Social stress and asthma: The role of corticosteroid insensitivity Angela Haczku, MD, PhD, Reynold A. Panettieri, MD  Journal of Allergy and Clinical Immunology  Volume 125, Issue 3, Pages 550-558 (March 2010) DOI: 10.1016/j.jaci.2009.11.005 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Mechanisms of glucocorticoid action. The activated GR homodimer binds to GREs, located within regulatory regions of glucocorticoid-responsive genes in the nucleus. A, Positive GRE mediates transcriptional upregulation of anti-inflammatory genes such as NF-κB inhibitor α (IκBα), the glucocorticoid-inducible leucine zipper (GILZ), or IL-10. B, Negative GRE mediates transcriptional downregulation. C and D, In monomeric form, the activated GR may interact with other transcription factors such as NF-κB. This interaction can occur indirectly through transcriptional cofactor (HDAC) binding (C) or by RNA polymerase dephosphorylation (D). Journal of Allergy and Clinical Immunology 2010 125, 550-558DOI: (10.1016/j.jaci.2009.11.005) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Hypothesized mechanisms by which glucocorticoid resistance could occur. A, Glucocorticoid binding to the GR induces molecular rearrangement of the GR–heat shock protein 90 heterocomplex and promotes GR nuclear translocation, homodimerization, and DNA binding. B, This process can be modulated by GR/NF-κB interactions, directly by affecting transactivation (GRE-mediated) as well as transrepression of GR functions. C, Indirect inhibition of the GR function maybe achieved by transcription factor “tethering.” Journal of Allergy and Clinical Immunology 2010 125, 550-558DOI: (10.1016/j.jaci.2009.11.005) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Proposed mechanism of how stress-induced glucocorticoid insensitivity could affect the innate immune system during the allergic airway response. A, Altered corticosteroid responsiveness of airway epithelial cells may inhibit SP-D production. B, Stress abrogates corticosteroid responsiveness of proinflammatory dendritic cells. C, Diminished SP-D levels will result in a failure to protect against dendritic cell and TH2-cell activation and the consequent allergic airway response. AHR, Airway hyperreactivity. Journal of Allergy and Clinical Immunology 2010 125, 550-558DOI: (10.1016/j.jaci.2009.11.005) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions