Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis

British Journal of Pharmacology

Volumn 159, Issue 4, 2010, Pages 842-855

  Schafer, P H ^a   Parton, A ^a   Gandhi, A K ^a   Capone, L ^a   Adams, M ^a   Wu, L ^a   Bartlett, J B ^a   Loveland, M A ^a   Gilhar, A ^b   Cheung, Y F ^c   Baillie, Gs ^c   Houslay, M D ^c   Man, H W ^a   Muller, G W ^a   Stirling, D I ^a  

^a CELGENE CORPORATION   (United States)

^b TECHNION ISRAEL INSTITUTE OF TECHNOLOGY   (Israel)

^c UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

Anti inflammatory drugs; Chemokines; Immunopharmacology; Inflammation; PDE inhibitor; Skin pharmacology

Indexed keywords

APREMILAST; BACTERIAL PROTEIN; CC 10004; CD11B ANTIGEN; CD18 ANTIGEN; CXCL9 CHEMOKINE; CYCLOSPORIN A; CYTOKINE; ENDOTOXIN; GAMMA INTERFERON; GAMMA INTERFERON INDUCIBLE PROTEIN 10; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HLA DR ANTIGEN; IMMUNOGLOBULIN; INTERCELLULAR ADHESION MOLECULE 1; INTERLEUKIN 12; INTERLEUKIN 12P70; INTERLEUKIN 1BETA; INTERLEUKIN 2; INTERLEUKIN 23; INTERLEUKIN 6; INTERLEUKIN 8; LEUKOTRIENE B4; MACROPHAGE INFLAMMATORY PROTEIN 1ALPHA; MESSENGER RNA; MONOCYTE CHEMOTACTIC PROTEIN 1; PHOSPHODIESTERASE IV INHIBITOR; RANTES; SUPERANTIGEN; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; ZYMOSAN;

ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CELL ACTIVATION; CELL PROLIFERATION; CELL STIMULATION; CELLULAR IMMUNITY; CLINICAL ARTICLE; CONTROLLED STUDY; CYTOKINE PRODUCTION; EPIDERMIS; HISTOPATHOLOGIC SKIN REACTION; HUMAN; HUMAN CELL; HUMAN TISSUE; KERATINOCYTE; MOUSE; NATURAL KILLER CELL; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; POLYMORPHONUCLEAR CELL; PRIORITY JOURNAL; PSORIASIS; SKIN INFLAMMATION; SKINFOLD THICKNESS; ULTRAVIOLET B RADIATION; XENOTRANSPLANTATION;

ADMINISTRATION, ORAL; ADULT; ANIMALS; ANTI-INFLAMMATORY AGENTS; CELL PROLIFERATION; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 4; CYTOKINES; DISEASE MODELS, ANIMAL; DOSE-RESPONSE RELATIONSHIP, DRUG; ENTEROTOXINS; GENE EXPRESSION REGULATION; HUMANS; INFLAMMATION MEDIATORS; KERATINOCYTES; KILLER CELLS, NATURAL; LEUKOCYTES, MONONUCLEAR; LIPOPOLYSACCHARIDES; MICE; MICE, SCID; MIDDLE AGED; PHOSPHODIESTERASE INHIBITORS; PSORIASIS; RNA, MESSENGER; SEVERITY OF ILLNESS INDEX; SKIN; SKIN TRANSPLANTATION; THALIDOMIDE; TIME FACTORS; TRANSPLANTATION, HETEROLOGOUS; U937 CELLS; ULTRAVIOLET RAYS; ZYMOSAN;

EID: 77249116286     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/j.1476-5381.2009.00559.x     Document Type: Article

References (70)

1. Au BT, Teixeira MM, Collins PD, Williams TJ (1998). Effect of PDE4 inhibitors on zymosan-induced IL-8 release from human neutrophils: synergism with prostanoids and salbutamol. Br J Pharmacol 123 (6 1260 1266.
2. Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG (1999). The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 113 (5 752 759.
3. Baillie GS, Houslay MD (2005). Arrestin times for compartmentalised cAMP signalling and phosphodiesterase-4 enzymes. Curr Opin Cell Biol 17 (2 129 134.
4. Barber R, Baillie GS, Bergmann R, Shepherd MC, Sepper R, Houslay MD et al. (2004). Differential expression of PDE4 cAMP phosphodiesterase isoforms in inflammatory cells of smokers with COPD, smokers without COPD, and nonsmokers. Am J Physiol Lung Cell Mol Physiol 287 (2 L332 L343.
5. Barnes PJ, Adcock IM (1998). Transcription factors and asthma. Eur Respir J 12 (1 221 234.
6. Bolger GB, McPhee I, Houslay MD (1996). Alternative splicing of cAMP-specific phosphodiesterase mRNA transcripts. Characterization of a novel tissue-specific isoform, RNPDE4A8. J Biol Chem 271 (2 1065 1071.
7. Bolger GB, Erdogan S, Jones RE, Loughney K, Scotland G, Hoffmann R et al. (1997). Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene. Biochem J 328 (Pt 2 539 548.
8. Bos JD, de Rie MA, Teunissen MB, Piskin G (2005). Psoriasis: dysregulation of innate immunity. Br J Dermatol 152 (6 1098 1107.
9. Bour H, Demidem A, Garrigue JL, Krasteva M, Schmitt D, Claudy A et al. (1995). In vitro T cell response to staphylococcal enterotoxin B superantigen in chronic plaque type psoriasis. Acta Derm Venereol 75 (3 218 221.
10. Bowcock AM, Krueger JG (2005). Getting under the skin: the immunogenetics of psoriasis. Nat Rev Immunol 5 : 699 711.
11. Cameron AL, Kirby B, Fei W, Griffiths CE (2002). Natural killer and natural killer-T cells in psoriasis. Arch Dermatol Res 294 (8 363 369.
12. Chien AL, Elder JT, Ellis CN (2009). Ustekinumab: a new option in psoriasis therapy. Drugs 69 (9 1141 1152.
13. Claveau D, Chen SL, O'Keefe S, Zaller DM, Styhler A, Liu S et al. (2004). Preferential inhibition of T helper 1, but not T helper 2, cytokines in vitro by L-826,141 4-2-(3,4-Bisdifluromethoxyphenyl)-2-4-(1,1,1,3,3,3-hexafluoro-2- hydroxypropan-2-yl)-phenyl-ethyl3-methylpyridine-1-oxide, a potent and selective phosphodiesterase 4 inhibitor. J Pharmacol Exp Ther 310 (2 752 760.
14. Cockerill PN, Shannon MF, Bert AG, Ryan GR, Vadas MA (1993). The granulocyte-macrophage colony-stimulating factor/interleukin 3 locus is regulated by an inducible cyclosporin A-sensitive enhancer. Proc Natl Acad Sci USA 90 (6 2466 2470.
15. Conti M, Beavo J (2007). Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76 : 481 511.
16. Derian CK, Santulli RJ, Rao PE, Solomon HF, Barrett JA (1995). Inhibition of chemotactic peptide-induced neutrophil adhesion to vascular endothelium by cAMP modulators. J Immunol 154 (1 308 317.
17. Fan Chung K (2006). Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol 533 (1-3 110 117.
18. Feng WG, Wang YB, Zhang JS, Wang XY, Li CL, Chang ZL (2002). cAMP elevators inhibit LPS-induced IL-12 p40 expression by interfering with phosphorylation of p38 MAPK in murine peritoneal macrophages. Cell Res 12 (5-6 331 337.
19. Giembycz MA (2008). Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking? Br J Pharmacol 155 (3 288 290.
20. Gilhar A, Ullmann Y, Kerner H, Assy B, Shalaginov R, Serafimovich S et al. (2002). Psoriasis is mediated by a cutaneous defect triggered by activated immunocytes: induction of psoriasis by cells with natural killer receptors. J Invest Dermatol 119 (2 384 391.
