Stress is an important risk factors for human diseases. It activates the hypothalamic-pituitary-adrenal (HPA) axis and increases plasma glucocorticoids, which are powerful regulators of immune system. The response of the target cells to glucocorticoids depends not only on the plasma concentrations of cortisol and corticosterone but also on their local metabolism. This metabolism is catalyzed by 11β-hydroxysteroid dehydrogenases type 1 and 2, which interconvert glucocorticoid hormones cortisol and corticosterone and their 11-oxo metabolites cortisone and 11-dehydrocorticosterone. The goal of this study was to determine whether stress modulates glucocorticoid metabolism within lymphoid organs - the structures where immune cells undergo development and activation. Using the resident-intruder paradigm, we studied the effect of social stress on glucocorticoid metabolism in primary and secondary lymphoid organs of Fisher 344 (F344) and Lewis (LEW) rats, which exhibit marked differences in their HPA axis response to social stressors and inflammation. We show that repeated social defeat increased the regeneration of corticosterone from 11-dehydrocorticosterone in the thymus, spleen and mesenteric lymphatic nodes (MLN). Compared with the F344 strain, LEW rats showed higher corticosterone regeneration in splenocytes of unstressed rats and in thymic and MLN mobile cells after stress but corticosterone regeneration in the stroma of all lymphoid organs was similar in both strains. Inactivation of corticosterone to 11-dehydrocorticosterone was found only in the stroma of lymphoid organs but not in mobile lymphoid cells and was not upregulated by stress. Together, our findings demonstrate the tissue- and strain-dependent regeneration of glucocorticoids following social stress.

• Keywords
• Fisher 344 rats, Lewis rats, glucocorticoid metabolism, lymphoid organs, resident-intruder paradigm, social stress,
• Publication type
• Journal Article MeSH

Recent in vitro studies have shown the involvement of pro-inflammatory cytokines in the regulation of the local metabolism of glucocorticoids via 11beta-hydroxysteroid dehydrogenase type 1 and type 2 (11HSD1 and 11HSD2). However, direct in vivo evidence for a relationship among the local metabolism of glucocorticoids, inflammation and steroid enzymes is still lacking. We have therefore examined the changes in the local metabolism of glucocorticoids during colonic inflammation induced by TNBS and the consequences of corticosterone metabolism inhibition by carbenoxolone on 11HSD1, 11HSD2, cyclooxygenase 2 (COX-2), mucin 2 (MUC-2), tumor necrosis factor alpha (TNF-alpha), and interleukin 1beta (IL-1beta). The metabolism of glucocorticoids was measured in tissue slices in vitro and their 11HSD1, 11HSD2, COX-2, MUC-2, TNF-alpha, and IL-1beta mRNA abundances by quantitative reverse transcription-polymerase chain reaction. Colitis produced an up-regulation of colonic 11HSD1 and down-regulation of 11HSD2 in a dose-dependent manner, and these changes resulted in a decreased capacity of the inflamed tissue to inactivate tissue corticosterone. Similarly, 11HSD1 transcript was increased in colonic intraepithelial lymphocytes of TNBS-treated rats. Topical intracolonic application of carbenoxolone stimulated 11HSD1 mRNA and partially inhibited 11HSD2 mRNA and tissue corticosterone inactivation and these changes were blocked by RU-486. The administration of budesonide mimicked the effect of carbenoxolone. In contrast to the local metabolism of glucocorticoids, carbenoxolone neither potentiates nor diminishes gene expression for COX-2, TNF-alpha, and IL-1beta, despite the fact that budesonide down-regulated all of them. These data indicate that inflammation is associated with the down-regulation of tissue glucocorticoid catabolism. However, these changes in the local metabolism of glucocorticoids do not modulate the expression of COX-2, TNF-alpha, and IL-1beta in inflamed tissue.

• MeSH
• 11-beta-Hydroxysteroid Dehydrogenase Type 1 genetics   metabolism   MeSH
• 11-beta-Hydroxysteroid Dehydrogenase Type 2 genetics   metabolism   MeSH
• Hormone Antagonists pharmacology   MeSH
• Budesonide pharmacology   MeSH
• Cyclooxygenase 2 genetics   metabolism   MeSH
• Glucocorticoids antagonists & inhibitors   metabolism   pharmacology   MeSH
• Interleukin-1beta genetics   metabolism   MeSH
• Carbenoxolone pharmacology   MeSH
• Colitis chemically induced   metabolism   MeSH
• Colon drug effects   enzymology   metabolism   MeSH
• Corticosterone metabolism   MeSH
• Rats MeSH
• Trinitrobenzenesulfonic Acid MeSH
• RNA, Messenger metabolism   MeSH
• Mifepristone pharmacology   MeSH
• Disease Models, Animal MeSH
• Mucin-2 MeSH
• Mucins genetics   metabolism   MeSH
• Peroxidase metabolism   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Rats, Wistar MeSH
• Tumor Necrosis Factor-alpha genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 11-beta-Hydroxysteroid Dehydrogenase Type 1 MeSH
• 11-beta-Hydroxysteroid Dehydrogenase Type 2 MeSH
• Hormone Antagonists MeSH
• Budesonide MeSH
• Cyclooxygenase 2 MeSH
• Glucocorticoids MeSH
• Interleukin-1beta MeSH
• Carbenoxolone MeSH
• Corticosterone MeSH
• Trinitrobenzenesulfonic Acid MeSH
• RNA, Messenger MeSH
• Mifepristone MeSH
• Muc2 protein, rat MeSH Browser
• Mucin-2 MeSH
• Mucins MeSH
• Peroxidase MeSH
• Ptgs2 protein, rat MeSH Browser
• Tumor Necrosis Factor-alpha MeSH