Journal Article

Glucocorticoid resistance in inflammatory diseases

Barnes, Peter J, Adcock, Ian M

2009

Overview

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 κB, 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-δ inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.

• Publisher: Elsevier Ltd,Elsevier,Elsevier Limited
• Subject: Anti-Inflammatory Agents - therapeutic use / Asthma / Asthma - drug therapy / ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects / ATP-Binding Cassette, Sub-Family B, Member 1 - genetics / ATP-Binding Cassette, Sub-Family B, Member 1 - immunology / Biological and medical sciences / Calcineurin Inhibitors / Chronic obstructive pulmonary disease / Drug Resistance - drug effects / Drug Resistance - genetics / Drug Resistance - immunology / Drug therapy / General aspects / Genetic Predisposition to Disease - genetics / Glucocorticoids - therapeutic use / Histone Deacetylase 2 / Histone Deacetylases - drug effects / Histone Deacetylases - genetics / Histone Deacetylases - immunology / Humans / Inflammation - drug therapy / Inflammation - immunology / Inflammatory bowel disease / Inhibitors / Internal Medicine / Macrophage Migration-Inhibitory Factors - drug effects / Macrophage Migration-Inhibitory Factors - genetics / Macrophage Migration-Inhibitory Factors - immunology / Medical sciences / Mitogen-Activated Protein Kinases - drug effects / Mitogen-Activated Protein Kinases - genetics / Mitogen-Activated Protein Kinases - immunology / NF-kappa B - antagonists & inhibitors / Phosphodiesterase 4 Inhibitors / Proteins / Pulmonary Disease, Chronic Obstructive - drug therapy / Repressor Proteins - drug effects / Repressor Proteins - genetics / Repressor Proteins - immunology / Respiratory distress syndrome / Rheumatoid arthritis / Side effects / Steroids / Transcription Factor AP-1 - drug effects / Transcription Factor AP-1 - genetics / Transcription Factor AP-1 - immunology / Transcriptional Activation - drug effects / Transcriptional Activation - genetics / Transcriptional Activation - immunology / Vitamin D