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Kortikosteroid s2
Kortikosteroid s2
Department of Respiratory Medicine, Adelaide and Meath Hospital, Tallaght, Dublin 24, Eire
Abstract
Corticosteroids are the most potent anti-inflammatory
agents used to treat chronic inflammatory diseases such as
bronchial asthma. However, there are a small number
(,5%) of asthmatic patients who do not respond well, or
at all, to corticosteroid therapy the corticosteroidresistant and corticosteroid-dependent patients. Although
this phenomenon is relatively uncommon, it poses a
dicult therapeutic problem because few alternative
therapies are available and these patients account for
.50% of the health care costs of asthma. If the mechanisms for corticosteroid insensitivity are understood they
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Corticosteroid-resistant asthma
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dexamethasone was able to inhibit AP-1- and NF-Bdriven gene transcription but the ability to facilitate
GRE-mediated eects such as cortisol suppression and
thymocyte apoptosis was markedly attenuated. This also
suggests that the development of glucocorticoids with a
greater therapeutic window is possible.
In addition, corticosteroids may also play a role in
repressing the action of MAPKs such as the extracellular
regulated kinase (ERK) and JNK (Rider et al. 1996,
Caelles et al. 1997, Swantek et al. 1997, Hirasawa et al.
1998). Thus, Caelles and colleagues have demonstrated
that corticosteroids inhibit the phosphorylation and activation of JNK, resulting in a failure to phosphorylate c-Jun
and Elk-1, reduced c-fos transcription and a marked
reduction in AP-1 activity. More recently it has been
shown that dexamethasone can rapidly induce the dual
specificity MAPK inhibitor MKP-1 and thereby attenuate
p38 MAPK activation (Kassel et al. 2001, Lasa et al. 2001,
2002). Rogatsky et al. (1998) have, in turn, shown
reciprocal inhibition of rat GR reporter gene activity by
JNKs by a direct phosphorylation of serine 246 whereas
ERK can inhibit GR action by an indirect eect, possibly
through phosphorylation of a co-factor.
Corticosteroid resistance
Although corticosteroids are highly eective in the control
of asthma and other chronic inflammatory or immune
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Figure 1 How glucocorticoids switch off inflammatory genes. Inflammatory genes are activated by inflammatory stimuli, such as IL-1 or
TNF, acting through their receptors (CyR), resulting in activation of the transcription factors NF-B and AP-1. Upon activation, these are
able to bind to specific recognition sites within the promoter regions of responsive genes (TF-RE) and stimulate transcription of
inflammatory genes such as cytokines and other mediators following recruitment of the basal transcription complex (BTC). GRs, after
activation by corticosteroids, translocate to the nucleus and bind to either a negative GR response element (nGRE) in the promoter of
inflammatory genes inhibiting gene transcription or, more commonly, interact with and block the ability of AP-1 and NF-B from
enhancing gene expression.
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Corticosteroid-resistant asthma
Figure 2 Enhanced expression of c-Fos in the bronchial airways of steroid (corticosteroid)-resistant (SR) asthmatics compared with
steroid-sensitive subjects (SS). Increased intensity of dark brown immunohistological staining of c-Fos within the airway epithelium and
infiltrating mononuclear cells in SR compared with SS subjects.
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Figure 3 Potential mechanisms for corticosteroid insensitivity. Corticosteroids are lipophilic molecules that diffuse readily through cell
membranes to interact with cytoplasmic receptors. Upon ligand binding, receptors (GR) are activated and translocate into the nucleus
where they bind to specific DNA elements. Upon DNA binding, they induce acetylation of lysine residues 5 (K5 +) and 16 (K16 +) on
histone H4 leading to modulation of gene transcription. Alternatively, GR can repress NF-B- or AP-1-induced gene transcription. In some
steroid-insensitive subjects (Group 1) GR is unable to translocate to the nucleus, possibly as a result of p38 MAPK-induced
phosphorylation, and is thereby ineffective. In other steroid-insensitive subjects (Group 2), although GR can successfully translocate to the
nucleus, it is unable to inhibit NF-B and AP-1 and, in addition, has a reduced ability to induce histone acetylation on K5.
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Corticosteroid-resistant asthma
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