PRESENTATION
Peroxisome Proliferator–activated Receptor Gamma in the Colon Inflammation and Innate Antimicrobial Immunity Silvia Speca, PhD,*w Laurent Dubuquoy, PhD,*w and Pierre Desreumaux, MD, PhD*wz
Abstract: Peroxisome proliferator–activated receptor g (PPARg) is a nuclear receptor, originally described in adipose tissue, which controls the expression of a large number of regulatory genes in lipid metabolism and insulin sensitization. Well known by endocrinologists, thiazolidinedionesare classical PPARg synthetic agonists, which were currently used as insulin-sensitizing agents in the treatment of type 2 diabetes. Although the clinical benefits of thiazolidinediones in treating metabolic disorders have been clearly demonstrated, studies performed in animal models of colitis and in patients with ulcerative colitis have also revealed the key roles of PPARg activation in the regulation of inflammation and immune response, notably in the colon through epithelial cells. Key Words: PPARg, inflammation, immunity, IBD
(J Clin Gastroenterol 2014;48:S23–S27)
P
eroxisome proliferator–activator receptor g (PPARg) is a nuclear receptor belonging to the PPARs family, together with PPARa and PPARb/d. The members of PPARs family were first cloned as steroids hormone receptors homologues activated by a class of rodent hepatocarcinogens causing peroxisomes proliferation.1 Encoded by distinct genes located on different chromosomes, PPARs display a high degree of From the *INSERM U995; wUniversite´ Lille Nord de France; and zCHU Lille, Service des maladies de l’appareil digestif et de la nutrition, Hoˆpital Claude Huriez, Lille, France. Supported by industry from 2004 to 2014: Astra-Zeneca, Paris, France; Danisco France SAS, Paris, France; Danone France, Massy Palaiseau, France; Ferring, St Prex, Suisse; Ferring, San Diego; Ferring, Southampton, UK; Giuliani SpA, Milano, Italy; Lesaffre, Marcq en Baroeul, France; Ocera Therapeutics, San Diego, CA; Roquette, Lestrem, France; Sanofi-Synthelabo, Paris, France; UCB Pharma, Paris, France; Yoplait, Paris, France; Omega Pharma, Belgium. S.S.: lecture fees from speaking at ECCO congress sponsored by Giuliani SpA, Milano, Italy; P.D.: consulting fees or paid advisory boards: Biofortis, Nantes, France; Danisco France SAS, Paris, France; Danone France, Massy Palaiseau, France; Ferring, St Prex, Suisse; Giuliani SpA, Milano, Italy; Roquette, Lestrem, France; UCB Pharma, Paris, France; Txcell, Nice, France; Biofortis, France; Lesaffre, Marcq en Baroeul, France; MSD, France; Abbott, France; Norgine, France; Genfit, France; OmegaPharma International; lecture fees from speaking at continuing medical education events indirectly sponsored by a commercial sponsor: 1. Procter and Gamble, London, UK. 2. Ferring, Paris, France. 3. Ferring, London, UK. 4. Schering Plough, Paris, France. 5. Shire Pharmaceuticals, USA. 6. UCB Pharma, Paris, France. 7. MSD, France. 8. Norgine, France. 9. Abbott, France; L.D. declares that there is nothing to disclose. Reprints: Pierre Desreumaux, MD, PhD, Inserm U995, Amphis J&K, Bd Pr Jules Leclercq, Lille 59045, Cedex, France (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
J Clin Gastroenterol
sequence and structural homology, specific patterns of tissue distribution, and cellular functions. Three different protein isoforms of PPARg are described, such as PPARg1, PPARg2, and PPARg3. The 1 and 3 isotypes are structurally identical and are expressed in nearly all cells, whereas PPARg2 shows an additional region of 30 amino acids at the NH2-terminal and is exclusively expressed in adipose tissue. PPARg plays a critical role in the control of a broad range of cellular processes, such as differentiation of adipocytes, glucose homeostasis, and lipid metabolism.2,3
PPARg IN THE COLON: MECHANISMS OF ACTION AND REGULATION The different activities of PPARg are mainly performed via endogenous and/or exogenous ligands. The presence of a large T-shaped hydrophobic pocket in the Cterminal ligand-binding domain (LBD) allows, indeed, the binding of a wide variety of natural and also synthetic modulators, which carry out the distinct functions of PPARg, depending on the cellular context. The molecular mechanisms of transactivation of selective target genes performed by PPARg in response to specific ligands are currently widely known. PPARg operates as functional heterodimer with the retinoid X receptors (RXR). In absence of ligands PPAR/RXR heterodimer resides in the nucleus bound to the peroxisome proliferator response elements (PPREs), located in the target gene promoter,3 in a complex with transcriptional corepressors, such as silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and nuclear receptor corepressor (NCoR). PPREs are bi-hexameric DNA sequences presenting direct repeats (DRs) with the core sequence AGG(A/T)CA separated by one or two base-pairs, experimentally identified in >70 target genes.3–6 Following the interaction with specific ligands, PPAR/RXR undergoes conformational changes that induce a corepressor for coactivator complex exchange resulting in the transcriptional activation of target genes.7,8 Despite these, molecular mechanisms are quietly similar among all members and subgroups of PPARs family, the specificity of the single PPARg functions depends, indeed, by the specific cellular and tissue context in which it is expressed. Originally described as orphan nuclear receptor, mainly expressed in adipose tissue, PPARg can be tracked in a broad spectrum of different tissues, among which the colon represents the main site where PPARg achieves tissue expression levels comparable to adipose tissue.9–11 PPARg expression in the colon follows a specific trend to increase on proximal to distal axis. It involves the majority of cells in mucosal barriers, mainly the intestinal
Volume 48, Supp. 1, November/December 2014
www.jcge.com |
S23
Speca et al
J Clin Gastroenterol
epithelial cells (IEC) and, to lower degree, monocytes/ macrophages and lymphocytes, and regulates a wide variety of function ranging from epithelial cell motility and differentiation to homeostatic mechanisms, such as proliferation, epithelial integrity, and, more specifically, regulation of mucosal bacterial-induced inflammation.10,12 All evidences were mainly established by using specific natural or synthetic PPARg ligands. In particular, the main suggestions derived from the clinical benefits of a class of insulin-sensitizing agents used in the treatment of type 2 diabetes, the thiazolidinediones (TZDs), not only in treating metabolic disorders but also in experimental animal models of colitis and in patients with irritable bowel disease or ulcerative colitis (UC).9,13 The latter, together with Crohn’s disease (CD), represents the clinical manifestation of the inflammatory bowel disease (IBD), gastrointestinal disorders in which a dysregulated immune response to intraluminal antigens, such as resident luminal bacteria, bacterial products, or dietary antigens, generate a chronic defective mucosal barrier. A significantly impaired PPARg expression was observed in colonic epithelial cells of UC patients, compared with controls and CD patients, suggesting that the disruption of PPARg signaling may represent a critical step of the UC pathophysiology.9 One of the oldest anti-inflammatory drug used in the treatment of IBD is the 5-aminosalycilic acid (5-ASA). In vitro studies, mainly performed on colon epithelial cell line, showed the ability of this compound to induce PPARg expression and to direct the turn of events leading the transactivation of target genes. In addition, genetically engineered heterozygous knockout at the PPARg locus (PPARg + / ) mice not only showed increased susceptibility to chemically induced colitis, highlighting the genetic involvement of PPARg in the control on inflammation, but also appeared refractory to 