21. Gottlieb AB (2005). Psoriasis: emerging therapeutic strategies. Nat Rev Drug Discov 4 (1 19 34.
22. Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA et al. (2005). TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol 175 (4 2721 2729.
23. Gottlieb AB, Strober B, Krueger JG, Rohane P, Jones M, Sutherland D et al. (2008). An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin 24 (5 1529 1538.
24. Hanifin JM, Chan SC, Cheng JB, Tofte SJ, Henderson WR Jr., Kirby DS et al. (1996). Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol 107 (1 51 56.
25. Houslay MD, Schafer P, Zhang KY (2005). Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 10 (22 1503 1519.
26. Houslay MD, Baillie GS, Maurice DH (2007). cAMP specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalised cAMP signalling. Circ Res 100 (7 950 966.
27. Huston E, Pooley L, Julien P, Scotland G, McPhee I, Sullivan M et al. (1996). The human cyclic AMP-specific phosphodiesterase PDE-46 (HSPDE4A4B) expressed in transfected COS7 cells occurs as both particulate and cytosolic species that exhibit distinct kinetics of inhibition by the antidepressant rolipram. J Biol Chem 271 (49 31334 31344.
28. Huston E, Lumb S, Russell A, Catterall C, Ross AH, Steele MR et al. (1997). Molecular cloning and transient expression in COS7 cells of a novel human PDE4B cAMP-specific phosphodiesterase, HSPDE4B3. Biochem J 328 (Pt 2 549 558.
29. Huston E, Houslay TM, Baillie GS, Houslay MD (2006). cAMP phosphodiesterase-4A1 (PDE4A1) has provided the paradigm for the intracellular targeting of phosphodiesterases, a process that underpins compartmentalized cAMP signalling. Biochem Soc Trans 34 (Pt 4 504 509.
30. Kaymakcalan Z, Sakorafas P, Bose S, Scesney S, Xiong L, Hanzatian DK et al. (2009). Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. Clin Immunol 131 (2 308 316.
31. Keshavarzian A, Mutlu E, Guzman JP, Forsyth C, Banan A (2007). Phosphodiesterase 4 inhibitors and inflammatory bowel disease: emerging therapies in inflammatory bowel disease. Expert Opin Investig Drugs 16 (9 1489 1506.
32. Khobzaoui M, Gutke HJ, Burnet M (2005). Apremilast. Curr Opin Investig Drugs 6 (5 518 525.
33. Lipworth BJ (2005). Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 365 (9461 167 175.
34. Liu J, Chen M, Wang X (2000). Calcitonin gene-related peptide inhibits lipopolysaccharide-induced interleukin-12 release from mouse peritoneal macrophages, mediated by the cAMP pathway. Immunology 101 (1 61 67.
35. Lobban M, Shakur Y, Beattie J, Houslay MD (1994). Identification of two splice variant forms of type-IVB cyclic AMP phosphodiesterase, DPD (rPDE-IVB1) and PDE-4 (rPDE-IVB2) in brain: selective localization in membrane and cytosolic compartments and differential expression in various brain regions. Biochem J 304 (Pt 2 399 406.
36. Lowes MA, Bowcock AM, Krueger JG (2007). Pathogenesis and therapy of psoriasis. Nature 445 (7130 866 873.
37. Lynch MJ, Baillie GS, Mohamed A, Li X, Maisonneuve C, Klussmann E et al. (2005). RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with beta arrestin to control the protein kinase A/AKAP79-mediated switching of the beta2-adrenergic receptor to activation of ERK in HEK293B2 cells. J Biol Chem 280 (39 33178 33189.
38. Ma W, Gee K, Lim W, Chambers K, Angel JB, Kozlowski M et al. (2004). Dexamethasone inhibits IL-12p40 production in lipopolysaccharide-stimulated human monocytic cells by down-regulating the activity of c-Jun N-terminal kinase, the activation protein-1, and NF-kappa B transcription factors. J Immunol 172 (1 318 330.
39. MacKenzie SJ, Houslay MD (2000). Action of rolipram on specific PDE4 cAMP phosphodiesterase isoforms and on the phosphorylation of cAMP-response-element- binding protein (CREB) and p38 mitogen-activated protein (MAP) kinase in U937 monocytic cells. Biochem J 347 (Pt 2 571 578.
40. MacKenzie SJ, Baillie GS, McPhee I, MacKenzie C, Seamons R, McSorley T et al. (2002). Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A-mediated phosphorylation of a single serine residue in upstream conserved region 1 (UCR1). Br J Pharmacol 136 (3 421 433.
41. Mammone T, Marenus K, Maes D, Lockshin RA (1998). The induction of terminal differentiation markers by the cAMP pathway in human HaCaT keratinocytes. Skin Pharmacol Appl Skin Physiol 11 (3 152 160.
42. Man HW, Schafer P, Wong LM, Patterson RT, Corral LG, Raymon H et al. (2009). Discovery of (S)-N-2-1-(3-ethoxy-4-methoxyphenyl)-2- methanesulfonylethyl-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor. J Med Chem 52 (6 1522 1524.
43. Marchmont RJ, Ayad SR, Houslay MD (1981). Purification and properties of the insulin-stimulated cyclic AMP phosphodiesterase from rat liver plasma membranes. Biochem J 195 (3 645 652.
44. Martina SD, Ismail MS, Vesta KS (2006). Cilomilast: orally active selective phosphodiesterase-4 inhibitor for treatment of chronic obstructive pulmonary disease. Ann Pharmacother 40 (10 1822 1828.
45. Matsumoto K, Murao K, Imachi H, Nishiuchi T, Cao W, Yu X et al. (2008). The role of calcium/calmodulin-dependent protein kinase cascade on MIP-1alpha gene expression of ATL cells. Exp Hematol 36 (4 390 400.
46. Mitra RS, Judge TA, Nestle FO, Turka LA, Nickoloff BJ (1995). Psoriatic skin-derived dendritic cell function is inhibited by exogenous IL-10. Differential modulation of B7-1 (CD80) and B7-2 (CD86) expression. J Immunol 154 (6 2668 2677.
47. Muller GW, Shire MG, Wong LM, Corral LG, Patterson RT, Chen Y et al. (1998). Thalidomide analogs and PDE4 inhibition. Bioorg Med Chem Lett 8 (19 2669 2674.
48. Nickoloff BJ, Kunkel SL, Burdick M, Strieter RM (1995). Severe combined immunodeficiency mouse and human psoriatic skin chimeras. Validation of a new animal model. Am J Pathol 146 (3 580 588.
49. Ottaviani C, Nasorri F, Bedini C, de Pità O, Girolomoni G, Cavani A (2006). CD56brightCD16(-) NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation. Eur J Immunol 36 (1 118 128. Links.
50. Owens RJ, Lumb S, Rees-Milton K, Russell A, Baldock D, Lang V et al. (1997). Molecular cloning and expression of a human phosphodiesterase 4C. Cell Signal 9 (8 575 585.
51. Papp K, Bolduc C, Rohane P, Sutherland D, Jones M, Hu A et al. (2008). A Phase 2 Study Demonstrating the Efficacy and Safety of the Oral Therapy CC-10004 in Subjects with Moderate-to-Severe Psoriasis. 66th Annual AAD Meeting, San Antonio, Texas, Feb 1-5.
52. Parry GC, Mackman N (1997). Role of cyclic AMP response element-binding protein in cyclic AMP inhibition of NF-kappaB-mediated transcription. J Immunol 159 (11 5450 5456.
53. Persson E, Voznesensky OS, Huang YF, Lerner UH (2005). Increased expression of interleukin-6 by vasoactive intestinal peptide is associated with regulation of CREB, AP-1 and C/EBP, but not NF-kappaB, in mouse calvarial osteoblasts. Bone 37 (4 513 529.
