Molecular Mechanisms of Corticosteroid Resistance
2009; Elsevier BV; Volume: 135; Issue: 2 Linguagem: Inglês
10.1378/chest.08-2385
ISSN1931-3543
AutoresAntonella Tonello, Giovanni Poli,
Tópico(s)Electrolyte and hormonal disorders
ResumoTo the Editor:In a recent issue of CHEST (August 2008), Adcock and Barnes1Adcock IM Barnes PJ Molecular mechanisms of corticosteroid resistance.Chest. 2008; 134: 394-401Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar presented a very interesting and informative study on the molecular mechanism of glucocorticoid (GC) resistance. As the author stated, understanding in detail the action, and inaction, of GCs may lead to the development of new antiinflammatory drugs that are able to subvert the relative corticosteroid insensitivity that is characteristic of patients with severe asthma and COPD. We want to call attention to the prereceptor metabolism of GCs, another mechanism that may have a role in GC resistance. Within target tissues, cortisol and its inactive metabolite, cortisone, are interconverted through the activity of 11β-hydroxysteroid dehydrogenase (11β-HSD).2Seckl JR 11β-hydroxysteroid dehydrogenases: changing glucocorticoid action.Curr Opin Pharmacol. 2004; 4: 597-602Crossref PubMed Scopus (152) Google Scholar Two 11β-HSD isoforms have been characterized and are expressed in lung tissue and immunity cells. In particular, 11β-HSD1 acts as a ketoreductase by virtue of the intracellular localization within the lumen of the endoplasmic reticulum in proximity to the hexose-phosphate dehydrogenase (H6PD).3Tomlinson JW Walker EA Bujalska IJ et al.11β-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.Endocr Rev. 2004; 25: 831-866Crossref PubMed Scopus (824) Google Scholar H6PD couples the oxidation of hexose-6-phosphate to the reduction of nicotinamide adenine dinucleotide phosphate (NADPH). It is the generation of NADPH within the endoplasmic reticulum adjacent to 11β-HSD1 that drives its reaction direction. Intracellular GC regeneration by 11β-HSD1 is dependent not just on its steroid substrate, but also on G6P import into the endoplasmic reticulum and H6PD-mediated production of NADPH.In case of oxidative stress, which is common in patients with severe asthma and COPD, the regeneration of endoplasmic NADPH may be impaired and so may be 11β-HSD1 activity. This mechanism may have a great relevance in GC resistance. Prednisolone and prednisone are substrates for 11β-HSD1, and dexamethasone may also be regenerated by 11β-HSD1.3Tomlinson JW Walker EA Bujalska IJ et al.11β-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.Endocr Rev. 2004; 25: 831-866Crossref PubMed Scopus (824) Google Scholar The physiologic role of 11β-HSD1 in amplifying the GC signal is evidenced by the fact that GCs themselves increase 11β-HSD1 expression in many cells.4Sai S Esteves CL Kelly V et al.Glucocorticoid regulation of the promoter of 11β-hydroxysteroid dehydrogenase type 1 is indirect and requires CCAAT/enhancer-binding protein-β.Mol Endocrinol. 2008; 22: 2049-2060Crossref PubMed Scopus (70) Google Scholar The induction is indirect and requires new protein synthesis activated by CCAAT/enhancer-binding protein (C/EBP)β. (C/EBP)β is a key mediator of metabolic and inflammatory signaling and mediates the effects of GCs on genes that lack GC binding sites in many cell types, among which are the H441 and A549 lung epithelial cells.4Sai S Esteves CL Kelly V et al.Glucocorticoid regulation of the promoter of 11β-hydroxysteroid dehydrogenase type 1 is indirect and requires CCAAT/enhancer-binding protein-β.Mol Endocrinol. 2008; 22: 2049-2060Crossref PubMed Scopus (70) Google Scholar It is possible that GC enhancement of local innate host defense mechanisms is mediated via (C/EBP)β, in contrast to the antiinflammatory mechanisms of GCs, which are predominantly mediated through interference with nuclear factor-κB and activator protein-1 functions.4Sai S Esteves CL Kelly V et al.Glucocorticoid regulation of the promoter of 11β-hydroxysteroid dehydrogenase type 1 is indirect and requires CCAAT/enhancer-binding protein-β.Mol Endocrinol. 2008; 22: 2049-2060Crossref PubMed Scopus (70) Google Scholar Pharmacologic manipulation of 11β-HSD1 activity might contribute to overcoming GC resistance, and promoting (C/EBP)β functions might permit a reduction of the exacerbation of asthma and COPD, in which infectious organisms serve as triggering factors, avoiding the reduction in antioxidant defenses that is associated with nuclear factor-κB and activator protein-1 repression.5Lu SC Regulation of glutathione synthesis.Mol Aspects Med. 2008 June 14; ([Epub ahead of print])PubMed Google Scholar To the Editor: In a recent issue of CHEST (August 2008), Adcock and Barnes1Adcock IM Barnes PJ Molecular mechanisms of corticosteroid resistance.Chest. 