Glucocorticoid resistance in inflammatory diseases

Lancet. 2009 May 30;373(9678):1905-17. doi: 10.1016/S0140-6736(09)60326-3.

Abstract

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.

Publication types

  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / immunology
  • Anti-Inflammatory Agents / therapeutic use*
  • Asthma / drug therapy
  • Calcineurin Inhibitors
  • Drug Resistance* / drug effects
  • Drug Resistance* / genetics
  • Drug Resistance* / immunology
  • 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
  • Macrophage Migration-Inhibitory Factors / drug effects
  • Macrophage Migration-Inhibitory Factors / genetics
  • Macrophage Migration-Inhibitory Factors / immunology
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / immunology
  • NF-kappa B / antagonists & inhibitors
  • Phosphodiesterase 4 Inhibitors
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Repressor Proteins / drug effects
  • Repressor Proteins / genetics
  • Repressor Proteins / immunology
  • 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

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Inflammatory Agents
  • Calcineurin Inhibitors
  • Glucocorticoids
  • Macrophage Migration-Inhibitory Factors
  • NF-kappa B
  • Phosphodiesterase 4 Inhibitors
  • Repressor Proteins
  • Transcription Factor AP-1
  • Mitogen-Activated Protein Kinases
  • Histone Deacetylase 2
  • Histone Deacetylases