IL-13-induced changes in endogenous glucocorticoid metabolism in the lung regulate the proasthmatic response

• Published in: American journal of physiology. Lung cellular and molecular physiology 2012-09, Vol.303 (5), p.L382-L390
• Main Authors: Josephson, Maureen B, Jiao, Junfang, Xu, Shuyun, Hu, Aihua, Paranjape, Chinmay, Grunstein, Judith S, Grumbach, Yael, Nino, Gustavo, Kreiger, Portia A, McDonough, Joseph, Grunstein, Michael M
• Format: Article
• Language: English
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; 11-beta-Hydroxysteroid Dehydrogenase Type 2 - antagonists & inhibitors; 11-beta-Hydroxysteroid Dehydrogenase Type 2 - genetics; 11-beta-Hydroxysteroid Dehydrogenase Type 2 - metabolism; Animals; Asthma; Asthma - enzymology; Asthma - metabolism; Asthma - pathology; Bronchoconstrictor Agents - pharmacology; Carbenoxolone - pharmacology; Chemokines, CC - genetics; Chemokines, CC - metabolism; Cortisone; Cortisone - metabolism; Enzymes; Gene Expression; Glucocorticoids - metabolism; Hydrocortisone - metabolism; Interleukin-13 - administration & dosage; Interleukin-13 - physiology; Isoenzymes - antagonists & inhibitors; Isoenzymes - genetics; Isoenzymes - metabolism; Lung - enzymology; Lung - metabolism; Lung - pathology; Lungs; Metabolism; Methacholine Chloride - pharmacology; Muscle, Smooth - enzymology; Muscle, Smooth - metabolism; Physiology; Pneumonia - enzymology; Pneumonia - metabolism; Rabbits; Respiratory Mucosa - enzymology; Respiratory Mucosa - metabolism; Trachea - pathology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00125.2012

Endogenous glucocorticoid (GC) activation is regulated by the intracellular GC-activating and -inactivating enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD)1 and 11β-HSD2, respectively, that catalyze interconversion of inert cortisone and its bioactive metabolite cortisol. Because endogenous GCs are critically implicated in suppressing the asthmatic state, this study examined the roles of the 11β-HSD enzymes in regulating GC activation and bronchoprotection during proasthmatic stimulation. Airway hyperresponsiveness to methacholine and inflammation were assessed in rabbits following inhalation of the proasthmatic/proinflammatory cytokine IL-13 with and without pretreatment with the 11β-HSD inhibitor carbenoxolone (CBX). Additionally, IL-13-induced changes in 11β-HSD isozyme expression and GC metabolism were examined in epithelium-intact and -denuded tracheal segments and peripheral lung tissues. Finally, the effects of pretreatment with CBX or 11β-HSD2-targeted siRNAs were investigated with respect to cortisol prevention of IL-13-induced airway constrictor hyperresponsiveness and eotaxin-3 production by airway epithelial cells. IL-13-exposed rabbits exhibited airway hyperresponsiveness, inflammation, and elevated bronchoalveolar lung fluid levels of eotaxin-3. These responses were inhibited by pretreatment with CBX, suggesting a permissive proasthmatic role for 11β-HSD2. Supporting this concept, extended studies demonstrated that 1) IL-13-treated tracheal epithelium and peripheral lung tissues exhibit upregulated 11β-HSD2 activity, 2) the latter impairs cortisone-induced cortisol accumulation and the ability of administered cortisol to prevent both IL-13-induced heightened airway contractility and eotaxin-3 release from epithelial cells, and 3) these proasthmatic responses are prevented by cortisol administration in the presence of 11β-HSD2 inhibition. Collectively, these data demonstrate that the proasthmatic effects of IL-13 are enabled by impaired endogenous GC activation in the lung that is attributed to upregulation of 11β-HSD2 in the pulmonary epithelium.