{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:02:57Z","timestamp":1791223377042,"version":"4.1.0"},"reference-count":21,"publisher":"Rockefeller University Press","issue":"9","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1997,11,3]]},"abstract":"<jats:p>In many chronic inflammatory disorders, glucocorticoid (GC) insensitivity is a challenging clinical problem associated with life-threatening disease progression. The molecular basis of GC insensitivity, however, is unknown. Alternative splicing of the GC receptor (R) pre\u2013messenger RNA generates a second GCR, termed GCR-\u03b2, which does not bind GCs but antagonizes the transactivating activity of the classic GCR, termed GCR-\u03b1. In the current study, we demonstrate that GC-insensitive asthma is associated with a significantly higher number of GCR-\u03b2\u2013immunoreactive cells in peripheral blood than GC-sensitive asthmatics or normal controls. Furthermore, we show that patients with GC-insensitive asthma have cytokine-induced abnormalities in the DNA binding capability of the GCR. These abnormalities can be reproduced by transfection of cell lines with the GCR-\u03b2 gene resulting in significant reduction of their GCR-\u03b1 DNA binding capacity. We conclude that increased expression of GCR-\u03b2 is cytokine inducible and may account for GC insensitivity in this common inflammatory condition.<\/jats:p>","DOI":"10.1084\/jem.186.9.1567","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:49:30Z","timestamp":1027702170000},"page":"1567-1574","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":339,"title":["Association of Glucocorticoid Insensitivity with Increased Expression of Glucocorticoid Receptor \u03b2"],"prefix":"10.1084","volume":"186","author":[{"given":"Donald Y.M.","family":"Leung","sequence":"first","affiliation":[{"name":"From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the \u2021Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the \u00a7Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the \u00a7Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qutayba","family":"Hamid","sequence":"additional","affiliation":[{"name":"From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the \u2021Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the \u00a7Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the \u00a7Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Vottero","sequence":"additional","affiliation":[{"name":"From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the \u2021Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the \u00a7Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the \u00a7Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley J.","family":"Szefler","sequence":"additional","affiliation":[{"name":"From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the \u2021Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the \u00a7Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the \u00a7Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Surs","sequence":"additional","affiliation":[{"name":"From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the \u2021Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the \u00a7Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the \u00a7Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"Minshall","sequence":"additional","affiliation":[{"name":"From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the \u2021Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the \u00a7Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the \u00a7Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George P.","family":"Chrousos","sequence":"additional","affiliation":[{"name":"From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the \u2021Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the \u00a7Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the \u00a7Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dwight J.","family":"Klemm","sequence":"additional","affiliation":[{"name":"From the *Divisions of Allergy-Immunology and Clinical Pharmacology, National Jewish Medical and Research Center, and the \u2021Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; the \u00a7Meakins-Christie Laboratories and Departments of Pathology, McGill University, Montreal, Quebec, Canada; and the \u00a7Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","reference":[{"key":"2023072507525966700_B1"},{"key":"2023072507525966700_B2","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1164\/ajrccm\/144.5.1016","article-title":"Glucocorticoid resistance in chronic asthma: glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro.","volume":"144","author":"Corrigan","year":"1991","journal-title":"Am Rev Respir Dis"},{"key":"2023072507525966700_B3","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/0091-6749(92)90379-G","article-title":"Steroid-resistant asthma: immunologic and pharmacologic features","volume":"89","author":"Alvarez","year":"1992","journal-title":"J Allergy Clin Immunol"},{"key":"2023072507525966700_B4","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1164\/ajrccm\/144.5.page","article-title":"Glucocorticoid resistance in chronic asthma: peripheral blood T lymphocyte activation and comparison of the T lymphocyte inhibitory effects of glucocorticoids and cyclosporin A","volume":"144","author":"Corrigan","year":"1991","journal-title":"Am Rev Respir Dis"},{"key":"2023072507525966700_B5","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1164\/ajrccm\/154.2_Pt_2.S2","article-title":"Glucocorticoid receptors: ATP and cell cycle dependence, phosphorylation and hormone resistance","volume":"141","author":"Bodwell","year":"1996","journal-title":"Am J Respir Crit Care Med"},{"key":"2023072507525966700_B6","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1172\/JCI116963","article-title":"Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy","volume":"93","author":"Sher","year":"1994","journal-title":"J Clin Invest"},{"key":"2023072507525966700_B7","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.4049\/jimmunol.151.7.3460","article-title":"The combined effects of IL-2 and IL-4 alter the binding affinity of the glucocorticoid receptor","volume":"151","author":"Kam","year":"1993","journal-title":"J Immunol"},{"key":"2023072507525966700_B8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1084\/jem.181.1.33","article-title":"Dysregulation of interleukin 4, interleukin 5, and interferon \u03b3 gene expression in steroid-resistant asthma","volume":"181","author":"Leung","year":"1995","journal-title":"J Exp Med"},{"key":"2023072507525966700_B9","doi-asserted-by":"crossref","first-page":"3500","DOI":"10.4049\/jimmunol.154.7.3500","article-title":"Differences in binding of glucocorticoid receptor to DNA in steroid resistant asthma","volume":"154","author":"Adcock","year":"1995","journal-title":"J Immunol"},{"key":"2023072507525966700_B10","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1164\/ajrccm\/136.1.225","article-title":"Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma","volume":"136","author":"American Thoracic Society","year":"1987","journal-title":"Am Rev Respir Dis"},{"key":"2023072507525966700_B11","first-page":"5881","article-title":"Simian virus 40 small tumor antigen inhibits dephosphorylation of protein kinase A\u2013phosphorylated CREB and regulates CREB transcriptional stimulation","volume":"14","author":"Wheat","year":"1994","journal-title":"Mol Cell Biol"},{"key":"2023072507525966700_B12","doi-asserted-by":"crossref","first-page":"19740","DOI":"10.1016\/S0021-9258(19)77697-2","article-title":"Characterization of the cAMP responsive elements from the genes for the \u03b1-subunit of glycoprotein hormones and phosphoenolpyruvate carboxykinase (GTP)","volume":"263","author":"Bokar","year":"1988","journal-title":"J Biol Chem"},{"key":"2023072507525966700_B13","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/BF03401643","article-title":"The non-ligand binding beta-isoform of the human glucocorticoid receptor (hGR beta): tissue levels, mechanism of action, and potential physiologic role","volume":"2","author":"de Castro","year":"1996","journal-title":"Mol Med"},{"key":"2023072507525966700_B14","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1016\/0140-6736(93)90694-C","article-title":"Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis","volume":"341","author":"Giaid","year":"1993","journal-title":"Lancet"},{"key":"2023072507525966700_B15","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/318635a0","article-title":"Primary structure and expression of a functional human glucocorticoid receptor cDNA","volume":"318","author":"Hollenberg","year":"1985","journal-title":"Nature (Lond)"},{"key":"2023072507525966700_B16"},{"key":"2023072507525966700_B17","doi-asserted-by":"crossref","first-page":"9550","DOI":"10.1074\/jbc.271.16.9550","article-title":"The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function","volume":"271","author":"Oakley","year":"1996","journal-title":"J Biol Chem"},{"key":"2023072507525966700_B18","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1111\/j.1365-2222.1989.tb02408.x","article-title":"The relative risk of sensitivity to grass pollen, house dust mite and cat dander in the development of childhood asthma","volume":"19","author":"Sears","year":"1989","journal-title":"Clin Exp Allergy"},{"key":"2023072507525966700_B19","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1164\/ajrccm\/147.4.826","article-title":"Particulate air pollution and hospital emergency room visits for asthma in Seattle","volume":"147","author":"Schwartz","year":"1993","journal-title":"Am Rev Respir Dis"},{"key":"2023072507525966700_B20","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1056\/NEJM199409153311103","article-title":"Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma","volume":"331","author":"Haahtela","year":"1994","journal-title":"N Engl J Med"},{"key":"2023072507525966700_B21","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/0954-6111(94)90044-2","article-title":"Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children","volume":"88","author":"Agertoft","year":"1994","journal-title":"Respir Med"}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/186\/9\/1567\/1687481\/97-0914.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/186\/9\/1567\/1687481\/97-0914.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T08:46:17Z","timestamp":1690274777000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/186\/9\/1567\/51182\/Association-of-Glucocorticoid-Insensitivity-with"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,11,3]]},"references-count":21,"journal-issue":{"issue":"9","published-print":{"date-parts":[[1997,11,3]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.186.9.1567","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,11,3]]}}}