The inverse agonist DG172 triggers a PPAR β/δ -independent myeloid lineage shift and promotes GM-CSF/IL-4-induced dendritic cell differentiation

Molecular Pharmacology

Volumn 87, Issue 2, 2015, Pages 162-173

  Lieber, Sonja ^a   Scheer, Frithjof ^a   Finkernagel, Florian ^a   Meissner, Wolfgang ^a   Giehl, Gavin ^a   Brendel, Cornelia ^a   Diederich, Wibke E ^a   Müller Brüsselbach, Sabine ^a   Müller, Rolf ^a  

^a Fachbereich Medizin der Universitat Marburg   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2 BROMOPHENYL) 3 [[4 (1 METHYLPIPERAZINE)AMINO]PHENYL]ACRYLONITRILE; 2 (4 CHLOROPHENYL) 3 [4 (4 METHYLPIPERAZINE 1 YL)PHENYL]ACRYLONITRILE; ACRYLONITRILE; BIOLOGICAL MARKER; GLYCOPROTEIN P 15095; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 4; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA; PIPERAZINE DERIVATIVE; STILBENE DERIVATIVE; TRANSCRIPTION FACTOR; TRANSCRIPTOME; UNCLASSIFIED DRUG; 2-(2-BROMOPHENYL)-3-((4-(1-METHYLPIPERAZINE)AMINO)PHENYL)ACRYLONITRILE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA;

ANIMAL CELL; ARTICLE; BONE MARROW CELL; CEBPE GENE; CELL DIFFERENTIATION; CELL LINEAGE; CONTROLLED STUDY; DENDRITIC CELL; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; GENE; GENE REPRESSION; GFI1 GENE; GRANULOCYTE; IN VITRO STUDY; IRF8 GENE; IRT4 GENE; KLF5 GENE; MACROPHAGE; MOUSE; NEUTROPHIL; NONHUMAN; PROTEIN EXPRESSION; SPIB GENE; SPIC GENE; STRUCTURE ACTIVITY RELATION; UPREGULATION; AGONISTS; ANALOGS AND DERIVATIVES; ANIMAL; C57BL MOUSE; CELL CULTURE; DRUG EFFECTS; DRUG POTENTIATION; INVERSE AGONISM; KNOCKOUT MOUSE; METABOLISM; PHYSIOLOGY;

ACRYLONITRILE; ANIMALS; BONE MARROW CELLS; CELL DIFFERENTIATION; CELL LINEAGE; CELLS, CULTURED; DENDRITIC CELLS; DRUG INVERSE AGONISM; DRUG SYNERGISM; GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR; INTERLEUKIN-4; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; PIPERAZINES; PPAR GAMMA; PPAR-BETA;

EID: 84919715317     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.114.094672     Document Type: Article

References (53)

