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11beta-Hydroxysteroid dehydrogenase 1 (11HSD1) regulates local glucocorticoid activity and plays an important role in various diseases. Here, we studied whether arthritis modulates 11HSD1, what is the role of pro-inflammatory cytokines in this process and whether altered local metabolism of glucocorticoids may contribute to the feedback regulation of inflammation. Adjuvant arthritis increased synovial 11HSD1 mRNA and 11-reductase activity but treatments with tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) antagonists etanercept and anakinra reduced 11HSD1 upregulation. Treatment with carbenoxolone, an 11HSD inhibitor, increased expression of TNF-alpha, cyclooxygenase 2, and osteopontin mRNA without any changes in the plasma levels of corticosterone. Similar changes were observed when arthritic rats were treated with RU486, an antagonist of GR. This study suggests that arthritis upregulates synovial 11HSD1, this upregulation is controlled by TNF-alpha and IL-1beta and that the increased supply of local corticosterone might contribute to feedback regulation of inflammation., (2010 Elsevier Ireland Ltd. All rights reserved.)

Glucocorticoids (GCs) are hormones that are released in response to stressors and exhibit many activities, including immunomodulatory and anti-inflammatory activities. They are primarily synthesized in the adrenal gland but are also produced in peripheral tissues via regeneration of adrenal 11-oxo metabolites or by de novo synthesis from cholesterol. The present study investigated the influence of the microbiota on de novo steroidogenesis and regeneration of corticosterone in the intestine of germ-free (GF) and specific pathogen-free mice challenged with a physical stressor (anti-CD3 antibody i.p. injection). In the small intestine, acute immune stress resulted in increased mRNA levels of the proinflammatory cytokines IL1β, IL6 and Tnfα and genes involved in de novo steroidogenesis (Stard3 and Cyp11a1), as well as in regeneration of active GCs from their 11-oxo metabolites (Hsd11b1). GF mice showed a generally reduced transcriptional response to immune stress, which was accompanied by decreased intestinal corticosterone production and reduced expression of the GC-sensitive marker Fkbp5. In contrast, the interaction between stress and the microbiota was not detected at the level of plasma corticosterone or the transcriptional response of adrenal steroidogenic enzymes. The results indicate a differential immune stress-induced intestinal response to proinflammatory stimuli and local corticosterone production driven by the gut microbiota. [ABSTRACT FROM AUTHOR]

The circadian clock system drives many physiological processes, including plasma concentration of glucocorticoids and epithelial transport of some ions and nutrients. As glucocorticoids entrain the circadian rhythms in various peripheral organs, we examined whether adrenalectomy affects the expression and circadian rhythmicity of intestinal transporters of the solute carrier (SLC) and ATP-binding cassette (ABC) families, which participate in intestinal barriers for absorption of nutrients, nonnutrients and oral drugs. The rat jejunum showed rhythmic circadian profiles of Sglt1, Pept1, Nhe3, Mdr1 and Mrp2 but not Mct1, Oct1, Octn1 , Oatp1, Cnt1 and Bcrp. With the exception of Pept1 and Mct1 , adrenalectomy decreased the expression of all rhythmic and arrhythmic transporters including the amplitude of Sglt1 and Nhe3 rhythms but minimally affected the phases of rhythmic transporters except of Nhe3. Similarly, adrenalectomy downregulated the expression of rhythmic (Pparα , Hlf , Pgc1α) and arrhythmic (Hnf1β , Hnf4α) transcription factors, which are known to regulate the expression of transporters. We conclude that endogenous corticosteroids have a profound effect on the expression of intestinal SLC and ABC transporters and their nuclear transcription factors. The circulating corticosteroids are necessary for maintaining upregulated expression of Sglt1, Oct1, Octn1, Oatp1, Cnt1, Nhe3, Mdr1, Bcrp, Mrp2, Pparα, Pgc1α, Hnf1β, Hnf4α and Hlf and for maintaining the high amplitude of Sglt1, Nhe3, Pparα, Pgc1α and Hlf circadian rhythms. The study demonstrates that signals from the adrenal gland are necessary for maintaining the expression of arrhythmic and rhythmic intestinal transporters and that changes in the secretion of corticosteroids associated with stress might reorganize intestinal transport barriers. Unlabelled Image • Expression of some intestinal transporter genes showed circadian rhythmicity, others were arrhythmic. • Corticosteroids maintained upregulated expression of majority of studied rhythmic and arrhythmic transporters. • Phase angle of circadian rhythms of rhythmic transporters was not modulated by adrenalectomy. • Corticosteroids modulated expression of nuclear receptors and factors known to regulate transcription of transporter genes. [ABSTRACT FROM AUTHOR]

The bioavailability of glucocorticoids is modulated by enzyme 11β-hydroxysteroid dehydrogenase type 1 (11HSD1), which catalyzes the conversion of inactive 11-oxo-glucocorticoids to active 11-hydroxy-glucocorticoids cortisol and corticosterone and is regulated by pro-inflammatory cytokines. Our aim was to assess the effect of colitis on the expression of 11HSD1 in specific microanatomical compartments of the mucosal immune system. Using qRT-PCR we quantified the expression of 11HSD1 and cytokines in the colon, mesenteric lymph nodes (MLN) and spleen of mice with colitis. Microsamples of the MLN cortex, paracortex and medulla, colonic crypt epithelium (CCE), lamina propria and isolated intestinal lymphoid follicles (ILF) were harvested by laser microdissection, whereas splenic and MLN lymphocytes by flow cytometry. Colitis increased 11HSD1 in the CCE, ILF, and MLN cortex but not in the lamina propria and the MLN paracortex and medulla. Expression of IL-4, IL-21 and TNFα was increased in both the cortex of MLN and ILF, whereas IL-1β and IL-10 were only increased in the follicles. No positive effect was observed in the case of IFNγ and TGFβ. 11HSD1 was positively correlated with TNFα and less strongly with IL-21, IL-1β, and IL-4. Colitis also upregulated the 11HSD1 expression of T cells in the spleen and MLN. The study demonstrates the stimulatory effect of inflammation on local glucocorticoid metabolism only in particular compartments of the mucosal immune system. The correlation between cytokines and 11HSD1 in the ILF and MLN cortex indicates that pro-inflammatory cytokines may amplify glucocorticoid signals in inductive compartments of the mucosal immune system. [ABSTRACT FROM AUTHOR]