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1、One Hormone Two Actions:Anti-and Pro-inflammatory Effects of GlucocorticoidsDiana Cruz-Topete and John A.CidlowskiLaboratory of Signal Transduction,National Institute of Environmental Health Sciences(NIEHS),National Institutes of Health,Department of Health and Human Services,Research Triangle Park,

2、NC 27709,USAAbstractGlucocorticoids are essential steroid hormones secreted from the adrenal gland in response to stress.Since their discovery in the 1940s,glucocorticoids have been widely prescribed to treat inflammatory disorders and hematological cancers.In the traditional view,glucocorticoids ar

3、e regarded as anti-inflammatory molecules;however,emerging evidence suggests that glucocorticoid actions are more complex than previously anticipated.The anti-inflammatory activity of glucocorticoids is attributed to the repression of pro-inflammatory genes through signal transduction by their stero

4、id receptor,the glucocorticoid receptor(GR).The mechanisms modulating the pro-inflammatory effects of glucocorticoids are not well understood.In this review,we discuss recent findings that provide insights into the mechanism by which GR signaling can play a dual role in the regulation of the immune

5、response.We hypothesize that these apparently opposite processes are working together to prepare the immune system to respond to a stressor(pro-inflammatory effects)and subsequently restore homeostasis(anti-inflammatory effects).Finally,we propose that determining the mechanisms which underlie the t

6、issue-specific effects of glucocorticoids will provide an excellent tool to develop more efficient and selective glucocorticoid therapies.KeywordsGlucocorticoids;Stress Hormones;Glucocorticoid Receptor;Inflammation;Immunity;pro-inflammatory and anti-inflammatoryGlucocorticoids and the Stress Respons

7、eGlucocorticoids are steroid hormones synthesized and secreted by the adrenal gland in response to stress 1.Upon exposure to stress,the hypothalamus is stimulated to release corticotrophin-releasing hormone(CRH),which then acts on the anterior pituitary gland to stimulate the synthesis of adrenocort

8、icotropic hormone(ACTH).ACTH then acts on the adrenal cortex to induce the secretion of glucocorticoids 2.Once in circulation,glucocorticoids exert a variety of tissue-specific effects(Figure 1)25.Therefore,glucocorticoid imbalances can result in pathological conditions such as the severe Correspond

9、ence and reprint requests:Dr.John A.Cidlowski,Laboratory of Signal Transduction,National Institute of Environmental Health Sciences,Research Triangle Park,NC 27709,Phone:(919)541-156,Fax:(919)541-1367,cidlows1niehs.nih.gov.NIH Public AccessAuthor ManuscriptNeuroimmunomodulation.Author manuscript;ava

10、ilable in PMC 2016 January 01.Published in final edited form as:Neuroimmunomodulation.2015;22(0):2032.doi:10.1159/000362724.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptcardiovascular,metabolic and immunological complications observed in Cushings syndrome(glucocorticoid ex

11、cess)and Addisons disease(glucocorticoid deficiency).Glucocorticoid therapy was first introduced by Dr.Philip Hench in the 1940s for the treatment of rheumatoid arthritis 6.Since then,glucocorticoids have commonly been prescribed to treat inflammatory disorders,including asthma,allergic rhinitis,ulc

12、erative colitis,and several other dermatological,ophthalmic,neurological and autoimmune diseases 7,8.Despite their therapeutic benefits,glucocorticoid use,in traditional high doses 5 mg/day,is associated with severe side effects,including diabetes,hypertension,glaucoma,muscle atrophy and growth reta

13、rdation 7,9.However,the magnitude of the positive or negative effects of glucocorticoids will depend on the dose,duration of the treatment,glucocorticoid receptor levels,and cell-and tissue-specific glucocorticoid signal transduction 1012.Long-term treatment with glucocorticoids can also be associat

14、ed with glucocorticoid resistance,which results in the inability of glucocorticoids to exert their effects on target tissues,limiting the efficacy of the therapy 13.Therefore,understanding how glucocorticoids exert their actions in a dose and tissue-specific manner should help to develop novel thera

15、pies using these agents that may decrease their undesired effects.This review examines evidence that emphasizes the pro-and anti-inflammatory actions of glucocorticoids on the immune system.These apparently opposite effects appear to work together as a defense mechanism to“prepare”the immune system

16、to respond to a stressor,and subsequently to shut down the immune response to restore homeostasis 14.Molecular Mechanisms of GlucocorticoidsGlucocorticoid Receptor StructureGlucocorticoids exert their actions by binding to their receptor,the glucocorticoid receptor(GR),a ligand-induced transcription