1. Adhikary T, Kaddatz K, Finkernagel F, Schönbauer A, Meissner W, Scharfe M, Jarek M, Blöcker H, Müller-Brüsselbach S, and Müller R (2011) Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferatoractivated receptor-β/δ (PPARβ/δ). PLoS ONE 6:e16344.
2. Barak Y, Liao D, He W, Ong ES, Nelson MC, Olefsky JM, Boland R, and Evans RM (2002) Effects of peroxisome proliferator-activated receptor delta on placentation, adiposity, and colorectal cancer. Proc Natl Acad Sci USA 99:303-308.
3. Becker AM, Michael DG, Satpathy AT, Sciammas R, Singh H, and Bhattacharya D (2012) IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoidmouse progenitors. Blood 119:2003-2012.
4. Bedi R, Du J, Sharma AK, Gomes I, and Ackerman SJ (2009) Human C/EBP-epsilon activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation. Blood 113:317-327.
5. Bessede A, Gargaro M, Pallotta MT, Matino D, Servillo G, Brunacci C, Bicciato S, Mazza EM, Macchiarulo A, and Vacca C et al. (2014) Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 511:184-190.
6. Cho SD, Lei P, Abdelrahim M, Yoon K, Liu S, Guo J, Papineni S, Chintharlapalli S, and Safe S (2008) 1,1-bis(39-indolyl)-1-(p-methoxyphenyl)methane activates Nur77-independent proapoptotic responses in colon cancer cells. Mol Carcinog 47: 252-263.
7. Dahl R, Iyer SR, Owens KS, Cuylear DD, and Simon MC (2007) The transcriptional repressor GFI-1 antagonizes PU.1 activity through protein-protein interaction. J Biol Chem 282:6473-6483.
8. Dearman RJ, Cumberbatch M, Maxwell G, Basketter DA, and Kimber I (2009) Tolllike receptor ligand activation of murine bone marrow-derived dendritic cells. Immunology 126:475-484.
9. Desvergne B, Michalik L, and Wahli W (2006) Transcriptional regulation of metabolism. Physiol Rev 86:465-514.
10. Diakiw SM, Kok CH, To LB, Lewis ID, Brown AL, and D'Andrea RJ (2012) The granulocyte-associated transcription factor Krüppel-like factor 5 is silenced by hypermethylation in acute myeloid leukemia. Leuk Res 36:110-116.
11. DuSell CD, Nelson ER, Wittmann BM, Fretz JA, Kazmin D, Thomas RS, Pike JW, and McDonnell DP (2010) Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol 24:33-46.
12. Garrett-Sinha LA, Dahl R, Rao S, Barton KP, and Simon MC (2001) PU.1 exhibits partial functional redundancy with Spi-B, but not with Ets-1 or Elf-1. Blood 97: 2908-2912.
13. Halene S, Gaines P, Sun H, Zibello T, Lin S, Khanna-Gupta A, Williams SC, Perkins A, Krause D, and Berliner N (2010) C/EBPepsilon directs granulocytic-vs-monocytic lineage determination and confers chemotactic function via Hlx. Exp Hematol 38: 90-103.
14. Hanna RN, Carlin LM, Hubbeling HG, Nackiewicz D, Green AM, Punt JA, Geissmann F, and Hedrick CC (2011) The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C-monocytes. Nat Immunol 12: 778-785.
15. Hayashi S, Lewis P, Pevny L, and McMahon AP (2002) Efficient gene modulation in mouse epiblast using a Sox2Cre transgenic mouse strain. Mech Dev 119 (Suppl 1): S97-S101.
16. Hock H, Hamblen MJ, Rooke HM, Traver D, Bronson RT, Cameron S, and Orkin SH (2003) Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation. Immunity 18:109-120.
17. Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, Muramatsu S, and Steinman RM (1992) Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colonystimulating factor. J Exp Med 176:1693-1702.
18. Kaddatz K, Adhikary T, Finkernagel F, Meissner W, Müller-Brüsselbach S, and Müller R (2010) Transcriptional profiling identifies functional interactions of TGF β and PPAR β/δ signaling: synergistic induction of ANGPTL4 transcription. J Biol Chem 285:29469-29479.
19. Kanakasabai S, Chearwae W, Walline CC, Iams W, Adams SM, and Bright JJ (2010) Peroxisome proliferator-activated receptor delta agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis. Immunology 130:572-588.
20. Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B, and Lee CH (2008) Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab 7:485-495.
21. Kostadinova R, Wahli W, and Michalik L (2005) PPARs in diseases: Control mechanisms of inflammation. Curr Med Chem 12:2995-3009.
22. Laslo P, Spooner CJ, Warmflash A, Lancki DW, Lee HJ, Sciammas R, Gantner BN, Dinner AR, and Singh H (2006) Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 126:755-766.
23. Lee PY, Wang JX, Parisini E, Dascher CC, and Nigrovic PA (2013) Ly6 family proteins in neutrophil biology. J Leukoc Biol 94:585-594.
24. Lee WH and Kim SG (2010) AMPK-dependent metabolic regulation by PPAR agonists. PPAR Res 2010:549101.
25. León B, Martínez del Hoyo G, Parrillas V, Vargas HH, Sánchez-Mateos P, Longo N, López-Bravo M, and Ardavín C (2004) Dendritic cell differentiation potential of mouse monocytes: monocytes represent immediate precursors of CD82 and CD81 splenic dendritic cells. Blood 103:2668-2676.
26. Lieber S, Scheer F, Meissner W, Naruhn S, Adhikary T, Müller-Brüsselbach S, Diederich WE, and Müller R (2012) (Z)-2-(2-bromophenyl)-3-{[4-(1-methylpiperazine) amino]phenyl}acrylonitrile (DG172): An orally bioavailable PPARβ/δ selective ligand with inverse agonistic properties. J Med Chem 55:2858-2868.
27. Lim H, Gupta RA, Ma WG, Paria BC, Moller DE, Morrow JD, DuBois RN, Trzaskos JM, and Dey SK (1999) Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta. Genes Dev 13:1561-1574.