5-ASA therapy, suggesting that the clinical benefits of this compound are mediated, at least in part, by PPARg.9 A further indication regarding the anti-inflammatory properties of the ligand-dependent PPARg activation in the colon was also provided by its expression on several immunological cell types, such as activated macrophages, dendritic cells (DC), naive and activated T cells, and B cells. Moreover, PPARg is able to interfere with chemo-attraction and cell adhesion of these inflammatory cell types, by inhibiting the expression of monocyte-chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and intracellular adhesion molecule (ICAM).14,15 In addition, multiple studies have reported that PPARg ligands are able to stimulate monocytes differentiation to macrophages.5,15,16 Monocyte recruitment to sites of injury and their activation in resident macrophages represent the key events orchestrating both initiation of inflammation, by which macrophages execute a first protection of the host, and its own resolution. Active silencing of inflammatory gene induced by TZD represents an important demonstration of PPARg involvement into the control of the macrophage inflammatory response. Specific mechanisms action, limiting magnitude, and duration of macrophage inflammation, are an attractive aim of several investigations. Inhibition of the production of inducible nitric oxide synthase (iNOS), an enzyme responsible for high-output release of NO from larginine strongly upregulated in inflammatory response, seems to represent one of the main effects of the PPARg-induced monocyte differentiation to macrophages.15,16 Nevertheless, the contribution of PPARg in the
S24 | www.jcge.com
Volume 48, Supp. 1, November/December 2014
regulation of intestinal inflammation is suggested by its specific immunolocalization to colonocytes, intestinal epithelial cells whose participation in the installation and the perpetuation of the intestinal inflammation is currently defined. Pioneering studies performed by Adachi and colleagues showed, indeed, an enhanced susceptibility to the chemically induced colitis in mice with epithelium-specific loss of PPARg expression. In addition, clinical reports indicated decreased levels of PPARg in the gut of patients with ulcerative colitis compared with healthy subjects, substaining the hypothesis of a crucial role of PPARg in IEC in regulating of mucosal inflammation and suggesting that epithelial cells represent a prime target for PPARg ligands.13,17–19 In addition, several evidences, mainly based on the action of TZDs in the stimulus-dependent production of the main inflammatory mediators (TNFa, IL-6, MCP1, PAI-1) in colonic epithelial cells, have supplied solid indications that PPARg acts as key molecule in the network of negative feedback mechanisms that control mucosal inflammation by interfering with the activity of transcription factors, such as members of the NF-kB and AP-1 families, in a mechanism known as “transrepression.” More specifically, TZD-induced PPARg activation has proven to be directly implied in the repression the signal-dependent NF-kB activity.19,20 The NF-kB family consists of 5 members, p65 (RELA), REL-B, c-REL, p50, and p52, which function as homodimers or heterodimers. In the basal state, NF-kB is sequestered in the cytoplasm by an inhibitory molecule, IkBa or IkBb. Following a wide-range of stimulation, IkBa and IkBb are phosphorylated by the activation of the high molecular weight kinase complex, IkB kinase (IKK), ubiquinated and degraded. Then, NF-kB translocates into the nucleus where it binds to target promoters inducing the expression of proinflammatory cytokines, enzymes, and adhesion molecules.21 Several evidences suggest that the antagonistic action of PPARg on NF-kB can involve several molecular mechanisms, ranging from the direct increase of IkB expression (a negative regulatory feedback loop) to the protein-protein crosstalk interaction, among which the physical interaction with NF-kB, the competition for a pool of coactivators essential to the NFkB signal transduction, the histone modification, and the blockage of signal-dependent clearance of corepressor complexes and sumoylation, a highly transient posttranslational protein modification.20 The mechanistic basis by which PPARg switches from activator of transcription to a promoterspecific repressor of NF-kB target genes is still under investigation. As the first barrier to luminal bacteria, intestinal epithelial cells play a pivotal role in the detection of microorganisms, acting in concert with the resident microflora, and determining the development of an appropriate and complex mucosal immune response. Considered as immunoeffector cells, epithelial cells secrete antibacterial peptides and cytokines (eg, IL-10 and TGF-b) in the lamina propria and express a specific pattern recognition receptors such as the extracellular Toll-like receptors (TLR) and the intracellular nucleotide oligomerization domain/caspase recruitment domain (NOD/CARD)-like receptors (NLRs),22 able to bind specific components of bacterial cell walls, notably known as pathogen-associated molecular patterns (PAMP), to trigger a host defence response against invading pathogens and to activate signalling pathways that induce the expression of immune and proinflammatory genes.22 r
2014 Lippincott Williams & Wilkins
J Clin Gastroenterol
Volume 48, Supp. 1, November/December 2014
TLR are constitutively expressed in IEC and their activation, mediated via PAMPs, such as lipopolysaccharide (LPS) or butyrate, as well as intestinal flora and probiotics are able to lead in turn sequential events culminating with the activation and recruitment of transcription factors, among which NF-kB seems to be the most implied in the immune response to the microbial invasion. Both an increased mucosal expression of TLRs and TLR polymorphisms in the intestine of patients with IBD have been observed23–26 and represent the underlying mechanisms leading to the abnormal host reaction18 and to the defective immune tolerance to commensal bacteria,25,26 respectively. The mutual antagonizing action between PPARg and NF-kB, as well as the high expression levels in intestinal epithelial cells, represent some of the elements that support the key role of PPARg in controlling immune response in the colon and intestinal homeostasis. In line with this idea, in vivo studies performed on mice lacking PPARg in the colonic epithelium showed a reduced microbicidal activity against microbes, such as Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli as compared with wild-type littermates.27 At the same time several evidences demonstrated a close relationship between expression of PPARg on intestinal epithelial cells and commensal intestinal flora. Colonic epithelium showed upregulation of PPARg expression in presence of bacteria belonging to a murin or human flora compared with germ-free condition. The effect of commensal flora on PPARg expression is well-established also by in vitro studies on IEC stimulated by LPS, or by direct stimulation with Helicobacter pylori or Saccharomyces boulardii.13,27–31 In addition, a basic study performed by Dubuquoy et al13 on TLR-4-transfected IEC and mice presenting a nonfunctional TLR4 (C3H/HeJ Lpsd/ Lpsdmice) established as PPARg overexpression in IEC is in part related to the LPS recognition Toll-like receptor (TLR)-4 signaling. These evidences represent a walk-through of the contribution of luminal microbes to the pathogenesis of IBD. UC and CD patients show an imbalanced charge of pathogens and nonpathogens micro-organisms. Because of the defective mucosal barrier, lamina propria immune cells are continuously exposed to the luminal antigens induce, indeed, elevated levels of TLR-4 that, associated to the impaired PPARg expression observed in UC patients, may determine an alteration of tolerance to luminal bacteria triggering, amplifying, and maintaining the local inflammation.9 On the other side, a very recent study performed indicates a discordance between the effects specifically induced by Salmonella typhimurium and the others enteric pathogens. PPARg expression in the intestinal epithelium was decreased of at least 60% by S. typhimurium in a TLR4-dependent way and at the same time the specific ablation of PPARg in intestinal epithelium was associated with a much more sever colitis induced by this pathogen.32 All evidences led to consider the importance of intestinal-epithelium PPARg in regulation of colitis, even if the effect of the various pathogens on the regulation of this receptor can vary on the strength of the bacterial species that colonize and infect the host intestine.32 A further confirmation of the critical role of PPARg in the regulation of immune response was established by a study performed by Peyrin-Biroulet and colleagues in which PPARg-induced microbial killing activity has proven to be r
2014 Lippincott Williams & Wilkins
Intestinal Peroxisome Proliferator–activated Receptor
due to the induction of b-defensin expression in IEC. bdefensins are small antimicrobial cationic peptides contributing to innate host defense via direct bacteriocidal and candidacidal activity. Constitutively or inducibly expressed, b-defensins recognize and neutralize invading gram-negative and gram-positive bacteria, fungi, viruses, and protozoa in a quick and specific manner representing the first line of host defense. Peyrin-Biroulet and colleagues showed that PPARg was an essential regulator of innate immunity in colon and ileum. PPARg deficient mice (PPAR / mice) showed both reduced expression and bactericidial activity of certain b-defensins compared with WT littermates. b-defensins are downregulated in CD patient and targeting PPARg therapies may point, thus, to increase in the expression of a subset of b-defensins enhancing microbial killing by the colonic mucosa and controlling the excessive inflammation.27 In addition, a very recent study performed in our laboratory demonstrated for the first time that PPARg expression in IEC is directly regulated by glucocorticoids (GCs).33 GCs, are steroid hormones with immunosuppressive and anti-inflammatory properties already widely used in the treatment of several inflammatory and immunemediated disorders.34–36 Mainly produced is in the adrenal cortex, GCs are also de novo synthesized by other organs and notably by epithelial cells. At intestinal level, IEC represent a significant source of cortisol and the role of extra adrenal-produced GCs is still not fully elucidated, even if the main researches provides clues on their role in the regulation of local immunological functions and gut homeostasis.37,38 Moreover, Coste et al39 demonstrated inverse relationship between severity of inflammation in colons of IBD patients and local endogenous glucocorticoid synthesis. On the strength of these evidences we supposed a link between endogenous GCs and PPARg activation and expression. Our hypothesis was corroborated by the presence of the several highly probable GCs response elements (GREs) on the PPARg promoter region, suggesting PPARg as putative GC target gene. In addition, synthesis of GC in intestinal epithelial is controlled by liver receptor homolog-1 (LRH-1), a transcription factor able to activate first the cholesterol sidechain cleavage enzyme CYP11A1 and then CYP11B1, key enzymes in steroidogenesis.40 IEC isolated from UC patients, showed reduced LRH-1 expression, directly correlating with PPARg expression. This evidence was confirmed in our study by using Caco-2 cells lacking LRH-1, supporting the hypothesis that PPARg expression in colonocytes is controlled by cortisol in UC patients and the decreased expression of PPARg could be a direct effect of the impaired steroidogenesis in the colon.33 All these evidences highlight the crucial role of PPARg in the control of inflammation and immunity in colon, representing new clues in understanding gut homeostasis and representing a solid proof to consider PPARg as target of new therapeutic approaches in IBD.
THERAPEUTIC DEVELOPMENT PPARg has always represented an intriguing target for new therapeutic approaches in several diseases, above all for its pleiotropic action in a wide range of cellular mechanisms, from the development to the adipocytes differentiation, glucose homeostasis, lipids metabolism, and control of inflammation. The high PPARg expression levels in the colonic epithelial cells (100-fold more concentrated than in the small www.jcge.com |
S25
J Clin Gastroenterol
Speca et al
intestine) made this receptor a key molecule in the network of negative feedback mechanisms controlling inflammation in IBD. PPARg is naturally activated by prostaglandins (PG-D1 and PG-D2) and the PG derivative 15-deoxy-D12,14-PGJ2 and it is a good molecular target of a growing variety for synthetic ligands, such as thiazolidinediones (TZD) and 5aminosalicylic acid (5-ASA). It has been widely showed that 5-ASA or glitazone, but also glucocorticoids, are able to in induce and maintain the clinical remission as well as mucosal healing in patients with UC.41–44 In addition, a high rate of remission in UC patient was induced by 5-ASA in combination with corticosteroids, compared with monotherapy and this effect could be due both to the additive effect of the 2 drugs but also to their synergistic effect on PPARg activation and expression.45 Due to safety issues concerning particularly the greater risk of myocardial infarction, use of TZDs has been severely limited for the treatment of type 2 diabetes and/or inflammatory diseases, justifying the development of a new family of PPARg agonists with major transrepressive effects and with limited toxicity. By the demonstration that the anti-inflammatory effects of 5-aminosalicylic acid (5-ASA) in patients with ulcerative colitis were mediated by PPARg activation, several molecules having 5-ASA similarities have been developed and screened leading to the selection of a aminophenyl-alpha-methoxy-propionic acids named GED-0507-34-Levo (GED). This compound activating PPARg has 100- to 150-fold higher anti-inflammatory activity than 5-ASA. This new PPAR modulator is giving promising results both in vitro and in vivo, without toxicity and is currently evaluated in a phase 2 clinical trial. REFERENCES 1. Feige JN, Gelman L, Michalik L, et al. From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res. 2006;45:120–159. 2. Rousseaux C, Desreumaux P. The peroxisome-proliferatoractivated gamma receptor and chronic inflammatory bowel disease (PPARgamma and IBD). J Soc Biol. 2006;200:121–131. 3. Houseknecht KL, Cole BM, Steele PJ. Peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands: a review. Domest Anim Endocrinol. 2002;22:1–23. 4. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998;391:82–86. 5. Ricote M, Li AC, Willson TM, et al. The peroxisome proliferatoractivated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82. 6. Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 2008;77:289–312. 7. Ho¨rlein AJ, Na¨a¨r AM, Heinzel T, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature. 1995;377:397–404. 8. Chen JD, Evans RM. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature. 1995;377: 454–457. 9. Dubuquoy L, Rousseaux C, Thuru X, et al. PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut. 2006;55:1341–1349. 10. Lefebvre M, Paulweber B, Fajas L, et al. Peroxisome proliferator-activated receptor gamma is induced during differentiation of colon epithelium cells. J Endocrinol. 1999; 162:331–340. 11. Katayama K, Wada K, Nakajima A, et al. A novel PPAR gamma gene therapy to control inflammation associated with inflammatory bowel disease in a murine model. Gastroenterology. 2003;124:1315–1324.
