Chapman, Karen E

Odermatt, Alex

English

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     Edinburgh Research Explorer                                      SteroidsCitation for published version:Chapman, KE & Odermatt, A 2010, 'Steroids: Modulators of inflammation and immunity' The Journal ofSteroid Biochemistry and Molecular Biology, vol 120, no. 2-3, pp. 67-8., 10.1016/j.jsbmb.2010.04.022Digital Object Identifier (DOI):10.1016/j.jsbmb.2010.04.022Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Preprint (usually an early version)Published In:The Journal of Steroid Biochemistry and Molecular BiologyGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 20. Feb. 2015Journal of Steroid Biochemistry & Molecular Biology 120 (2010) 67–68Contents lists available at ScienceDirectJournal of Steroid Biochemistry and Molecular Biologyjourna l homepage: www.e lsev ier .com/ locate / j sbmbEditorialSteroids: Modulators of inﬂammation and immunityThe study of steroids started in the ﬁrst half of the last century.Following the discoveries of sex steroids and then glucocorticoidsbetween the 1920s and 1940s, they rapidly made their way intothe clinic. From the beginning, glucocorticoids proved themselvesto be potent anti-inﬂammatory agents and they remain the mosteffective therapy for many allergic and chronic inﬂammatory dis-eases, although their use, especially at high pharmacological dose,is limited by their diverse side effects. Endogenous steroids areimportant modulators of the immune system. It is well known thatmen andwomen differ in their immunity, withwomen beingmoresusceptible to auto-immune disease, but less susceptible to infec-tions. Sex steroids modulate immunity and inﬂammation – someof these effects may be indirect, but the presence of oestrogen andandrogen receptors within immune cells highlights the importantand direct effects they have. Recently, the involvement of othersteroids in immunity has attracted attention, in particular the roleof noncalcemic actions of vitamin D in immune cells (especially Tcells), and there is considerable promise in the use of vitamin Dto treat some allergic diseases. Some immunomodulatory steroids,the prime example being dehydroepiandrosterone (DHEA) and itssulfated form, DHEAS, do not even bind to members of the nuclearreceptor family. The exact mechanism how DHEA exerts its effectsstill remains unknown.This special issue of the Journal of Steroid Biochemistry andMolecular Biology highlights the effects of these steroids uponinﬂammation and immunity. Inﬂammation is, of course, a normalprocess, being a host defence mechanism activated in response toinjury or infection that serves to control and eliminate invadingpathogens and promote the repair of damaged tissues. Many nor-mal body processes harness aspects of the inﬂammatory response,a prime example of this being the female reproductive system,with its cycles of tissue damage and repair - follicular rup-ture and release of the oocyte from the ovary, shedding of theendometrium at menstruation with subsequent repair and regen-eration ready for the next cycle. It is when the inﬂammatoryresponsegoes awryor the initial stimuluspersists thatproblemssetin and chronic inﬂammation ensues. Administered therapeutically,glucocorticoids are immuno-suppressive and anti-inﬂammatoryand are widely used to control chronic inﬂammatory diseasessuch as asthma, rheumatoid arthritis and dermatitis. Endoge-nous glucocorticoids are immunomodulatory rather than simplyimmunosuppressive (some of their actions can be consideredpro-inﬂammatory) and exert their effects through two membersof the nuclear receptor superfamily. Under some circumstancesthe mineralocorticoid receptor (MR) acts as a high afﬁnity glu-cocorticoid receptor, and may be responsible for some of thepro-inﬂammatory effects of glucocorticoids, particularlywithin thevasculature. However,most glucocorticoid actions aremediated bythe glucocorticoid receptor (GR) which is expressed almost ubiq-uitously, including in immune cells. Its mechanism of action hasbeen extensively investigated, although exactly how and whereit exerts its anti-inﬂammatory effects in vivo remains the sub-ject of some debate. In the ﬁrst paper in this volume, Baschantand Tuckermann describe the use of conditional GR knock-out andGR function-selective mouse models to elucidate the cell-speciﬁcroles of GR in modulating inﬂammation and immunity. A majorclinical problem is glucocorticoid resistance, whereby patients are(or become) non-responsive to glucocorticoids. Understanding thecellular mechanisms that give rise to glucocorticoid resistance iskey to improving therapy. These mechanisms are reviewed in thepaper from Barnes, together with potential treatments to reverseor by-pass glucocorticoid resistance. A key target in the develop-ment of glucocorticoid resistance may be regulatory T cells (Tregcells). RegulatoryT cells are critical tomaintain “tolerance” andpre-vent inappropriate immune activation in response to ubiquitousnon-harmful allergens. Induction of regulatory T cells in patientsmay be an effective therapy to treat allergic disease, especially inglucocorticoid resistant patients. The inﬂuences of steroids on reg-ulatory T cell induction and function is discussed by Dimeloe etal. This is followed by a paper from De Bosscher who describesthe development of novel selective glucocorticoid receptor mod-ulators; compounds which maintain the therapeutically usefulanti-inﬂammatory actions of glucocorticoids, without the detri-mental metabolic side effects. Some of these drugs are showingpromise and may soon reach the clinic.The levelsof circulating sex steroidsdecline in later life,with lossof the cardio-protective effects of oestrogen following menopausein women, although whether this is reversed with hormonereplacement therapy remains controversial. This topic is coveredbyGilliver, who has reviewed the effects of sex steroids upon immunecell function. This is an area that will be increasingly importantto understand and exploit to our advantage as we move towardsan increasingly elderly population. Normal inﬂammatory and anti-inﬂammatory effects of sex steroids in the human reproductivesystem are reviewed by King and Critchley, who also highlightthe important role played by steroid metabolising enzymes in themodulation of intracellular steroid access to receptors. As well assex steroids, levels of some other steroids also decline during laterlife. DHEA and DHEAS, precursors to sex steroids, are abundant inplasma in young adults, but decline thereafter. There is popularinterest in the use of DHEA as a supplement to counter the manyeffects of aging including those associated with immune senes-0960-0760/$ – see front matter © 2010 Published by Elsevier Ltd.doi:10.1016/j.jsbmb.2010.04.02268 Editorial / Journal of Steroid Biochemistry & Molecular Biology 120 (2010) 67–68cence, but the evidence as to whether and how it exerts theseeffects has been debated. In the ﬁnal review article, Hazeldine etal. look at the evidence regarding the immunomodulatory effectsof DHEA and DHEAS, and speculate on the mechanisms by whichthese steroids may act.The subject of this volume is large and the papers included hereby nomeans offer comprehensive coverage of the ﬁeld, but they dogive a ﬂavour of the current state of the ﬁeld and highlight excitingand promising avenues for future research.We would like to thank all the Authors who have contributedmanuscripts to this special issue.Wewould also like to thank all theReviewers who have given their time and effort to evaluating themanuscript submissions. Last, but not least, thank you to the edito-rial staff at Elsevier, especially Lijuan Wang and Malini Sangenenifor keeping us on track and to time with this issue.Karen E. ChapmanAlex Odermatt ∗University of Basel, Department of PharmaceuticalSciences, Molecular and Systems Toxicology,Klingelbergstrasse 50, 4056 Basel, Switzerland∗Corresponding author. Tel.: +41 61 267 1530;fax: +41 61 267 1515.E-mail address: alex.odermatt@unibas.ch(A. Odermatt)

Steroids:Modulators of inflammation and immunity

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