title: IL-13-induced changes in endogenous glucocorticoid metabolism in the lung regulate the proasthmatic response.
abstract: 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.
authors: Div. of Pulmonary Medicine, Abramson Research Bldg., Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Maureen B
authors: MB
authors: Josephson
authors: Junfang
authors: J
authors: Jiao
authors: Shuyun
authors: S
authors: Xu
authors: Aihua
authors: A
authors: Hu
authors: Chinmay
authors: C
authors: Paranjape
authors: Judith S
authors: JS
authors: Grunstein
authors: Yael
authors: Y
authors: Grumbach
authors: Gustavo
authors: G
authors: Nino
authors: Portia A
authors: PA
authors: Kreiger
authors: Joseph
authors: J
authors: McDonough
authors: Michael M
authors: MM
authors: Grunstein
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002229:Carbenoxolone / Q000494:pharmacology; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism; D003348:Cortisone / Q000378:metabolism; D015870:Gene Expression; D005938:Glucocorticoids / Q000378:metabolism*; D006854:Hydrocortisone / Q000378:metabolism; D018793:Interleukin-13 / Q000008:administration & dosage / Q000502:physiology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016210:Methacholine Chloride / Q000494:pharmacology; D009130:Muscle, Smooth / Q000201:enzymology / Q000378:metabolism; D011014:Pneumonia / Q000201:enzymology / Q000378:metabolism; D011817:Rabbits; D020545:Respiratory Mucosa / Q000201:enzymology / Q000378:metabolism; D014132:Trachea / Q000473:pathology
chemical_list: D016085:Bronchoconstrictor Agents; D019742:Chemokines, CC; D005938:Glucocorticoids; D018793:Interleukin-13; D007527:Isoenzymes; D016210:Methacholine Chloride; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D002229:Carbenoxolone; D003348:Cortisone; D006854:Hydrocortisone