Figures & data
Table 1 Diagnoses that may masquerade as difficult/therapy-resistant asthma
Table 2 Factors that may be responsible for poor asthma control Incorrect diagnosis
Figure 1 Mechanism of glucocorticoid action. After diffusion across the cytoplasmic membrane, glucocorticoid (GC) binds to the glucocorticoid receptor (GR) which dissociates from heat shock protein 90 (HSP90) then dimerises. In the cell cytoplasm it may interact with transcriptional regulatory proteins such as AP-1; such interactions are mutually inhibitory. Nuclear translocation of the ligand bound GR is regulated by chemical modifications, such as phosphorylation, and possibly other mechanisms. Once inside the nucleus, the ligand bound receptor may interact directly with binding regions (glucocorticoid regulatory elements, GRE) adjacent to genes, either increasing (A) or decreasing (B, negative GRE) transcription of these genes. More usually, however, the ligand-bound GR interacts with DNA as part of a highly dynamic complex of proteins including transcriptional regulatory proteins such as AP-1, NFκB and cyclic AMP response element binding protein (CREB) (see text). The complexity of these interactions in individual cells accounts for the remarkable variability of glucocorticoid actions on cells according to their function and phenotype.
Figure 2 Regulation of activation of c-fos and c-jun, the components of AP-1. Transcription of c-fos is induced by serum response factor (SRF) which binds to the serum response element (SRE) adjacent to the c-fos gene. SRF is activated by phosphorylation by ELK-1, which is in turn activated by phosphorylation by a range of MAP kinases including ERK-1/2 and JNK (see text). Phosphorylated JNK also phosphorylates and activates c-jun, which together with c-fos forms the heterodimer complex AP-1. AP-1 increases the transcription of a number of asthma-relevant cytokine genes such as interleukin (IL)-4 and IL-5. This activity is inhibited by interaction with the ligand bound glucocorticoid receptor (GR) (see text and above). IL-4 and IL-5 may in turn further stimulate MAP kinase activity, forming a positive, feed-forward loop. Many other stimuli, including oxidative stress may also activate MAP kinases.
Figure 3 The tri-layer of kinases which activate c-jun. Environmental cytokines, ultraviolet light, serum factors, oxidative stress and many other stimuli phosphorylate and activate MEKK-1/4 through the Ras/Rho family of small GTP-binding proteins as shown. MEKK1 in turn phosphorylates JNKK1, which phosphorylates JNK, which binds to and phosphorylates c-jun, the active component of AP-1 (see text and above), and the regulatory protein activating transcription factor-2 (ATF-2). Phosphorylation may occur on threonine or tyrosine residues.
Abbreviations: GT(D)P, guanosine tri(di)phosphate; JNK, c-jun N-terminal kinase; JNKK1, c-jun N-terminal kinase kinase-1; MEKK-1/4, MAPK/ERK kinase kinase-1/4; SAPK, serum activated protein kinase; Ser, serine; SOS, son of sevenless; Thr, threonine; Tyr, tyrosine.
Table 3 Investigation of difficult/therapy resistant asthma