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.

Glucocorticoids Recruit Tgfbr3 and Smad1 to Shift Transforming Growth Factor-β Signaling from the Tgfbr1/Smad2/3 Axis to the Acvrl1/Smad1 Axis in Lung Fibroblasts

“…The myofibroblast is a key pathogenic mediator of asthma, chronic obstructive pulmonary disease, bronchopulmonary dysplasia, and acute respiratory distress syndrome (67), and the data presented here indicate that glucocorticoids may drive myofibroblast differentiation in the background of glucocorticoid use in these pathologies. Although not addressed in this study, our data suggest a mechanism by which TGF-␤ signaling may also be modulated by endogenous glucocorticoids, such as cortisol, which are active in lung and airway diseases such as asthma (68,69). Indeed, Smad1 signaling is reported to be activated (and proposed to drive pathology) in airway epithelial cells during experimental allergic airway inflammation (70), and it would be interesting to assess whether increased Smad1 activation might be due to or exacerbated by glucocorticoids, either endogenous or applied exogenously, because budesonide and fluticasone are the mainstay of asthma therapy today (3,4).…”

Pro-Asthmatic Cytokines Regulate Unliganded and Ligand-Dependent Glucocorticoid Receptor Signaling in Airway Smooth Muscle

“…As in other tissues, an important determinant of ASM responsiveness to endogenous and a variety of synthetic GCs is its ability to regulate pre-receptor GC bioavailability by modulating the activities of the GC-activating and -inactivating isozymes, 11ß-HSD1 and HSD2, respectively [25], [32]. Accordingly, exposure of HASM cells to proinflammatory cytokines (e.g., IL-13, IL-1β/TNFα, etc) was shown to upregulate 11ß-HSD1 and inhibit 11ß-HSD2 expression, thereby allowing for increased conversion of cortisone into its bioactive derivative, cortisol [22], [25], [32], [33], which serves to homeostatically suppress the opposing pro-asthmatic effects of the cytokine on airway contractility [25], [32]. The present study sought to determine whether the homeostatic response of HASM to proinflammatory cytokine exposure also includes changes in GR signaling by exploring unliganded and ligand-dependent GR activation in HASM cells stimulated by the key pro-asthmatic cytokine, IL-13.…”

Animal models of bronchopulmonary dysplasia. The preterm and term rabbit models

“…Adult rabbits have been used particularly extensively to model human asthma, since they are phylogenetically more closely related to humans than are rodents, have lungs that are more anatomically similar to humans, share qualities such as IgE mediation of anaphylaxis and relative capsaicin unresponsiveness with humans, and can model both early-and latephase airway responses (58,59). Recent work in a rabbit asthma model has elucidated the role of the proasthmatic cytokine IL-13 in producing impaired endogenous glucocorticoid activity via the upregulation of 11␤-hydroxysteroid dehydrogenase, showing the value of well-developed rabbit models for dissecting the pathogenesis of human asthma (57).…”