28. Mahnke K, Becher E, Ricciardi-Castagnoli P, Luger TA, Schwarz T, and Grabbe S (1997) CD14 is expressed by subsets of murine dendritic cells and upregulated by lipopolysaccharide. Adv Exp Med Biol 417:145-159.
29. Mak KS, Funnell AP, Pearson RC, and Crossley M (2011) PU.1 and haematopoietic cell fate: Dosage matters. Int J Cell Biol 2011: 808524.
30. Masurier C, Pioche-Durieu C, Colombo BM, Lacave R, Lemoine FM, Klatzmann D, and Guigon M (1999) Immunophenotypical and functional heterogeneity of dendritic cells generated from murine bone marrow cultured with different cytokine combinations: implications for anti-tumoral cell therapy. Immunology 96: 569-577.
31. Naruhn S,Meissner W, Adhikary T, Kaddatz K, Klein T, Watzer B, Müller-Brüsselbach S, and Müller R (2010) 15-hydroxyeicosatetraenoic acid is a preferential peroxisome proliferator-activated receptor β/δ agonist. Mol Pharmacol 77: 171-184.
32. Naruhn S, Toth PM, Adhikary T, Kaddatz K, Pape V, Dörr S, Klebe G, Müller-Brüsselbach S, Diederich WE, and Müller R (2011) High-affinity peroxisome proliferator-activated receptor β/δ-specific ligands with pure antagonistic or inverse agonistic properties. Mol Pharmacol 80:828-838.
33. Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, and Kishimoto T (2010) Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci USA 107:19961-19966.
34. Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, Subramanian V, Mukundan L, Ferrante AW, and Chawla A (2008) Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab 7:496-507.
35. Palkar PS, Borland MG, Naruhn S, Ferry CH, Lee C, Sk UH, Sharma AK, Amin S, Murray IA, and Anderson CR et al. (2010) Cellular and pharmacological selectivity of the peroxisome proliferator-activated receptor-beta/delta antagonist GSK3787. Mol Pharmacol 78:419-430.
36. Peraza MA, Burdick AD, Marin HE, Gonzalez FJ, and Peters JM (2006) The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR). Toxicol Sci 90:269-295.
37. Peters JM, Shah YM, and Gonzalez FJ (2012) The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer 12:181-195.
38. Resnitzky D, Yarden A, Zipori D, and Kimchi A (1986) Autocrine beta-related interferon controls c-myc suppression and growth arrest during hematopoietic cell differentiation. Cell 46:31-40.
39. Rosenbauer F and Tenen DG (2007) Transcription factors in myeloid development: balancing differentiation with transformation. Nat Rev Immunol 7:105-117.
40. Scholtysek C, Katzenbeisser J, Fu H, Uderhardt S, Ipseiz N, Stoll C, Zaiss MM, Stock M, Donhauser L, and Böhm C et al. (2013) PPARβ/δ governs Wnt signaling and bone turnover. Nat Med 19:608-613.
41. Schotte R, Nagasawa M, Weijer K, Spits H, and Blom B (2004) The ETS transcription factor Spi-B is required for human plasmacytoid dendritic cell development. J Exp Med 200:1503-1509.
42. Schuler G. , Lutz M.B., Bender A., Thurner B., Röder C., Young J., and Romani N. (1999) A guide to the isolation and propagation of dendritic cells, in Dendritic Cells: Biology and Clinical Applications (Lotze MT and Thomson AW eds) pp 515-533, Academic, San Diego, CA.
43. Shearer BG, Steger DJ, Way JM, Stanley TB, Lobe DC, Grillot DA, Iannone MA, Lazar MA, Willson TM, and Billin AN (2008) Identification and characterization of a selective peroxisome proliferator-activated receptor beta/delta (NR1C2) antagonist. Mol Endocrinol 22:523-529.
44. Shearer BG, Wiethe RW, Ashe A, Billin AN, Way JM, Stanley TB, Wagner CD, Xu RX, Leesnitzer LM, and Merrihew RV et al. (2010) Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversible peroxisome proliferator-activated receptor delta (PPARdelta) antagonist. J Med Chem 53:1857-1861.
45. Smyth G.K. (2005) Limma: Linear models for microarray data, in Bioinformatics and Computational Biology Solutions using R and Bioconductor (Gentleman R, Carey V, Dudoit S, Irizarry R, and Huber W eds) pp 397-420, Springer, New York.
46. Tamura T, Tailor P, Yamaoka K, Kong HJ, Tsujimura H, O'Shea JJ, Singh H, and Ozato K (2005) IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity. J Immunol 174:2573-2581.
47. Toth PM, Naruhn S, Pape VF, Dörr SM, Klebe G, Müller R, and Diederich WE (2012) Development of improved PPARβ/δ inhibitors. ChemMedChem 7:159-170.
48. Vogel CF, Wu D, Goth SR, Baek J, Lollies A, Domhardt R, Grindel A, and Pessah IN (2013) Aryl hydrocarbon receptor signaling regulates NF-κB RelB activation during dendritic-cell differentiation. Immunol Cell Biol 91:568-575.
49. Wahli W and Michalik L (2012) PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab 23:351-363.
50. Weischenfeldt J and Porse B (2008) Bone marrow-derived macrophages (BMM): Isolation and applications. CSH Protoc 2008: pdb.prot5080.
51. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, and Willson TM et al. (1999) Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 3:397-403.
52. Yamanaka R, Kim GD, Radomska HS, Lekstrom-Himes J, Smith LT, Antonson P, Tenen DG, and Xanthopoulos KG (1997) CCAAT/enhancer binding protein epsilon is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing. Proc Natl Acad Sci USA 94:6462-6467.
53. Yang Y, Lovett-Racke AE, and Racke MK (2010) Regulation of immune responses and autoimmune encephalomyelitis by PPARs. PPAR Res 2010:104705.