1. Update on glucocorticoid action and resistance
Kazuhiro Ito, DVM, PhD, K. Fian Chung, DSc, Ian M. Adcock, PhD 
Journal of Allergy and Clinical Immunology 
Volume 117, Issue 3, Pages (March 2006)
DOI: /j.jaci
Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

2. Fig 1
The GR can produce 8 distinct products (A, B, C1, C2, C3, D1, D2, and D3) by use of alternative translation initiation sites corresponding to methionine residues at 1, 27, 86, 90, 98, 316, 331, and 336. These alternative proteins can be produced from both GRα and GRβ transcripts. Posttranslational modification of GRs, particularly by means of phosphorylation and nitration, alters GR function and contributes to the potential for diverse function in distinct tissues. Other modifications, such as ubiquitination (Ub), sumoylation (Su), and acetylation (Ac), are also shown.
Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci )
Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

3. Fig 2
The GR is comprised of 9 exons. Alternative splicing of exon 9 at the 5′ end of the coding region leads to the formation of the classic GRα isoform and the dominant negative GRβ isoform. The multiple exon 1 variants that might control tissue-selective gene expression are also shown.
Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci )
Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

4. Fig 3
Mechanism of gene activation by the GR. Corticosteroids can freely diffuse across the plasma membrane, where they associate with the inactive cytosolic GR. On ligand binding, the GR is activated and can translocate to the nucleus, where it binds to a GRE within the controlling region for glucocorticoid-responsive target genes. These GREs might be 5′ or 3′ to the start site for transcription. Once bound to DNA, GRs recruit a complex containing basal transcription factors, coactivators (eg, CBP and SRC-1), and chromatin modifiers (eg, SWI/SNF and RNA polymerase II [RNAP II]), which together induce histone modifications, including acetylation (Ac) and chromatin remodeling, and subsequent production of mRNAs encoding various genes, including SLPI, MKP-1, CD163, and the β2-adrenoceptor. SLPI, Secretary leukocyte protease inhibitor.
Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci )
Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

5. Fig 4
Mechanisms of gene repression by the GR. Activated GRs acting as homodimers can bind to GREs that overlap the DNA-binding site for a proinflammatory transcription factor or the start site of transcription to prevent inflammatory gene expression (1). Activated GRs can repress AP-1/NF-κB–mediated gene expression by either inducing the expression of the NF-κB inhibitor IκBα or the AP-1 inhibitor glucocorticoid-inducible leucine zipper (GILZ) through classic gene induction mechanisms (2). Acting as a monomer, GRs can directly or indirectly suppress AP-1/NF-κB activity by (3) altering cofactor activity or by (4) dephosphorylating RNA polymerase II (RNA pol II). GRs can also reduce the levels of mRNA by either inducing the dual-specificity MAPK phosphatase 1 (MPK-1) that in turn regulates p38 MAPK-mediated mRNA stability or increasing the levels of cell ribonucleases and mRNA destabilizing proteins (5). Finally, GRs can induce rapid nongenomic effects either through a membrane receptor or affecting activation of kinases, such as ERK, Akt, or PI3K (6). Mechanisms that have been reported to be reduced under conditions of oxidative stress are shown as a circled “X”. PI3K, Phosphatidylinositol 3-kinase.
Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci )
Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

6. Fig 5
Rationale for dissociated glucocorticoids. Most anti-inflammatory actions of glucocorticoids are mediated through the GR monomer interacting with proinflammatory transcription factors, such as AP-1 and NF-κB, which activate gene expression by reversing the active state of chromatin. In contrast, gene-induction events mediated by a GR homodimer are responsible for many of the detrimental side effects of glucocorticoids, as well as the induction of some anti-inflammatory genes. RNA pol II, RNA polymerase II.
Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci )
Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions