Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists

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Abstract

Glucocorticoids (GC) are the most common used anti-inflammatory and immunosuppressive drugs in the treatment of rheumatic and other inflammatory diseases. Their therapeutic effects are considered to be mediated by four different mechanisms of action: the classical genomic mechanism of action caused by the cytosolic glucocorticoid receptor (cGCR); secondary non-genomic effects which are also initiated by the cGCR; membrane-bound glucocorticoid receptor (mGCR)-mediated non-genomic effects; non-specific, non-genomic effects caused by interactions with cellular membranes. The classical, genomic mechanism of GC-action can be divided into two processes: “transrepression”, which is responsible for a large number of desirable anti-inflammatory and immunomodulating effects, and “transactivation” which is associated with frequently occurring side effects as well as with some immunosuppressive activities [Ehrchen, J., Steinmuller, L., Barczyk, K., Tenbrock, K., Nacken, W., Eisenacher, M., Nordhues, U., Sorg, C., Sunderkotter, C., Roth, J., 2007. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Blood 109, 1265–1274]. Great efforts have been made to diminish glucocorticoid-induced adverse effects, but the improvement of conventional glucocorticoids has almost reached its limits. As a consequence, new variations of the conventional “good old drugs” are being tested and nitro-steroids and long circulating liposomal glucocorticoids indeed show promising results. Nevertheless, crux of the matter should be the design of qualitatively new drugs, such as selective glucocorticoid receptor agonists (SEGRAs). These innovative steroidal or non-steroidal molecules induce transrepression, while transactivation processes are less affected. First reports on two different GCR ligands, A276575 and ZK216348, show promising results. Here, we review the above-mentioned mechanisms of glucocorticoid action and give particular attention to the development of optimized glucocorticoids and SEGRAs.

Introduction

Glucocorticoids are successfully used in the treatment of a wide range of rheumatic and other inflammatory diseases. Clinically relevant in this regard are immunosuppressive, anti-inflammatory and anti-allergic effects that glucocorticoids exert on primary and secondary immune cells, tissues and organs. The most important effects of glucocorticoids on different cell types are listed in Table 1 (Buttgereit et al., 2005).

The inactive form of the glucocorticoid cortisol, so-called cortisone, has been isolated in the years 1936–1940 by different groups, and cortisol was first synthesised by Reichstein in 1937/1938. About 10 years later, glucocorticoids were introduced into clinical medicine and the researchers primarily involved were awarded the Nobel price for their fundamental work. Since then, glucocorticoids were more and more used to treat numerous diseases, but at the same time the potential of these drugs to induce unwanted effects became obvious. This downside was the reason why new glucocorticoid agents were synthesised in the 1950–1960s, e.g. prednisolone and methylprednisolone having stronger anti-inflammatory and immunosuppressive potencies, and lesser mineralcorticoid activities. Other examples for synthetic drugs are the fluorinated glucocorticoids dexamethasone and betamethasone. Another advancement was the delivery of these drugs directly to the side of inflammation, e.g. by inhalation in case of asthma, by topical application for eczema or in the case of rheumatic diseases by intra-articular injection. Glucocorticoids are relatively inexpensive drugs, but due to the enormous volume prescribed, the total market size is believed to be about US$ 10 billion per year (Schacke et al., 2002).

In spite of every effort to improve treatment with glucocorticoids, these drugs still carry significant risks (Buttgereit et al., 2002). Treatment with higher glucocorticoid dosages over longer periods of time causes adverse reactions, such as unwanted effects on metabolism (diabetes), bone tissue (osteoporosis), muscles (myopathy), eyes and skin (Schacke et al., 2002, Schacke et al., 2004). Furthermore, glucocorticoids may cause increased susceptibility to infections. Another major problem in the treatment of inflammatory diseases represents glucocorticoid resistance (Adcock and Lane, 2003, Wikstrom, 2003). In order to optimise the benefit–risk-ratio, it is important to understand better the underlying mechanisms of glucocorticoid action. Different studies have shown that glucocorticoid activities can be divided into genomic effects, mediated by the cytosolic glucocorticoid receptor alpha (cGCR) and different non-genomic effects (Buttgereit et al., 2004, Buttgereit et al., 2005, Buttgereit et al., in press, Adcock and Lane, 2003, Wikstrom, 2003, Almawi and Melemedjian, 2002, Buttgereit and Scheffold, 2002, Pratt, 1998). These non-genomic glucocorticoid activities can be subclassified further into three modes of action: cGCR-mediated non-genomic effects; non-specific non-genomic effects (for example, physicochemical interactions with the plasma membrane at high glucocorticoid concentrations); and effects that are considered to be mediated by membrane-bound glucocorticoid receptors (Fig. 2) (Buttgereit and Scheffold, 2002, Spies et al., 2006).

Section snippets

The classical genomic mechanism of glucocorticoid action is cGCR-mediated

The unligated cytosolic glucocorticoid receptor, a member of the steroid-hormone-receptor family, is a 94-kD protein which exists in the cytoplasm as a multiprotein complex containing several heat-shock proteins (Hsp), such as Hsp90, Hsp70, Hsp56 and Hsp40. There is also an interaction with immunophilins, (co)chaperones (such as p23 and Src (Wikstrom, 2003, Almawi and Melemedjian, 2002, Pratt, 1998)), and several kinases of the mitogen-activated protein kinase (MAPK) signalling system. The

Rapid effects of glucocorticoids are mediated by three different mechanisms

Three different non-genomic mechanisms have been proposed to explain rapid anti-inflammatory and immunosuppressive GC effects (Buttgereit and Scheffold, 2002, Falkenstein et al., 2000, Cato et al., 2002, Croxtall et al., 2000, Hafezi-Moghadam et al., 2002):

  • non-specific interactions of glucocorticoids with cellular membranes,

  • non-genomic effects which are mediated by the cytosolic GR (cGCR),

  • specific interactions with a membrane-bound GCR (mGCR).

We will now discuss these mechanisms that underlie

Optimized glucocorticoids and selective glucocorticoid receptor agonists

The different molecular mechanisms of glucocorticoid actions afford a certain number of starting points for the development of optimized and/or new glucocorticoids and glucocorticoid receptor ligands.

Conclusion

In summary, over the last years our knowledge on glucocorticoids – being the most important and most frequently used anti-inflammatory and immunosuppressive drugs – and their mechanisms of action has increased enormously. The cytosolic glucocorticoid receptor has been shown not only to mediate well-known genomic actions, but is also involved in rapid non-genomic effects due to complex interactions with various signalling processes. Other hot spots in glucocorticoid research are the therapeutic

Acknowledgements

Daniel Hommes is financially supported by The Netherlands Organization for Health Research and Development. Frank Buttgereit's work is supported by the DFG (BU 1015/7-1) and by the Federal Ministry of Education and Research (01GS0110/01GS0160/01GS0413).

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