Glucocorticoid receptors must be deacetylated by HDAC2 to block NF-κB-driven gene expression.

A new study by Ito and colleagues on page 7 may help explain why patients with a severe lung disease called chronic obstructive pulmonary disease (COPD) fail to respond to steroid treatment. Ito and colleagues show that steroids require the enzyme HDAC2 (histone deacetylase 2) to block the inflammatory transcription factor NF-κB. In patients with COPD, HDAC2 activity is reduced, rendering cells impervious to the soothing effects of steroids.

Steroids called glucocorticoids (GCs) are powerful antiinflammatory drugs used to treat chronic inflammatory disorders such as asthma and inflammatory bowel disease. But these drugs don't work in patients with COPD—a chronic inflammatory disease of the lungs linked to cigarette smoking.

When working properly, GCs calm inflammation in two ways. They bind to the cytoplasmic glucocorticoid receptor (GR), which then binds to NF-κB and prevents it from activating inflammatory gene expression. At high concentrations, GCs also induce the expression of HDAC proteins.

Consistent with the induction of HDAC expression in antiinflammatory responses, this group had previously shown that patients with more severe COPD had decreased expression of HDAC2, probably due to oxidative damage to the enzyme inflicted by cigarette smoke. HDAC2 is most well-known for plucking acetyl groups from histones, thus preventing the transcriptional machinery from binding to chromatin. But now Ito and colleagues find that HDAC2 also deacetylates GRs. GRs are acetylated in response to steroid binding, but must be deacetylated by HDAC2 to allow them to block NF-κB–driven inflammation.

Overexpressing HDAC2 in macrophages from patients with COPD restored GC-induced suppression of NF-κB–driven cytokine production. These data not only identify GR as the first nonhistone target for HDAC2, but also suggest that strategies aimed at increasing HDAC2 activity, combined with steroids, might be useful for treating patients with COPD.