17、 factor,a member of the nuclear receptor superfamily 15.GR is expressed in virtually all cell types and tissues 1,3,8.In terms of the structure,GR is composed of 3 major functional domains:the N-terminal domain(NTD);the central DNA-binding domain(DBD);a hinge region(region linking the DBD and ligand

18、-binding domain);and the C-terminal ligand-binding domain(LBD)(Figure 2A)2,14.Each domain comprises a specific function;for example,the NTD has a transcriptional activation function(AF-1)domain which contains a majority of the residues subject to post-translational modifications.The NTD is important

19、 for the recruitment of the basal transcriptional machinery.The DBD consists of two zinc fingers implicated in DNA binding,nuclear translocation,and GR dimerization 2.The LBD also contains an AF-2 domain which interacts with coregulators in a ligand-dependent manner 14,1618.GR Genomic and Non-Genomi

20、c EffectsUnder basal conditions,GR resides primarily in the cytoplasm in a complex with chaperone proteins hsp90,hsp70,and p23,and immunophilins FKBP51 and FKBP52,where it is largely considered to be functionless 2,5.Upon hormone binding,GR translocates into the nucleus to enhance or repress the tra

21、nscription of target genes by several mechanisms:1)direct binding to specific cis-acting DNA sequences(glucocorticoid responsive elements;Cruz-Topete and CidlowskiPage 2Neuroimmunomodulation.Author manuscript;available in PMC 2016 January 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Aut

22、hor ManuscriptGREs);2)tethering itself to other transcription factors;and/or 3)through direct binding to DNA and interacting with neighboring transcription factors,which is known as composite regulation(Figure 2B)2.The GRE consensus sequence is GAGAACAnnnTGTTCT,an imperfect palindrome containing two

23、 hexameric half sites separated by three base pairs 1820.GR binding to GREs typically leads to transactivation,where glucocorticoids induce target genes.However,recent studies have shown that GR occupancy of a GRE can also lead to gene repression,in a process known as“transrepression”(Figure 2B)21.G

24、R can also repress genes by tethering itself to other transcription factors.For example,GR can physically interact with nuclear factor-B(NF-B)and activator protein-1(AP-1),which represses their capacity to induce the transcription of pro-inflammatory genes(Figure 2B)22,23.GR has also known to bind t

25、o inverted palindromic sequences denominated as negative GREs(nGREs).The consensus sequence of these cis-acting negative response elements is CTCC(n)0-2GGAGA 24.Studies have shown that GR recruitment to nGREs promotes the assembly of a corepressor complex and the recruitment of histone deacetylases(

26、HDACs),which direct glucocorticoid-dependent repression of specific genes 25(Figure 2B).GR has also been proposed to exert“rapid”non-genomic actions by directly modulating signal transduction pathways 2.This process occurs via membrane-bound GR or cytosolic GR interactions with kinases,such as the e

27、xtracellular signal-regulated kinases(ERKs),the c-Jun NH2-terminal kinases(JNKs),the p38 isoforms(p38s),and ERK5 26(Figure 2B).To date,the detailed mechanism and biological implications of non-genomic effects of GR have not been fully elucidated;human studies suggest that this response might have im

28、portant physiological effects on the cardiovascular and immune system 26,27.Non-genomic effects of glucocorticoids are extensively discussed in a recent publication by Ayroldi,E.et al 26.GR IsoformsIn addition to the genomic and non-genomic actions of glucocorticoids,GR signaling is also dependent o

29、n the existence of multiple receptor isoforms and post-translational modifications(PTMs)2,4.GR is transcribed from a single gene,NR3C1,however,alternative splicing of this gene generates GR and GR isoforms,which differ in their C-terminal domain 28.Both isoforms are associated with distinct response

30、s to glucocorticoids 29.The existence of different isoforms explains in part how a“single”receptor can exert a plethora of pharmacological and cellular responses.Human GR,the classical GR protein,exerts most of the biological actions of glucocorticoids 29.Furthermore,GR expression is higher than GR

31、in tissues 30.In general,GR presents several distinct properties:it is located primarily in the nucleus,does not bind glucocorticoid agonists,and antagonizes the activity of GR 3133.Studies have shown that increased GR levels are associated with glucocorticoid resistance in inflammatory disorders,in

32、cluding asthma,rheumatoid arthritis,and ulcerative colitis 34.However,genome-wide microarray studies on cells selectively expressing GR have shown that GR regulates the expression of a large number of genes independently of GR activity 34,35.These findings raise interesting possibilities regarding G

33、R genomic effects and the physiological role of GR,although the molecular mechanisms governing GR actions are still unknown.In addition to GR,three less well-characterized isoforms have been reported:GR,GR-A Cruz-Topete and CidlowskiPage 3Neuroimmunomodulation.Author manuscript;available in PMC 2016