S26 | www.jcge.com
Volume 48, Supp. 1, November/December 2014
12. Su W, Bush CR, Necela BM, et al. Differential expression, distribution, and function of PPAR-gamma in the proximal and distal colon. Physiol Genomics. 2007;30:342–353. 13. Dubuquoy L, Jansson EA, Deeb S, et al. Impaired expression of peroxisome proliferator-activated receptor gamma in ulcerative colitis. Gastroenterology. 2003;124:1265–1276. 14. Debril MB, Renaud JP, Fajas L, et al. The pleiotropic functions of peroxisome proliferator-activated receptorg. J Mol Med. 2001;79:30–47. 15. Chinetti G, Fruchart JG, Staels B. Peroxisome proliferatoractivated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism, and inflammation. Inflam Res. 2000;49:497–505. 16. Gelman L, Fruchart GC, Auwerx J. An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs), and their roles in inflammation, and cancer. Cell Mol Life Sci. 1999;55:932–943. 17. Adachi M, Kurotani R, Morimura K, et al. Peroxisome proliferator activated receptor gamma in colonic epithelial cells protects against experimental inflammatory bowel disease. Gut. 2006;55:1104–1113. 18. Mohapatra SK, Guri AJ, Climent M, et al. Immunoregulatory actions of epithelial cell PPAR gamma at the colonic mucosa of mice with experimental inflammatory bowel disease. PLoS One. 2010;5:e10215. 19. Su CG, Wen X, Bailey ST, et al. A novel therapy for colitis utilizing PPAR-ligands to inhibit the epithelial inflammatory response. J Clin Invest. 1999;104:383–389. 20. Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol. 2010;10:365–376. 21. Hayden MS, Ghosh S. Shared principles in NF-kB signaling. Cell. 2008;132:344–362. 22. Liew FY, Xu D, Brint EK, et al. Negative regulation of tolllike receptor-mediated immune responses. Nat Rev Immunol. 2005;5:446–458. 23. Szebeni B, Veres G, Dezso˜fi A, et al. Increased expression of Toll-like receptor (TLR) 2 and TLR4 in the colonic mucosa of children with inflammatory bowel disease. Clin Exp Immunol. 2008;151:34–41. 24. Cario E, Podolsky DK. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infec Immun. 2000;68: 7010–7017. 25. Franchimont D, Vermeire S, El Housni H, et al. Deficient hostbacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn’s disease and ulcerative colitis. Gut. 2004;53:987–992. 26. Torok HP, Glas J, Tonenchi L, et al. Polymorphisms of the lipopolysaccharide-signaling complex in inflammatory bowel disease: association of a mutation in the Toll-like receptor 4 gene with ulcerative colitis. Clin Immunol. 2004; 112:85–91. 27. Peyrin-Biroulet L, Beisner J, Wang G, et al. Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc Natl Acad Sci USA. 2010;107:8772–8777. 28. Cuthbert AP, Fisher SA, Mirza MM, et al. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology. 2002;122:867–874. 29. Papo N, Shai Y. Can we predict biological activity of antimicrobial peptides from their interactions with model phospholipid membranes? Peptides. 2003;24:1693–1703. 30. Ayabe T, Satchell DP, Wilson CL, et al. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol. 2000;1:113–118. 31. Ouellette AJ. Defensin-mediated innate immunity in the small intestine. Best Pract Res Clin Gastroenterol. 2004;18:405–419. 32. Bouguen G, Langlois A, Djouina M, et al. Intestinal steroidogenesis controls PPARg expression in the colon and is impaired during UC. Gut. 2014 July 22 [published online ahead of print]. r
2014 Lippincott Williams & Wilkins
J Clin Gastroenterol
Volume 48, Supp. 1, November/December 2014
33. Kundu P, Ling TW, Korecka A, et al. Absence of intestinal PPARg aggravates acute infectious colitis in mice through a lipocalin-2-dependent pathway. PLoS Pathog. 2014;10:e1003887. 34. De Bosscher K, Haegeman G. Minireview: latest perspectives on anti-inflammatory actions of glucocorticoids. Mol Endocrinol. 2009;23:281–291. 35. Ishmael FT, Fang X, Houser KR, et al. The human glucocorticoid receptor as an RNA-binding protein: global analysis of glucocorticoid receptor-associated transcripts and identification of a target RNA motif. J Immunol. 2006;186:1189–1198. 36. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med. 2005;353:1711–1723. 37. Schmidt KL, Soma KK. Cortisol and corticosterone in the songbird immune and nervous systems: local vs. systemic levels during development. Am J Physiol Regul Integr Comp Physiol. 2008;295:R103–R110. 38. Taves MD, Gomez-Sanchez CE, Soma KK. Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function. Am J Physiol Endocrinol Metab. 2011;301:E11–E24. 39. Coste A, Dubuquoy L, Barnouin R, et al. LRH-1-mediated glucocorticoid synthesis in enterocytes protects against
r
2014 Lippincott Williams & Wilkins
40.
41.
42.
43.
44.
45.