54. Prehn JL, Landers C, Muller GW, Man HW, Stirling DI, Targan SR (2001). Potent inhibition of cytokine production from intestinal lamina propria T cells by phosphodiesterase-4 inhibitory thalidomide analogues. J Clin Immunol 21 (5 357 364.
55. Press NJ, Banner KH (2009). 2 PDE4 inhibitors - a review of the current field. Prog Med Chem 47 : 37 74.
56. Schudt C, Winder S, Forderkunz S, Hatzelmann A, Ullrich V (1991). Influence of selective phosphodiesterase inhibitors on human neutrophil functions and levels of cAMP and Cai. Naunyn Schmiedebergs Arch Pharmacol 344 (6 682 690.
57. Schreiber S, Keshavarzian A, Isaacs KL, Schollenberger J, Guzman JP, Orlandi C et al. (2007). A randomized, placebo-controlled, phase II study of tetomilast in active ulcerative colitis. Gastroenterology 132 (1 76 86.
58. Seldon PM, Barnes PJ, Giembycz MA (1998). Interleukin-10 does not mediate the inhibitory effect of PDE-4 inhibitors and other cAMP-elevating drugs on lipopolysaccharide-induced tumors necrosis factor-alpha generation from human peripheral blood monocytes. Cell Biochem Biophys 29 (1-2 179 201.
59. Shepherd MC, Baillie GS, Stirling DI, Houslay MD (2004). Remodelling of the PDE4 cAMP phosphodiesterase isoform profile upon monocyte-macrophage differentiation of human U937 cells. Br J Pharmacol 142 (2 339 311.
60. Spina D (2008). PDE4 inhibitors: current status. Br J Pharmacol 155 (3 308 315.
61. Stawiski MA, Rusin LJ, Burns TL, Weinstein GD, Voorhees JJ (1979). Ro 20-1724: an agent that significantly improves psoriatic lesions in double-blind clinical trials. J Invest Dermatol 73 (4 261 263.
62. Tasken K, Aandahl EM (2004). Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol Rev 84 (1 137 167.
63. Teixeira MM, Rossi AG, Williams TJ, Hellewell PG (1994). Effects of phosphodiesterase isoenzyme inhibitors on cutaneous inflammation in the guinea-pig. Br J Pharmacol 112 (1 332 340.
64. Tenor H, Hatzelmann A, Wendel A, Schudt C (1995). Identification of phosphodiesterase IV activity and its cyclic adenosine monophosphate-dependent up-regulation in a human keratinocyte cell line (HaCaT). J Invest Dermatol 105 (1 70 74.
65. Terrin A, Di Benedetto G, Pertegato V, Cheung YF, Baillie G, Lynch MJ et al. (2006). PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different cAMP: role of compartmentalized phosphodiesterases. J Cell Biol 175 (3 441 451.
66. Videla S, Vilaseca J, Medina C, Mourelle M, Guarner F, Salas A et al. (2006). Selective inhibition of phosphodiesterase-4 ameliorates chronic colitis and prevents intestinal fibrosis. J Pharmacol Exp Ther 316 (2 940 945.
67. Wilkinson I, Engels P, Houslay MD (1997). Rolipram inhibition of the human cyclic AMP specific phosphodiesterase splice variant PDE4D3 expressed in yeast. Pharmacol Revs Commun 9 : 215 226.
68. Willoughby D, Baillie GS, Lynch MJ, Ciruela A, Houslay MD, Cooper DM (2007). Dynamic regulation, desensitization, and cross-talk in discrete subcellular microdomains during beta2-adrenoceptor and prostanoid receptor cAMP signaling. J Biol Chem 282 (47 34235 34249.
69. Wrone-Smith T, Nickoloff BJ (1996). Dermal injection of immunocytes induces psoriasis. J Clin Invest 98 (8 1878 1887.
70. Yao W, Tian XY, Chen J, Setterberg RB, Lundy MW, Chmielzwski P et al. (2007). Rolipram, a phosphodiesterase 4 inhibitor, prevented cancellous and cortical bone loss by inhibiting endosteal bone resorption and maintaining the elevated periosteal bone formation in adult ovariectomized rats. J Musculoskelet Neuronal Interact 7 (2 119 130.