2008; 134: 394-401Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar presented a very interesting and informative study on the molecular mechanism of glucocorticoid (GC) resistance. As the author stated, understanding in detail the action, and inaction, of GCs may lead to the development of new antiinflammatory drugs that are able to subvert the relative corticosteroid insensitivity that is characteristic of patients with severe asthma and COPD. We want to call attention to the prereceptor metabolism of GCs, another mechanism that may have a role in GC resistance. Within target tissues, cortisol and its inactive metabolite, cortisone, are interconverted through the activity of 11β-hydroxysteroid dehydrogenase (11β-HSD).2Seckl JR 11β-hydroxysteroid dehydrogenases: changing glucocorticoid action.Curr Opin Pharmacol. 2004; 4: 597-602Crossref PubMed Scopus (152) Google Scholar Two 11β-HSD isoforms have been characterized and are expressed in lung tissue and immunity cells. In particular, 11β-HSD1 acts as a ketoreductase by virtue of the intracellular localization within the lumen of the endoplasmic reticulum in proximity to the hexose-phosphate dehydrogenase (H6PD).3Tomlinson JW Walker EA Bujalska IJ et al.11β-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.Endocr Rev. 2004; 25: 831-866Crossref PubMed Scopus (824) Google Scholar H6PD couples the oxidation of hexose-6-phosphate to the reduction of nicotinamide adenine dinucleotide phosphate (NADPH). It is the generation of NADPH within the endoplasmic reticulum adjacent to 11β-HSD1 that drives its reaction direction. Intracellular GC regeneration by 11β-HSD1 is dependent not just on its steroid substrate, but also on G6P import into the endoplasmic reticulum and H6PD-mediated production of NADPH. In case of oxidative stress, which is common in patients with severe asthma and COPD, the regeneration of endoplasmic NADPH may be impaired and so may be 11β-HSD1 activity. This mechanism may have a great relevance in GC resistance. Prednisolone and prednisone are substrates for 11β-HSD1, and dexamethasone may also be regenerated by 11β-HSD1.3Tomlinson JW Walker EA Bujalska IJ et al.11β-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.Endocr Rev. 2004; 25: 831-866Crossref PubMed Scopus (824) Google Scholar The physiologic role of 11β-HSD1 in amplifying the GC signal is evidenced by the fact that GCs themselves increase 11β-HSD1 expression in many cells.4Sai S Esteves CL Kelly V et al.Glucocorticoid regulation of the promoter of 11β-hydroxysteroid dehydrogenase type 1 is indirect and requires CCAAT/enhancer-binding protein-β.Mol Endocrinol. 2008; 22: 2049-2060Crossref PubMed Scopus (70) Google Scholar The induction is indirect and requires new protein synthesis activated by CCAAT/enhancer-binding protein (C/EBP)β. (C/EBP)β is a key mediator of metabolic and inflammatory signaling and mediates the effects of GCs on genes that lack GC binding sites in many cell types, among which are the H441 and A549 lung epithelial cells.4Sai S Esteves CL Kelly V et al.Glucocorticoid regulation of the promoter of 11β-hydroxysteroid dehydrogenase type 1 is indirect and requires CCAAT/enhancer-binding protein-β.Mol Endocrinol. 2008; 22: 2049-2060Crossref PubMed Scopus (70) Google Scholar It is possible that GC enhancement of local innate host defense mechanisms is mediated via (C/EBP)β, in contrast to the antiinflammatory mechanisms of GCs, which are predominantly mediated through interference with nuclear factor-κB and activator protein-1 functions.4Sai S Esteves CL Kelly V et al.Glucocorticoid regulation of the promoter of 11β-hydroxysteroid dehydrogenase type 1 is indirect and requires CCAAT/enhancer-binding protein-β.Mol Endocrinol. 2008; 22: 2049-2060Crossref PubMed Scopus (70) Google Scholar Pharmacologic manipulation of 11β-HSD1 activity might contribute to overcoming GC resistance, and promoting (C/EBP)β functions might permit a reduction of the exacerbation of asthma and COPD, in which infectious organisms serve as triggering factors, avoiding the reduction in antioxidant defenses that is associated with nuclear factor-κB and activator protein-1 repression.5Lu SC Regulation of glutathione synthesis.Mol Aspects Med. 2008 June 14; ([Epub ahead of print])PubMed Google Scholar
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