Intestinal Peroxisome Proliferator–activated Receptor
inflammatory bowel disease. Proc Natl Acad Sci USA. 2007; 104:13098–13103. Mueller M, Cima I, Noti M, et al. The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine. J Exp Med. 2006;203:2057–2062. Sutherland L, Macdonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2006a;CD000543. Feagan BG, Macdonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;10:CD000544. Lewis JD, Lichtenstein GR, Deren JJ, et al. Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial. Gastroenterology. 2008;134:688–695. Ho GT, Chiam P, Drummond H, et al. The efficacy of corticosteroid therapy in inflammatory bowel disease: analysis of a 5-year UK inception cohort. Aliment Pharmacol Ther. 2006;24:319–330. Regueiro M, Loftus EV Jr, Steinhart AH, et al. Medical management of leftsided ulcerative colitis and ulcerative proctitis: critical evaluation of therapeutic trials. Inflamm Bowel Dis. 2006;12:979–994.
www.jcge.com |
S27
Peroxisome Proliferator–activated Receptor Gamma in the Colon Inflammation and Innate Antimicrobial Immunity Silvia Speca, PhD,*w Laurent Dubuquoy, PhD,*w and Pierre Desreumaux, MD, PhD*wz
Abstract: Peroxisome proliferator–activated receptor g (PPARg) is a nuclear receptor, originally described in adipose tissue, which controls the expression of a large number of regulatory genes in lipid metabolism and insulin sensitization. Well known by endocrinologists, thiazolidinedionesare classical PPARg synthetic agonists, which were currently used as insulin-sensitizing agents in the treatment of type 2 diabetes. Although the clinical benefits of thiazolidinediones in treating metabolic disorders have been clearly demonstrated, studies performed in animal models of colitis and in patients with ulcerative colitis have also revealed the key roles of PPARg activation in the regulation of inflammation and immune response, notably in the colon through epithelial cells. Key Words: PPARg, inflammation, immunity, IBD
(J Clin Gastroenterol 2014;48:S23–S27)
P
eroxisome proliferator–activator receptor g (PPARg) is a nuclear receptor belonging to the PPARs family, together with PPARa and PPARb/d. The members of PPARs family were first cloned as steroids hormone receptors homologues activated by a class of rodent hepatocarcinogens causing peroxisomes proliferation.1 Encoded by distinct genes located on different chromosomes, PPARs display a high degree of From the *INSERM U995; wUniversite´ Lille Nord de France; and zCHU Lille, Service des maladies de l’appareil digestif et de la nutrition, Hoˆpital Claude Huriez, Lille, France. Supported by industry from 2004 to 2014: Astra-Zeneca, Paris, France; Danisco France SAS, Paris, France; Danone France, Massy Palaiseau, France; Ferring, St Prex, Suisse; Ferring, San Diego; Ferring, Southampton, UK; Giuliani SpA, Milano, Italy; Lesaffre, Marcq en Baroeul, France; Ocera Therapeutics, San Diego, CA; Roquette, Lestrem, France; Sanofi-Synthelabo, Paris, France; UCB Pharma, Paris, France; Yoplait, Paris, France; Omega Pharma, Belgium. S.S.: lecture fees from speaking at ECCO congress sponsored by Giuliani SpA, Milano, Italy; P.D.: consulting fees or paid advisory boards: Biofortis, Nantes, France; Danisco France SAS, Paris, France; Danone France, Massy Palaiseau, France; Ferring, St Prex, Suisse; Giuliani SpA, Milano, Italy; Roquette, Lestrem, France; UCB Pharma, Paris, France; Txcell, Nice, France; Biofortis, France; Lesaffre, Marcq en Baroeul, France; MSD, France; Abbott, France; Norgine, France; Genfit, France; OmegaPharma International; lecture fees from speaking at continuing medical education events indirectly sponsored by a commercial sponsor: 1. Procter and Gamble, London, UK. 2. Ferring, Paris, France. 3. Ferring, London, UK. 4. Schering Plough, Paris, France. 5. Shire Pharmaceuticals, USA. 6. UCB Pharma, Paris, France. 7. MSD, France. 8. Norgine, France. 9. Abbott, France; L.D. declares that there is nothing to disclose. Reprints: Pierre Desreumaux, MD, PhD, Inserm U995, Amphis J&K, Bd Pr Jules Leclercq, Lille 59045, Cedex, France (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
J Clin Gastroenterol
sequence and structural homology, specific patterns of tissue distribution, and cellular functions. Three different protein isoforms of PPARg are described, such as PPARg1, PPARg2, and PPARg3. The 1 and 3 isotypes are structurally identical and are expressed in nearly all cells, whereas PPARg2 shows an additional region of 30 amino acids at the NH2-terminal and is exclusively expressed in adipose tissue. PPARg plays a critical role in the control of a broad range of cellular processes, such as differentiation of adipocytes, glucose homeostasis, and lipid metabolism.2,3
PPARg IN THE COLON: MECHANISMS OF ACTION AND REGULATION The different activities of PPARg are mainly performed via endogenous and/or exogenous ligands. The presence of a large T-shaped hydrophobic pocket in the Cterminal ligand-binding domain (LBD) allows, indeed, the binding of a wide variety of natural and also synthetic modulators, which carry out the distinct functions of PPARg, depending on the cellular context. The molecular mechanisms of transactivation of selective target genes performed by PPARg in response to specific ligands are currently widely known. PPARg operates as functional heterodimer with the retinoid X receptors (RXR). In absence of ligands PPAR/RXR heterodimer resides in the nucleus bound to the peroxisome proliferator response elements (PPREs), located in the target gene promoter,3 in a complex with transcriptional corepressors, such as silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and nuclear receptor corepressor (NCoR). PPREs are bi-hexameric DNA sequences presenting direct repeats (DRs) with the core sequence AGG(A/T)CA separated by one or two base-pairs, experimentally identified in >70 target genes.3–6 Following the interaction with specific ligands, PPAR/RXR undergoes conformational changes that induce a corepressor for coactivator complex exchange resulting in the transcriptional activation of target genes.7,8 Despite these, molecular mechanisms are quietly similar among all members and subgroups of PPARs family, the specificity of the single PPARg functions depends, indeed, by the specific cellular and tissue context in which it is expressed. Originally described as orphan nuclear receptor, mainly expressed in adipose tissue, PPARg can be tracked in a broad spectrum of different tissues, among which the colon represents the main site where PPARg achieves tissue expression levels comparable to adipose tissue.9–11 PPARg expression in the colon follows a specific trend to increase on proximal to distal axis. It involves the majority of cells in mucosal barriers, mainly the intestinal
Volume 48, Supp. 1, November/December 2014
www.jcge.com |
S23
Speca et al
J Clin Gastroenterol
epithelial cells (IEC) and, to lower degree, monocytes/ macrophages and lymphocytes, and regulates a wide variety of function ranging from epithelial cell motility and differentiation to homeostatic mechanisms, such as proliferation, epithelial integrity, and, more specifically, regulation of mucosal bacterial-induced inflammation.10,12 All evidences were mainly established by using specific natural or synthetic PPARg ligands. In particular, the main suggestions derived from the clinical benefits of a class of insulin-sensitizing agents used in the treatment of type 2 diabetes, the thiazolidinediones (TZDs), not only in treating metabolic disorders but also in experimental animal models of colitis and in patients with irritable bowel disease or ulcerative colitis (UC).9,13 The latter, together with Crohn’s disease (CD), represents the clinical manifestation of the inflammatory bowel disease (IBD), gastrointestinal disorders in which a dysregulated immune response to intraluminal antigens, such as resident luminal bacteria, bacterial products, or dietary antigens, generate a chronic defective mucosal barrier. A significantly impaired PPARg expression was observed in colonic epithelial cells of UC patients, compared with controls and CD patients, suggesting that the disruption of PPARg signaling may represent a critical step of the UC pathophysiology.9 One of the oldest anti-inflammatory drug used in the treatment of IBD is the 5-aminosalycilic acid (5-ASA). In vitro studies, mainly performed on colon epithelial cell line, showed the ability of this compound to induce PPARg expression and to direct the turn of events leading the transactivation of target genes. In addition, genetically engineered heterozygous knockout at the PPARg locus (PPARg + / ) mice not only showed increased susceptibility to chemically induced colitis, highlighting the genetic involvement of PPARg in the control on inflammation, but also appeared refractory to 5-ASA therapy, suggesting that the clinical benefits of this compound are mediated, at least in part, by PPARg.9 A further indication regarding the anti-inflammatory properties of the ligand-dependent PPARg activation in the colon was also provided by its expression on several immunological cell types, such as activated macrophages, dendritic cells (DC), naive and activated T cells, and B cells. Moreover, PPARg is able to interfere with chemo-attraction and cell adhesion of these inflammatory cell types, by inhibiting the expression of monocyte-chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and intracellular adhesion molecule (ICAM).14,15 In addition, multiple studies have reported that PPARg ligands are able to stimulate monocytes differentiation to macrophages.5,15,16 Monocyte recruitment to sites of injury and their activation in resident macrophages represent the key events orchestrating both initiation of inflammation, by which macrophages execute a first protection of the host, and its own resolution. Active silencing of inflammatory gene induced by TZD represents an important demonstration of PPARg involvement into the control of the macrophage inflammatory response. Specific mechanisms action, limiting magnitude, and duration of macrophage inflammation, are an attractive aim of several investigations. Inhibition of the production of inducible nitric oxide synthase (iNOS), an enzyme responsible for high-output release of NO from larginine strongly upregulated in inflammatory response, seems to represent one of the main effects of the PPARg-induced monocyte differentiation to macrophages.15,16 Nevertheless, the contribution of PPARg in the
S24 | www.jcge.com
Volume 48, Supp. 1, November/December 2014
regulation of intestinal inflammation is suggested by its specific immunolocalization to colonocytes, intestinal epithelial cells whose participation in the installation and the perpetuation of the intestinal inflammation is currently defined. Pioneering studies performed by Adachi and colleagues showed, indeed, an enhanced susceptibility to the chemically induced colitis in mice with epithelium-specific loss of PPARg expression. In addition, clinical reports indicated decreased levels of PPARg in the gut of patients with ulcerative colitis compared with healthy subjects, substaining the hypothesis of a crucial role of PPARg in IEC in regulating of mucosal inflammation and suggesting that epithelial cells represent a prime target for PPARg ligands.13,17–19 In addition, several evidences, mainly based on the action of TZDs in the stimulus-dependent production of the main inflammatory mediators (TNFa, IL-6, MCP1, PAI-1) in colonic epithelial cells, have supplied solid indications that PPARg acts as key molecule in the network of negative feedback mechanisms that control mucosal inflammation by interfering with the activity of transcription factors, such as members of the NF-kB and AP-1 families, in a mechanism known as “transrepression.” More specifically, TZD-induced PPARg activation has proven to be directly implied in the repression the signal-dependent NF-kB activity.19,20 The NF-kB family consists of 5 members, p65 (RELA), REL-B, c-REL, p50, and p52, which function as homodimers or heterodimers. In the basal state, NF-kB is sequestered in the cytoplasm by an inhibitory molecule, IkBa or IkBb. Following a wide-range of stimulation, IkBa and IkBb are phosphorylated by the activation of the high molecular weight kinase complex, IkB kinase (IKK), ubiquinated and degraded. Then, NF-kB translocates into the nucleus where it binds to target promoters inducing the expression of proinflammatory cytokines, enzymes, and adhesion molecules.21 Several evidences suggest that the antagonistic action of PPARg on NF-kB can involve several molecular mechanisms, ranging from the direct increase of IkB expression (a negative regulatory feedback loop) to the protein-protein crosstalk interaction, among which the physical interaction with NF-kB, the competition for a pool of coactivators essential to the NFkB signal transduction, the histone modification, and the blockage of signal-dependent clearance of corepressor complexes and sumoylation, a highly transient posttranslational protein modification.20 The mechanistic basis by which PPARg switches from activator of transcription to a promoterspecific repressor of NF-kB target genes is still under investigation. As the first barrier to luminal bacteria, intestinal epithelial cells play a pivotal role in the detection of microorganisms, acting in concert with the resident microflora, and determining the development of an appropriate and complex mucosal immune response. Considered as immunoeffector cells, epithelial cells secrete antibacterial peptides and cytokines (eg, IL-10 and TGF-b) in the lamina propria and express a specific pattern recognition receptors such as the extracellular Toll-like receptors (TLR) and the intracellular nucleotide oligomerization domain/caspase recruitment domain (NOD/CARD)-like receptors (NLRs),22 able to bind specific components of bacterial cell walls, notably known as pathogen-associated molecular patterns (PAMP), to trigger a host defence response against invading pathogens and to activate signalling pathways that induce the expression of immune and proinflammatory genes.22 r
2014 Lippincott Williams & Wilkins
J Clin Gastroenterol
Volume 48, Supp. 1, November/December 2014
TLR are constitutively expressed in IEC and their activation, mediated via PAMPs, such as lipopolysaccharide (LPS) or butyrate, as well as intestinal flora and probiotics are able to lead in turn sequential events culminating with the activation and recruitment of transcription factors, among which NF-kB seems to be the most implied in the immune response to the microbial invasion. Both an increased mucosal expression of TLRs and TLR polymorphisms in the intestine of patients with IBD have been observed23–26 and represent the underlying mechanisms leading to the abnormal host reaction18 and to the defective immune tolerance to commensal bacteria,25,26 respectively. The mutual antagonizing action between PPARg and NF-kB, as well as the high expression levels in intestinal epithelial cells, represent some of the elements that support the key role of PPARg in controlling immune response in the colon and intestinal homeostasis. In line with this idea, in vivo studies performed on mice lacking PPARg in the colonic epithelium showed a reduced microbicidal activity against microbes, such as Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli as compared with wild-type littermates.27 At the same time several evidences demonstrated a close relationship between expression of PPARg on intestinal epithelial cells and commensal intestinal flora. Colonic epithelium showed upregulation of PPARg expression in presence of bacteria belonging to a murin or human flora compared with germ-free condition. The effect of commensal flora on PPARg expression is well-established also by in vitro studies on IEC stimulated by LPS, or by direct stimulation with Helicobacter pylori or Saccharomyces boulardii.13,27–31 In addition, a basic study performed by Dubuquoy et al13 on TLR-4-transfected IEC and mice presenting a nonfunctional TLR4 (C3H/HeJ Lpsd/ Lpsdmice) established as PPARg overexpression in IEC is in part related to the LPS recognition Toll-like receptor (TLR)-4 signaling. These evidences represent a walk-through of the contribution of luminal microbes to the pathogenesis of IBD. UC and CD patients show an imbalanced charge of pathogens and nonpathogens micro-organisms. Because of the defective mucosal barrier, lamina propria immune cells are continuously exposed to the luminal antigens induce, indeed, elevated levels of TLR-4 that, associated to the impaired PPARg expression observed in UC patients, may determine an alteration of tolerance to luminal bacteria triggering, amplifying, and maintaining the local inflammation.9 On the other side, a very recent study performed indicates a discordance between the effects specifically induced by Salmonella typhimurium and the others enteric pathogens. PPARg expression in the intestinal epithelium was decreased of at least 60% by S. typhimurium in a TLR4-dependent way and at the same time the specific ablation of PPARg in intestinal epithelium was associated with a much more sever colitis induced by this pathogen.32 All evidences led to consider the importance of intestinal-epithelium PPARg in regulation of colitis, even if the effect of the various pathogens on the regulation of this receptor can vary on the strength of the bacterial species that colonize and infect the host intestine.32 A further confirmation of the critical role of PPARg in the regulation of immune response was established by a study performed by Peyrin-Biroulet and colleagues in which PPARg-induced microbial killing activity has proven to be r
2014 Lippincott Williams & Wilkins
Intestinal Peroxisome Proliferator–activated Receptor
due to the induction of b-defensin expression in IEC. bdefensins are small antimicrobial cationic peptides contributing to innate host defense via direct bacteriocidal and candidacidal activity. Constitutively or inducibly expressed, b-defensins recognize and neutralize invading gram-negative and gram-positive bacteria, fungi, viruses, and protozoa in a quick and specific manner representing the first line of host defense. Peyrin-Biroulet and colleagues showed that PPARg was an essential regulator of innate immunity in colon and ileum. PPARg deficient mice (PPAR / mice) showed both reduced expression and bactericidial activity of certain b-defensins compared with WT littermates. b-defensins are downregulated in CD patient and targeting PPARg therapies may point, thus, to increase in the expression of a subset of b-defensins enhancing microbial killing by the colonic mucosa and controlling the excessive inflammation.27 In addition, a very recent study performed in our laboratory demonstrated for the first time that PPARg expression in IEC is directly regulated by glucocorticoids (GCs).33 GCs, are steroid hormones with immunosuppressive and anti-inflammatory properties already widely used in the treatment of several inflammatory and immunemediated disorders.34–36 Mainly produced is in the adrenal cortex, GCs are also de novo synthesized by other organs and notably by epithelial cells. At intestinal level, IEC represent a significant source of cortisol and the role of extra adrenal-produced GCs is still not fully elucidated, even if the main researches provides clues on their role in the regulation of local immunological functions and gut homeostasis.37,38 Moreover, Coste et al39 demonstrated inverse relationship between severity of inflammation in colons of IBD patients and local endogenous glucocorticoid synthesis. On the strength of these evidences we supposed a link between endogenous GCs and PPARg activation and expression. Our hypothesis was corroborated by the presence of the several highly probable GCs response elements (GREs) on the PPARg promoter region, suggesting PPARg as putative GC target gene. In addition, synthesis of GC in intestinal epithelial is controlled by liver receptor homolog-1 (LRH-1), a transcription factor able to activate first the cholesterol sidechain cleavage enzyme CYP11A1 and then CYP11B1, key enzymes in steroidogenesis.40 IEC isolated from UC patients, showed reduced LRH-1 expression, directly correlating with PPARg expression. This evidence was confirmed in our study by using Caco-2 cells lacking LRH-1, supporting the hypothesis that PPARg expression in colonocytes is controlled by cortisol in UC patients and the decreased expression of PPARg could be a direct effect of the impaired steroidogenesis in the colon.33 All these evidences highlight the crucial role of PPARg in the control of inflammation and immunity in colon, representing new clues in understanding gut homeostasis and representing a solid proof to consider PPARg as target of new therapeutic approaches in IBD.
THERAPEUTIC DEVELOPMENT PPARg has always represented an intriguing target for new therapeutic approaches in several diseases, above all for its pleiotropic action in a wide range of cellular mechanisms, from the development to the adipocytes differentiation, glucose homeostasis, lipids metabolism, and control of inflammation. The high PPARg expression levels in the colonic epithelial cells (100-fold more concentrated than in the small www.jcge.com |
S25
J Clin Gastroenterol
Speca et al
intestine) made this receptor a key molecule in the network of negative feedback mechanisms controlling inflammation in IBD. PPARg is naturally activated by prostaglandins (PG-D1 and PG-D2) and the PG derivative 15-deoxy-D12,14-PGJ2 and it is a good molecular target of a growing variety for synthetic ligands, such as thiazolidinediones (TZD) and 5aminosalicylic acid (5-ASA). It has been widely showed that 5-ASA or glitazone, but also glucocorticoids, are able to in induce and maintain the clinical remission as well as mucosal healing in patients with UC.41–44 In addition, a high rate of remission in UC patient was induced by 5-ASA in combination with corticosteroids, compared with monotherapy and this effect could be due both to the additive effect of the 2 drugs but also to their synergistic effect on PPARg activation and expression.45 Due to safety issues concerning particularly the greater risk of myocardial infarction, use of TZDs has been severely limited for the treatment of type 2 diabetes and/or inflammatory diseases, justifying the development of a new family of PPARg agonists with major transrepressive effects and with limited toxicity. By the demonstration that the anti-inflammatory effects of 5-aminosalicylic acid (5-ASA) in patients with ulcerative colitis were mediated by PPARg activation, several molecules having 5-ASA similarities have been developed and screened leading to the selection of a aminophenyl-alpha-methoxy-propionic acids named GED-0507-34-Levo (GED). This compound activating PPARg has 100- to 150-fold higher anti-inflammatory activity than 5-ASA. This new PPAR modulator is giving promising results both in vitro and in vivo, without toxicity and is currently evaluated in a phase 2 clinical trial. REFERENCES 1. Feige JN, Gelman L, Michalik L, et al. From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res. 2006;45:120–159. 2. Rousseaux C, Desreumaux P. The peroxisome-proliferatoractivated gamma receptor and chronic inflammatory bowel disease (PPARgamma and IBD). J Soc Biol. 2006;200:121–131. 3. Houseknecht KL, Cole BM, Steele PJ. Peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands: a review. Domest Anim Endocrinol. 2002;22:1–23. 4. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998;391:82–86. 5. Ricote M, Li AC, Willson TM, et al. The peroxisome proliferatoractivated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82. 6. Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 2008;77:289–312. 7. Ho¨rlein AJ, Na¨a¨r AM, Heinzel T, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature. 1995;377:397–404. 8. Chen JD, Evans RM. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature. 1995;377: 454–457. 9. Dubuquoy L, Rousseaux C, Thuru X, et al. PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut. 2006;55:1341–1349. 10. Lefebvre M, Paulweber B, Fajas L, et al. Peroxisome proliferator-activated receptor gamma is induced during differentiation of colon epithelium cells. J Endocrinol. 1999; 162:331–340. 11. Katayama K, Wada K, Nakajima A, et al. A novel PPAR gamma gene therapy to control inflammation associated with inflammatory bowel disease in a murine model. Gastroenterology. 2003;124:1315–1324.