34、 January 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptand GR-P 31.Although their physiological role is poorly understood,studies suggest that their expression could be associated with the development of glucocorticoid resistance in some types of hematological cancers 31

35、.GR and GR can also undergo alternative translation initiation in exon two,which generates several GR isoforms with distinct properties.Eight additional isoforms of GR with truncated N-terminal are generated from GR:GR-A,GR-B,GR-C1,GR-C2,GR-C3,GR-D1,GR-D2,and GR-D3.Similar isoforms can be also gener

36、ated from GR 2.The structure,complexity and signaling properties of the GR isoforms are discussed in detail in a recent review by Oakley et al 2.GR Post-translational modificationsPost-translational modifications(PTMs)lead to important changes in the transcriptional activity of the GR.The most frequ

37、ently studied PTM of GR is phosphorylation 31.Human glucocorticoid receptor has been reported to be phosphorylated at several serine residues(S113,S134,S141,S143,S203,S211,S226,and S404)by various kinases,including MAPK,GSK-3 and cyclin-dependent kinase 36,37.Phosphorylation of GR has been shown to

38、impact its activity at multiple levels.Studies in COS-1 cells transfected with phosphorylation-deficient GR mutants showed that changes to the phosphorylation status of GR blocks the ability of the receptor to activate GR target genes 38.Phosphorylation of GR at S211,a substrate for p38 MAPK,is asso

39、ciated with increased GR-induced gene transcription 39.In contrast,phosphorylation of S226 is associated with decreased GR signaling transduction 40.Phosphorylation of GR S404 has also been shown to drive a specific transcriptional response to glucocorticoids 41.The phosphorylation state of GR influ

40、ences its response to hormone,cellular localization,and signaling activity.Furthermore recent studies have shown that S134-GR residue can be phosphorylated by p38 MAPK in response to stress in the absence of hormone binding 42.This study showed that mutations of Ser134(S134A-GR)lead to the dysregula

41、tion of genes associated with metabolic and inflammatory diseases 42,which indicate that hormone-independent phosphorylation events also are critical in the regulation of GR-dependent gene transcription.Other PTMs have also been reported to modulate GR activity and signaling.Ubiquitination of GR at

42、Lys-419 targets the receptor for proteasomal degradation 43.SUMOylation and acetylation also play a role in the modulation of GR transcriptional activity by enhancing or repressing its interactions with specific coregulators 44.For example,deacetylation of GR Lys-494 and Lys-495 residues has been re

43、ported to modulate GR repression of NF-B 45.In addition,studies suggest that acetylation of GR modulates the ability of the receptor to induce or repress glucocorticoid responsive genes in target tissues 46.In summary,the existence of multiple GR isoforms and the presence of numerous PTMs contribute

44、 to the diversity of the genomic and non-genomic actions of GR,and perhaps explain how a single receptor can exert a plethora of physiological actions.Cruz-Topete and CidlowskiPage 4Neuroimmunomodulation.Author manuscript;available in PMC 2016 January 01.NIH-PA Author ManuscriptNIH-PA Author Manuscr

45、iptNIH-PA Author ManuscriptAnti-and Pro-inflammatory effects of GlucocorticoidsThe discovery of the anti-inflammatory actions of glucocorticoids was a major breakthrough for the treatment of inflammatory disorders.Both natural and synthetic glucocorticoids are widely prescribed as anti-inflammatory

46、drugs 3,14.The anti-inflammatory activity of GR and glucocorticoids generally is attributed to the repression of pro-inflammatory genes through the direct interaction of GR with other transcription factors 21.However,anti-inflammatory activity of GR also can result via nonspecific interactions of gl

47、ucocorticoids with membrane components or through membrane bound GR 2.In addition,GR interactions with kinases also can affect inflammatory signaling pathways independently of gene transcription 14,26.Although glucocorticoid actions typically are described as anti-inflammatory,studies suggest that g

48、lucocorticoids also can exert pro-inflammatory effects in response to acute stress 47.For example,glucocorticoid treatment can exacerbate the peripheral immune response in delayed type hypersensitivity(DTH)4749.Also,the levels of pro-inflammatory cytokines such as IL-1 have been found to be increase

49、d in the central nervous system in response to acute stress associated with increase glucocorticoid secretion 47,50,51.In addition,recent studies suggest that chronic exposure to glucocorticoids,classically viewed as anti-inflammatory,may result in increased systemic trafficking of lymphocytes and m

50、onocytes 52.In the next sections we will review how glucocorticoids modulate inflammation by suppressing or augmenting the immune response.Classic Anti-inflammatory Effects of GlucocorticoidsAs noted above,the actions of glucocorticoids are classified as anti-inflammatory/immunosuppressive.Glucocort