How corticosteroids control inflammation: Quintiles Prize Lecture 2005

Abstract

Corticosteroids are the most effective anti-inflammatory therapy for many chronic inflammatory diseases, such as asthma but are relatively ineffective in other diseases such as chronic obstructive pulmonary disease (COPD). Chronic inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-kappaB and activator protein-1, that bind to and activate coactivator molecules, which then acetylate core histones to switch on gene transcription. Corticosteroids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases, such as asthma, mainly by reversing histone acetylation of activated inflammatory genes through binding of liganded glucocorticoid receptors (GR) to coactivators and recruitment of histone deacetylase-2 (HDAC2) to the activated transcription complex. At higher concentrations of corticosteroids GR homodimers also interact with DNA recognition sites to active transcription of anti-inflammatory genes and to inhibit transcription of several genes linked to corticosteroid side effects. In patients with COPD and severe asthma and in asthmatic patients who smoke HDAC2 is markedly reduced in activity and expression as a result of oxidative/nitrative stress so that inflammation becomes resistant to the anti-inflammatory actions of corticosteroids. Theophylline, by activating HDAC, may reverse this corticosteroid resistance. This research may lead to the development of novel anti-inflammatory approaches to manage severe inflammatory diseases.

Figures

Figure 1

Gene regulation by histone acetylation. Coactivator molecules such as CBP interact with transcription factors such as CREB, AP-1 and NF-κB, resulting in activation of their intrinsic HAT activity. This results in acetylation (Ac) of core histones, opening up the chromatin structure to allow binding on RNA polymerase II, which initiates gene transcription.

Figure 2

Corticosteroids may regulate gene expression in several ways. Corticosteroids enter the cell to bind to GR in the cytoplasm that translocate to the nucleus. GR homodimers bind to GRE in the promoter region of steroid-sensitive genes, which may encode anti-inflammatory proteins. Less commonly, GR homodimers interact with negative GREs to suppress genes, particularly those linked to side effects of corticosteroids. Nuclear GR also interact with coactivator molecules, such as CBP, which is activated by proinflammatory transcription factors, such as NF-κB, thus switching off the inflammatory genes that are activated by these transcription factors. Other abbreviations: SLPI: secretory leukoprotease inhibitor; MKP-1: mitogen-activated kinase phosphatase-1; IκB-α: inhibitor of NF-κB; GILZ: glucocorticoid-induced leucine zipper protein; POMC: proopiomelanocortin; CRF: corticotrophin-releasing factor.

Figure 3

Corticosteroids activation of anti-inflammatory gene expression. Corticosteroids bind to cytoplasmic GR, which translocate to the nucleus where they bind to GRE in the promoter region of steroid-sensitive genes and also directly or indirectly to coactivator molecules such as CBP, pCAF or GRIP-1, which have intrinsic HAT activity, causing acetylation of lysines on histone H4, which leads to activation of genes encoding anti-inflammatory proteins, such as SLPI, MKP-1, IκB-α and GILZ.

Figure 4

Corticosteroids suppression of activated inflammatory genes. Inflammatory genes are activated by inflammatory stimuli, such as IL-1β or TNF-α, resulting in activation of IKK2 (inhibitor of I-κB kinase-2), which activates the transcription factor NF-κB. A dimer of p50 and p65 NF-κB proteins translocates to the nucleus and binds to specific κB recognition sites and also to coactivators, such as CBP or pCAF, which have intrinsic HAT activity. This results in acetylation of core histone H4, resulting in increased expression of genes encoding multiple inflammatory proteins. GR after activation by corticosteroids translocate to the nucleus and bind to coactivators to inhibit HAT activity directly and recruiting HDAC2, which reverses histone acetylation leading in suppression of these activated inflammatory genes.

Figure 5

Acetylation of GR. Binding of a corticosteroid to GR results in its acetylation by HAT, such as CBP, and a dimmer of acetylated GR then binds to GRE to activate or suppress genes (such as side effect genes). Deacetylation of GR by HDAC2 is necessary for GR to interact with CBP and inhibit NF-κB to switch off inflammatory genes.

Figure 6

A proposed mechanism of corticosteroid resistance in COPD, severe asthma and smoking asthma. Stimulation of normal and asthmatic alveolar macrophages activates NF-κB and other transcription factors to switch on HAT leading to histone acetylation and subsequently to transcription of genes encoding inflammatory proteins, such as TNF-α, IL-8 and GM-CSF. Corticosteroids reverse this by binding to GR and recruiting HDAC2. This reverses the histone acetylation induced by NF-κB and switches off the activated inflammatory genes. In COPD and smoking asthmatic patients cigarette smoke generates oxidative stress (acting through the formation of peroxynitrite) to impair the activity of HDAC2. This amplifies the inflammatory response to NF-κB activation, but also reduces the anti-inflammatory effect of corticosteroids, as HDAC2 is now unable to reverse histone acetylation. A similar mechanism may operate in severe asthma where increased oxidative stress is generated by airway inflammation.

Figure 7

Possible mechanism of HDAC2 inactivation in COPD and smoking asthmatics. Cigarette smoking and inflammation in COPD lungs generates superoxide anions (O2−) and nitric oxide (NO) from iNOS, which combine to form peroxynitrite. Peroxynitrite nitrates certain tyrosine residues (Tyr) and this may inactive the catalytic activity of HDAC2 and also mark the enzyme for ubiquitination (Ub), resulting in destruction by the proteasome. This loss of HDAC2 results in increased histone acetylation, leading to amplification of inflammation and blocking the anti-inflammatory effects of corticosteroids.