How does 11B-hydroxysteroid dehydrogenase type I limit inflammation?

Lead Research Organisation: University of Edinburgh
Department Name: School of Clinical Sciences

Abstract

Anti-inflammatory steroids (glucocorticoids) are among the most commonly prescribed drugs in the UK. Glucocorticoids are also produced naturally by the body, in both active (cortisol) and inactive (cortisone) forms, which help to control inflammation. The inactive cortisone is converted to active cortisol by an enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which thus acts to amplify active steroid levels in specific tissues. Levels of 11beta-HSD1 are rapidly increased in inflamed tissues, where it may promote the successful resolution of inflammation by increasing ?local? glucocorticoid action. This suggests that 11beta-HSD1 is anti-inflammatory. We have shown that mice lacking 11beta-HSD1 have an exaggerated (more severe and earlier onset) inflammatory response. We now aim to identify the cells responsible for the anti-inflammatory effects of 11beta-HSD1 and determine the mechanism by which it exerts these important effects. The results will be of potential therapeutic importance to target anti-inflammatory treatment.

Technical Summary

Glucocorticoid (steroid) hormones circulate in the blood and have potent anti-inflammatory effects. However, intracellular glucocorticoid concentrations can differ greatly from blood levels due to metabolism by 11beta-hydroxysteroid dehydrogenase (11beta-HSD), an enzyme that interconverts active and inactive glucocorticoids. Two isozymes exist; 11beta-HSD1 predominantly reactivates glucocorticoids by converting inert 11-keto-glucocorticoids (cortisone in humans, 11-dehydrocorticosterone in rodents) into active forms (cortisol, 11-dehydrocorticosterone), thus amplifying glucocorticoid action in cells and tissues in which it is expressed. Levels of 11beta-HSD1 are rapidly increased in inflamed tissues and in macrophages, where it may promote the successful resolution of inflammation by increasing ?local? glucocorticoid action. Recently we have shown that mice lacking 11beta-HSD1 have an exaggerated (more severe and earlier onset) acute inflammatory response. These data allow the hypothesis that 11beta-HSD1 represents an endogenous anti-inflammatory mechanism engaged early during an inflammatory response that limits the onset and severity of inflammation and ?programmes? the trajectory of the subsequent resolution. We now aim to determine which cells and mechanisms are responsible for the acute anti-inflammatory effects of 11beta-HSD1, focussing on myeloid immune cells (mast cells, monocytes/macrophages) versus the host tissues (notably vasculature and fibroblasts).

Publications

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Chapman KE (2013) Changing glucocorticoid action: 11ß-hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation. in The Journal of steroid biochemistry and molecular biology

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Kipari T (2013) 11ß-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

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Vandermosten L (2018) Adrenal hormones mediate disease tolerance in malaria. in Nature communications

 
Title myeloid cell-specific knock-out of 11beta-hydroxysteroid dehydrogenase type 1 
Description A line of transgenic mice created by crossing LysM-Cre transgenic mice (which express Cre recombinase in myeloid cells) with "floxed" 11beta-hydroxysteroid dehydrogenase type 1 mice. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Research currently ongoing to detemine whether myeloid cell 11beta-HSD1 plays a role in the inflammatory phenotype. 
 
Description Joint supervision of PhD student 
Organisation University of Edinburgh
Department School of Clinical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint supervision of a PhD student (Dr Will Cawthorn is primary supervisor) on an 11beta-HSD1 project to investigate the role of glucocorticoids in marrow adipose tissue. I bring expertise and resources for glucocorticoid/11beta-HSD1 research.
Collaborator Contribution Expert in marrow adipose tissue.
Impact Talks and abstracts at conferences from the PhD student.
Start Year 2016
 
Description Microbiome and bioinformatics 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided the research question and the biological materials, the sequencing was carried out in the genome facility (MRC funded) in Edinburgh.
Collaborator Contribution The bioinformatic analysis of the data and interpretation.
Impact Publication: PMID 27885053 Funding application will be submitted in May 2017
Start Year 2012
 
Description Public lecture series 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Co-organiser of public lecture series (4 to 5 lectures annually) from 2010-2012; sole organiser from 2013 "Let's talk about...." aimed at the general public and part of "Pathways to the professions". Sponsored by the MRC. Audiences (2013/14) >100. See http://www.cvs.med.ed.ac.uk/lets-talk

Forms part of "Pathways to the Professions" widening participation efforts to help school pupils in entry to medical school.
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
URL http://www.cvs.med.ed.ac.uk/lets-talk