formation induced by TCR ligation, which directly correlates with the down-modulation of LFA-1 and CD2, but not LFA-3 or ICAM-1. Such down-modulation was paralleled by a decrease in the steady state mRNA level of LFA-1 and CD2 gene products, which suggests a direct GCS control of the expression of these genes. Finally, we show that GCS effects are mediated through the GCS receptor, since they can be completely reversed by the GCS-R antagonist RU-486. This study supports the concept that some of the immunosuppressive and anti-inflammatory effects of GCS are likely to be exerted by the inhibition of adhesion-dependent lymphocyte functions.
authors.affiliation: Rheumatology Unit, United Medical and Dental Schools of Guys and St. Thomas Hospitals, London, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Pitzalis
authors.forename: N
authors.initials: N
authors.lastname: Pipitone
authors.forename: G
authors.initials: G
authors.lastname: Bajocchi
authors.forename: M
authors.initials: M
authors.lastname: Hall
authors.forename: N
authors.initials: N
authors.lastname: Goulding
authors.forename: A
authors.initials: A
authors.lastname: Lee
authors.forename: G
authors.initials: G
authors.lastname: Kingsley
authors.forename: J
authors.initials: J
authors.lastname: Lanchbury
authors.forename: G
authors.initials: G
authors.lastname: Panayi
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018801:CD2 Antigens / Q000235:genetics / Q000378:metabolism; D018968:CD58 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D018801:CD2 Antigens; D018968:CD58 Antigens; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D003907:Dexamethasone