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Clinical and molecular aspects of glucocorticoid resistant asthma.

Corrigan CJ, Loke TK - Ther Clin Risk Manag (2007)

Bottom Line: It purports that, since glucocorticoid resistant asthmatics are not globally physiologically glucocorticoid resistant, then the phenomenon is most likely acquired, probably in immune cells (and most probably in T cells and monocyte/macrophages), as a result of local inflammatory and environmental influences.The molecular mechanisms which have been uncovered to date which could account for glucocorticoid resistance are discussed, in particular the roles of AP-1 and p38 MAP kinase signaling, the role of the beta-isoform of the glucocorticoid receptor and the role of histone proteins and DNA folding.Finally, there are suggestions for clinical management of these patients based on accumulated evidence.

View Article: PubMed Central - PubMed

Affiliation: Division of Asthma, Allergy and Lung Biology, King’s College London, London, England, UK; MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King’s College London London, England, UK.

ABSTRACT
This paper is an overview of the diagnosis, differential diagnosis and cellular and molecular mechanisms of glucocorticoid resistant asthma. It addresses the clinical definition and rationale for the diagnosis of therapy resistant asthma. It purports that, since glucocorticoid resistant asthmatics are not globally physiologically glucocorticoid resistant, then the phenomenon is most likely acquired, probably in immune cells (and most probably in T cells and monocyte/macrophages), as a result of local inflammatory and environmental influences. The molecular mechanisms which have been uncovered to date which could account for glucocorticoid resistance are discussed, in particular the roles of AP-1 and p38 MAP kinase signaling, the role of the beta-isoform of the glucocorticoid receptor and the role of histone proteins and DNA folding. Finally, there are suggestions for clinical management of these patients based on accumulated evidence.

No MeSH data available.


Related in: MedlinePlus

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 Figure 1 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.
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fig2: 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 Figure 1 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.

Mentions: The pro-inflammatory transcriptional element activator protein-1 (AP-1) is an important contributor to the expression of the asthma-relevant Th2 cytokines IL-4, IL-5 and IL-13. AP-1 comprises of variable heterodimers of Jun (c-Jun, JunB and JunD) and Fos (c-Fos, FosB, Fra1 and Fra2) family members. AP-1 is inducible by a variety of cytokines and growth factors (Lee et al 1987), and also by oxidative stress (see above). It is activated through the phosphorylation of c-Jun and the transcriptional regulation of c-Fos (Figure 2). Phosphorylation of c-Jun is the end result of the action of a trilayer of kinases (English and Cobb 2002). c-Jun itself is phosphorylated by Jun-N-terminal kinase (JNK), a member of the extracellular signal-related kinases/mitogen-activated protein kinases (ERK/MAPK) family of serine/threonine kinases. JNK is in turn activated by phosphorylation by JNK kinase, a member of the MAPK/ERK kinase (MEK) family of kinases that phosphorylate on both a tyrosine and a threonine or serine residue. Of the seven members of the MEK family, MEK4 or Jun-N-terminal kinase kinase is principally responsible for the phosphorylation of JNK. At the top end of the trilayer, the most upstream kinases in the cascade, are the MEK kinases (MEKK), serine/threonine kinases that are diverse in sequence and structure (Figure 3).


Clinical and molecular aspects of glucocorticoid resistant asthma.

Corrigan CJ, Loke TK - Ther Clin Risk Manag (2007)

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 Figure 1 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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376076&req=5

fig2: 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 Figure 1 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.
Mentions: The pro-inflammatory transcriptional element activator protein-1 (AP-1) is an important contributor to the expression of the asthma-relevant Th2 cytokines IL-4, IL-5 and IL-13. AP-1 comprises of variable heterodimers of Jun (c-Jun, JunB and JunD) and Fos (c-Fos, FosB, Fra1 and Fra2) family members. AP-1 is inducible by a variety of cytokines and growth factors (Lee et al 1987), and also by oxidative stress (see above). It is activated through the phosphorylation of c-Jun and the transcriptional regulation of c-Fos (Figure 2). Phosphorylation of c-Jun is the end result of the action of a trilayer of kinases (English and Cobb 2002). c-Jun itself is phosphorylated by Jun-N-terminal kinase (JNK), a member of the extracellular signal-related kinases/mitogen-activated protein kinases (ERK/MAPK) family of serine/threonine kinases. JNK is in turn activated by phosphorylation by JNK kinase, a member of the MAPK/ERK kinase (MEK) family of kinases that phosphorylate on both a tyrosine and a threonine or serine residue. Of the seven members of the MEK family, MEK4 or Jun-N-terminal kinase kinase is principally responsible for the phosphorylation of JNK. At the top end of the trilayer, the most upstream kinases in the cascade, are the MEK kinases (MEKK), serine/threonine kinases that are diverse in sequence and structure (Figure 3).

Bottom Line: It purports that, since glucocorticoid resistant asthmatics are not globally physiologically glucocorticoid resistant, then the phenomenon is most likely acquired, probably in immune cells (and most probably in T cells and monocyte/macrophages), as a result of local inflammatory and environmental influences.The molecular mechanisms which have been uncovered to date which could account for glucocorticoid resistance are discussed, in particular the roles of AP-1 and p38 MAP kinase signaling, the role of the beta-isoform of the glucocorticoid receptor and the role of histone proteins and DNA folding.Finally, there are suggestions for clinical management of these patients based on accumulated evidence.

View Article: PubMed Central - PubMed

Affiliation: Division of Asthma, Allergy and Lung Biology, King’s College London, London, England, UK; MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King’s College London London, England, UK.

ABSTRACT
This paper is an overview of the diagnosis, differential diagnosis and cellular and molecular mechanisms of glucocorticoid resistant asthma. It addresses the clinical definition and rationale for the diagnosis of therapy resistant asthma. It purports that, since glucocorticoid resistant asthmatics are not globally physiologically glucocorticoid resistant, then the phenomenon is most likely acquired, probably in immune cells (and most probably in T cells and monocyte/macrophages), as a result of local inflammatory and environmental influences. The molecular mechanisms which have been uncovered to date which could account for glucocorticoid resistance are discussed, in particular the roles of AP-1 and p38 MAP kinase signaling, the role of the beta-isoform of the glucocorticoid receptor and the role of histone proteins and DNA folding. Finally, there are suggestions for clinical management of these patients based on accumulated evidence.

No MeSH data available.


Related in: MedlinePlus