Glucocorticoid resistance in inflammatory diseases.
Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
Barnes
Peter J
PJ
National Heart and Lung Institute, Imperial College, London, UK. p.j.barnes@imperial.ac.uk
Adcock
Ian M
IM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy; D065095:Calcineurin Inhibitors; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005938:Glucocorticoids / Q000627:therapeutic use*; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D008263:Macrophage Migration-Inhibitory Factors / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000893:Anti-Inflammatory Agents; D065095:Calcineurin Inhibitors; D005938:Glucocorticoids; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D058988:Phosphodiesterase 4 Inhibitors; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D020928:Mitogen-Activated Protein Kinases; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases