Glucocorticoid resistance in inflammatory diseases
Abstract
Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
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Aberrant glucocorticoid signaling is a mechanism that can influence the maintenance or progression of these disorders.
“Although the role that altered glucocorticoid sensitivity plays in the etiology of these disease conditions remains unclear, there is little doubt that aberrant glucocorticoid signaling is a mechanism that can influence the maintenance or progression of these disorders”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Barnes & Adcock, 2009
Refractory COPD patients respond poorly to steroid treatment, exhibiting persistent airway inflammation.
“However, refractory COPD patients respond poorly to steroid treatment, exhibiting persistent airway inflammation [5].”
Cites
Global strategy for asthma management and prevention: GINA executive summary
Bateman, E. D., Hurd, S. S., Barnes, P. J., Bousquet, J., Drazen, J. M., FitzGerald, M., Gibson, P., Ohta, K., O'Byrne, P., Pedersen, S. E., et al. (2008) · European Respiratory Journal · doi:10.1183/09031936.00138707 · Cited by 3,203 · see citing works
Self-citationHDAC6 Regulates Hsp90 Acetylation and Chaperone-Dependent Activation of Glucocorticoid Receptor
Kovacs, J. J., Murphy, P. J. M., Gaillard, S., Zhao, X., Wu, J.-T., Nicchitta, C. V., Yoshida, M., Toft, D. O., Pratt, W. B., & Yao, T.-P. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.04.021 · Cited by 1,153 · see citing works
Abraham, S. M., Lawrence, T., Kleiman, A., Warden, P., Medghalchi, M., Tuckermann, J., Saklatvala, J., & Clark, A. R. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20060336 · Cited by 430 · see citing works
The Physiology of Human Glucocorticoid Receptor β (hGRβ) and Glucocorticoid Resistance
LEWIS‐TUFFIN, L. J., & CIDLOWSKI, J. A. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1351.001 · Cited by 242 · see citing works
Corticosteroids for idiopathic pulmonary fibrosis
Richeldi, L., Davies, H. R. H. R., Spagnolo, P., & Luppi, F. (2003) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002880 · Cited by 219 · see citing works
Roger, T., Chanson, A., Knaup‐Reymond, M., & Calandra, T. (2005) · European Journal of Immunology · doi:10.1002/eji.200535413 · Cited by 184 · see citing works
Human Glucocorticoid Receptor β Binds RU-486 and Is TranscriptionallyActive
Lewis-Tuffin, L. J., Jewell, C. M., Bienstock, R. J., Collins, J. B., & Cidlowski, J. A. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01439-06 · Cited by 175 · see citing works
A Role for STAT5 in the Pathogenesis of IL-2-Induced Glucocorticoid Resistance
Goleva, E., Kisich, K. O., & Leung, D. Y. M. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.10.5934 · Cited by 113 · see citing works
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Cited by
Sorted by citations
Slavich, G. M., & Irwin, M. R. (2014) · Psychological Bulletin · doi:10.1037/a0035302 · Cited by 2,206 · see citing works
Kirkham, P. A., & Barnes, P. J. (2013) · Chest · doi:10.1378/chest.12-2664 · Cited by 685 · see citing works
Self-citationRatman, D., Vanden Berghe, W., Dejager, L., Libert, C., Tavernier, J., Beck, I. M., & De Bosscher, K. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.12.014 · Cited by 411 · see citing works
Psychoneuroimmunology of early-life stress: the hidden wounds of childhood trauma?
Danese, A., & J Lewis, S. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.198 · Cited by 393 · see citing works
Immune and neuroendocrine mechanisms of stress vulnerability and resilience
Ménard, C., Pfau, M. L., Hodes, G. E., & Russo, S. J. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.90 · Cited by 374 · see citing works
The Effects of Airway Microbiome on Corticosteroid Responsiveness in Asthma
Goleva, E., Jackson, L. P., Harris, J. K., Robertson, C. E., Sutherland, E. R., Hall, C. F., Good, J. T., Gelfand, E. W., Martin, R. J., & Leung, D. Y. M. (2013) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201304-0775oc · Cited by 363 · see citing works
Fungal allergy in asthma-state of the art and research needs
Denning, D. W., Pashley, C., Hartl, D., Wardlaw, A., Godet, C., Del Giacco, S., Delhaes, L., & Sergejeva, S. (2014) · Clinical and Translational Allergy · doi:10.1186/2045-7022-4-14 · Cited by 357 · see citing works
Stress induces endotoxemia and low-grade inflammation by increasing barrier permeability
de Punder, K., & Pruimboom, L. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00223 · Cited by 321 · see citing works
Mechanisms and resistance in glucocorticoid control of inflammation
Barnes, P. J. (2010) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2010.02.018 · Cited by 317 · see citing works
Hidden wounds? inflammatory links between childhood trauma and psychopathology
Danese, A., & Baldwin, J. R. (2017) · Annual Review of Psychology · doi:10.1146/annurev-psych-010416-044208 · Cited by 286 · see citing works
Effects of social isolation on glucocorticoid regulation in social mammals
Hawkley, L. C., Cole, S. W., Capitanio, J. P., Norman, G. J., & Cacioppo, J. T. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2012.05.011 · Cited by 262 · see citing works
Izquierdo, M., de Souto Barreto, P., Arai, H., Bischoff-Ferrari, H. A., Cadore, E. L., Cesari, M., Chen, L.-K., Coen, P. M., Courneya, K. S., Duque, G., et al. (2025) · The Journal of nutrition, health and aging · doi:10.1016/j.jnha.2024.100401 · Cited by 273 · see citing works
Frolkis, A. D., Vallerand, I. A., Shaheen, A.-A., Lowerison, M. W., Swain, M. G., Barnabe, C., Patten, S. B., & Kaplan, G. G. (2019) · Gut · doi:10.1136/gutjnl-2018-317182 · Cited by 228 · see citing works
A family-oriented psychosocial intervention reduces inflammation in low-SES African American youth
Miller, G. E., Brody, G. H., Yu, T., & Chen, E. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1406578111 · Cited by 180 · see citing works
Reader, B. F., Jarrett, B. L., McKim, D. B., Wohleb, E. S., Godbout, J. P., & Sheridan, J. F. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.01.001 · Cited by 179 · see citing works
“Associated with the experience of social stress, it is this prolonged inflammatory state that has the potential to contribute to the etiology of depression and anxiety (Meduri and Yates, 2004; Barnes and Adcock, 2009).”
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Barnes, P. J. (2012) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2011.11.006 · Cited by 174 · see citing works
Self-citationGalliher-Beckley, A. J., Williams, J. G., & Cidlowski, J. A. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.05866-11 · Cited by 164 · see citing works
Bozinovski, S., Uddin, M., Vlahos, R., Thompson, M., McQualter, J. L., Merritt, A.-S., Wark, P. A. B., Hutchinson, A., Irving, L. B., Levy, B. D., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1109382109 · Cited by 163 · see citing works
HDAC2: a critical factor in health and disease
Krämer, O. H. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.09.007 · Cited by 157 · see citing works
Depressive symptoms enhance stress-induced inflammatory responses.
Fagundes, C. P., Glaser, R., Hwang, B. S., Malarkey, W. B., & Kiecolt-Glaser, J. K. (2013) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2012.05.006 · Cited by 151 · see citing works
The Glucocorticoid Receptor: Isoforms, Functions, and Contribution to Glucocorticoid Sensitivity
Lockett, J., Inder, W. J., & Clifton, V. L. (2024) · Endocrine Reviews · doi:10.1210/endrev/bnae008 · Cited by 135 · see citing works
Adcock, I. M., & Mumby, S. (2016) · Handbook of experimental pharmacology · doi:10.1007/164_2016_98 · Cited by 131 · see citing works
Selective inhibition of low-affinity memory CD8(+) T cells by corticosteroids
Tokunaga, A., Sugiyama, D., Maeda, Y., Warner, A. B., Panageas, K. S., Ito, S., Togashi, Y., Sakai, C., Wolchok, J. D., & Nishikawa, H. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20190738 · Cited by 124 · see citing works
Milligan Armstrong, A., Porter, T., Quek, H., White, A., Haynes, J., Jackaman, C., Villemagne, V., Munyard, K., Laws, S. M., Verdile, G., et al. (2021) · Biological Reviews · doi:10.1111/brv.12750 · Cited by 116 · see citing works
Todd, N., Scheraga, Galvin, Iacono, Britt, Luzina, Burke, & Atamas (2013) · Journal of Inflammation Research · doi:10.2147/jir.s40673 · Cited by 113 · see citing works
Glucocorticoid resistance as a major drive in sepsis pathology
Dendoncker, K., & Libert, C. (2017) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2017.04.002 · Cited by 85 · see citing works
McLaughlin, K. A., Basu, A., Walsh, K., Slopen, N., Sumner, J. A., Koenen, K. C., & Keyes, K. M. (2016) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000366 · Cited by 67 · see citing works
Cohen, J., Pretorius, C. J., Ungerer, J. P. J., Cardinal, J., Blumenthal, A., Presneill, J., Gatica-Andrades, M., Jarrett, P., Lassig-Smith, M., Stuart, J., et al. (2016) · Critical Care Medicine · doi:10.1097/ccm.0000000000001633 · Cited by 58 · see citing works
Regeneration and repair in the healing lung
Lucas, A., Yasa, J., & Lucas, M. (2020) · Clinical & Translational Immunology · doi:10.1002/cti2.1152 · Cited by 41 · see citing works
Repurposing of statins via inhalation to treat lung inflammatory conditions
Bradbury, P., Traini, D., Ammit, A. J., Young, P. M., & Ong, H. X. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.06.005 · Cited by 38 · see citing works
Higa, L. H., Jerez, H. E., de Farias, M. A., Portugal, R. V., Romero, E. L., & Morilla, M. J. (2017) · Nanomedicine · doi:10.2217/nnm-2016-0437 · Cited by 35 · see citing works
Keratinocyte-Targeted Overexpression of the Glucocorticoid Receptor Delays Cutaneous Wound Healing
Sanchis, A., Alba, L., Latorre, V., Sevilla, L. M., & Pérez, P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029701 · Cited by 35 · see citing works
Holownia, A., Mroz, R. M., Kolodziejczyk, A., Chyczewska, E., & Braszko, J. J. (2009) · European journal of medical research · doi:10.1186/2047-783x-14-s4-108 · Cited by 20 · see citing works
Jin, Y. (2011) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2011.01.019 · Cited by 16 · see citing works
Lee, K., Choi, J., Choi, B. K., Gu, Y.-M., Ryu, H. W., Oh, S.-R., & Lee, H.-J. (2019) · Molecules · doi:10.3390/molecules24102020 · Cited by 11 · see citing works
Teng, Y., Yan, Z.-Y., Wang, L.-L., Wang, Y.-H., Zhang, T.-Y., Li, Z., Liu, S., Cai, J., Chen, Y.-F., Li, M., et al. (2022) · Rheumatology · doi:10.1093/rheumatology/keab806 · Cited by 5 · see citing works
- Authors
- Barnes, P. J., & Adcock, I. M.
- Affiliations
- Imperial College London (GB)
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 373
- Issue
- 9678
- Pages
- 1905-1917
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2065764124
- Cited by
- 983
- References
- 8
- Citations by year
- 2026: 25 · 2025: 32 · 2024: 32 · 2023: 44 · 2022: 33 · 2021: 53 · 2020: 63 · 2019: 57 · 2018: 45 · 2017: 47 · 2016: 73 · 2015: 73 · 2014: 74 · 2013: 65 · 2012: 98
- FWCI
- 11.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Keywords
- glucocorticoid resistance, inflammatory diseases, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, rheumatoid arthritis, inflammatory bowel disease, MAPK signaling, activator protein-1, HDAC2, macrophage migration inhibitory factor, P-glycoprotein, calcineurin inhibitors, phosphodiesterase-4 inhibitors, NF-κB inhibitors, IL-10, theophylline, antioxidants, vitamin D
- MeSH terms
- Anti-Inflammatory Agents, Asthma, Drug Resistance, Glucocorticoids, Histone Deacetylases, Humans, Inflammation, Macrophage Migration-Inhibitory Factors, Repressor Proteins, Transcriptional Activation, NF-kappa B, Transcription Factor AP-1, Genetic Predisposition to Disease, ATP Binding Cassette Transporter, Subfamily B, Member 1, Mitogen-Activated Protein Kinases, Pulmonary Disease, Chronic Obstructive, Histone Deacetylase 2, Phosphodiesterase 4 Inhibitors, Calcineurin Inhibitors
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