S26 | www.jcge.com
Volume 48, Supp. 1, November/December 2014
12. Su W, Bush CR, Necela BM, et al. Differential expression, distribution, and function of PPAR-gamma in the proximal and distal colon. Physiol Genomics. 2007;30:342–353. 13. Dubuquoy L, Jansson EA, Deeb S, et al. Impaired expression of peroxisome proliferator-activated receptor gamma in ulcerative colitis. Gastroenterology. 2003;124:1265–1276. 14. Debril MB, Renaud JP, Fajas L, et al. The pleiotropic functions of peroxisome proliferator-activated receptorg. J Mol Med. 2001;79:30–47. 15. Chinetti G, Fruchart JG, Staels B. Peroxisome proliferatoractivated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism, and inflammation. Inflam Res. 2000;49:497–505. 16. Gelman L, Fruchart GC, Auwerx J. An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs), and their roles in inflammation, and cancer. Cell Mol Life Sci. 1999;55:932–943. 17. Adachi M, Kurotani R, Morimura K, et al. Peroxisome proliferator activated receptor gamma in colonic epithelial cells protects against experimental inflammatory bowel disease. Gut. 2006;55:1104–1113. 18. Mohapatra SK, Guri AJ, Climent M, et al. Immunoregulatory actions of epithelial cell PPAR gamma at the colonic mucosa of mice with experimental inflammatory bowel disease. PLoS One. 2010;5:e10215. 19. Su CG, Wen X, Bailey ST, et al. A novel therapy for colitis utilizing PPAR-ligands to inhibit the epithelial inflammatory response. J Clin Invest. 1999;104:383–389. 20. Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol. 2010;10:365–376. 21. Hayden MS, Ghosh S. Shared principles in NF-kB signaling. Cell. 2008;132:344–362. 22. Liew FY, Xu D, Brint EK, et al. Negative regulation of tolllike receptor-mediated immune responses. Nat Rev Immunol. 2005;5:446–458. 23. Szebeni B, Veres G, Dezso˜fi A, et al. Increased expression of Toll-like receptor (TLR) 2 and TLR4 in the colonic mucosa of children with inflammatory bowel disease. Clin Exp Immunol. 2008;151:34–41. 24. Cario E, Podolsky DK. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infec Immun. 2000;68: 7010–7017. 25. Franchimont D, Vermeire S, El Housni H, et al. Deficient hostbacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn’s disease and ulcerative colitis. Gut. 2004;53:987–992. 26. Torok HP, Glas J, Tonenchi L, et al. Polymorphisms of the lipopolysaccharide-signaling complex in inflammatory bowel disease: association of a mutation in the Toll-like receptor 4 gene with ulcerative colitis. Clin Immunol. 2004; 112:85–91. 27. Peyrin-Biroulet L, Beisner J, Wang G, et al. Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc Natl Acad Sci USA. 2010;107:8772–8777. 28. Cuthbert AP, Fisher SA, Mirza MM, et al. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology. 2002;122:867–874. 29. Papo N, Shai Y. Can we predict biological activity of antimicrobial peptides from their interactions with model phospholipid membranes? Peptides. 2003;24:1693–1703. 30. Ayabe T, Satchell DP, Wilson CL, et al. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol. 2000;1:113–118. 31. Ouellette AJ. Defensin-mediated innate immunity in the small intestine. Best Pract Res Clin Gastroenterol. 2004;18:405–419. 32. Bouguen G, Langlois A, Djouina M, et al. Intestinal steroidogenesis controls PPARg expression in the colon and is impaired during UC. Gut. 2014 July 22 [published online ahead of print]. r
2014 Lippincott Williams & Wilkins
J Clin Gastroenterol
Volume 48, Supp. 1, November/December 2014
33. Kundu P, Ling TW, Korecka A, et al. Absence of intestinal PPARg aggravates acute infectious colitis in mice through a lipocalin-2-dependent pathway. PLoS Pathog. 2014;10:e1003887. 34. De Bosscher K, Haegeman G. Minireview: latest perspectives on anti-inflammatory actions of glucocorticoids. Mol Endocrinol. 2009;23:281–291. 35. Ishmael FT, Fang X, Houser KR, et al. The human glucocorticoid receptor as an RNA-binding protein: global analysis of glucocorticoid receptor-associated transcripts and identification of a target RNA motif. J Immunol. 2006;186:1189–1198. 36. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med. 2005;353:1711–1723. 37. Schmidt KL, Soma KK. Cortisol and corticosterone in the songbird immune and nervous systems: local vs. systemic levels during development. Am J Physiol Regul Integr Comp Physiol. 2008;295:R103–R110. 38. Taves MD, Gomez-Sanchez CE, Soma KK. Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function. Am J Physiol Endocrinol Metab. 2011;301:E11–E24. 39. Coste A, Dubuquoy L, Barnouin R, et al. LRH-1-mediated glucocorticoid synthesis in enterocytes protects against
r
2014 Lippincott Williams & Wilkins
40.
41.
42.
43.
44.
45.
Intestinal Peroxisome Proliferator–activated Receptor
inflammatory bowel disease. Proc Natl Acad Sci USA. 2007; 104:13098–13103. Mueller M, Cima I, Noti M, et al. The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine. J Exp Med. 2006;203:2057–2062. Sutherland L, Macdonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2006a;CD000543. Feagan BG, Macdonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;10:CD000544. Lewis JD, Lichtenstein GR, Deren JJ, et al. Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial. Gastroenterology. 2008;134:688–695. Ho GT, Chiam P, Drummond H, et al. The efficacy of corticosteroid therapy in inflammatory bowel disease: analysis of a 5-year UK inception cohort. Aliment Pharmacol Ther. 2006;24:319–330. Regueiro M, Loftus EV Jr, Steinhart AH, et al. Medical management of leftsided ulcerative colitis and ulcerative proctitis: critical evaluation of therapeutic trials. Inflamm Bowel Dis. 2006;12:979–994.
www.jcge.com |
S27
