Suppression of p21Rac signaling and increased innate immunity mediate remission in Crohn's disease

Science Translational Medicine

Volumn 6, Issue 233, 2014, Pages

  Parikh, Kaushal ^a,b,c   Zhou, Lu ^a,d   Somasundaram, Rajesh ^c   Fuhler, Gwenny M ^c   Deuring, J Jasper ^c   Blokzijl, Tjasso ^a   Regeling, Anouk ^a   Kuipers, Ernst J ^c   Weersma, Rinse K ^a   Nuij, Veerle J ^c   Alves, Maria ^c   Vogelaar, Lauran ^c   Visser, Lydia ^a   De Haar, Colin ^c   Krishnadath, Kausilia K ^b   Van Der Woude, C Janneke ^c   Dijkstra, Gerard ^a   Faber, Klaas Nico ^a   Peppelenbosch, Maikel P ^a,c  

^a UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

^b ACADEMIC MEDICAL CENTER   (Netherlands)

^c ERASMUS MEDICAL CENTER   (Netherlands)

^d TIANJIN MEDICAL UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINO 6 [2 [[4 (DIETHYLAMINO) 1 METHYLBUTYL]AMINO] 6 METHYL 4 PYRIMIDINYL] 2 METHYLQUINOLINE; GUANINE NUCLEOTIDE EXCHANGE FACTOR; GUANOSINE DIPHOSPHATE; GUANOSINE TRIPHOSPHATASE; GUANOSINE TRIPHOSPHATE; INTERLEUKIN 8; P21RAC1 GUANOSINE TRIPHOSPHATASE; TIOGUANINE; UNCLASSIFIED DRUG; CYCLIN DEPENDENT KINASE INHIBITOR 1A; ENZYME INHIBITOR; GUANOSINE TRIPHOSPHATASE ACTIVATING PROTEIN; PROTEIN KINASE; RAC1 PROTEIN;

ARTICLE; BACTERICIDAL ACTIVITY; CLINICAL ARTICLE; COLON BIOPSY; COLON MUCOSA; CONTROLLED STUDY; CROHN DISEASE; CYTOKINE PRODUCTION; DOWN REGULATION; ESCHERICHIA COLI; FEMALE; HUMAN; HUMAN CELL; HUMAN TISSUE; INNATE IMMUNITY; MALE; MONOCYTE; PHAGOCYTOSIS; PRIORITY JOURNAL; PROTEIN HYDROLYSIS; REMISSION; SIGNAL TRANSDUCTION; ULCERATIVE COLITIS; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOPSY; HYDROLYSIS; IMMUNOLOGY; INFLAMMATION; INTESTINE MUCOSA; METABOLISM; PATHOLOGY;

ANIMALS; BIOPSY; CROHN DISEASE; CYCLIN-DEPENDENT KINASE INHIBITOR P21; DOWN-REGULATION; ENZYME INHIBITORS; GTPASE-ACTIVATING PROTEINS; GUANINE NUCLEOTIDE EXCHANGE FACTORS; GUANOSINE DIPHOSPHATE; GUANOSINE TRIPHOSPHATE; HUMANS; HYDROLYSIS; IMMUNITY, INNATE; INFLAMMATION; INTESTINAL MUCOSA; PROTEIN KINASES; RAC1 GTP-BINDING PROTEIN; REMISSION INDUCTION; SIGNAL TRANSDUCTION; THIOGUANINE;

EID: 84899495785     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3006763     Document Type: Article

References (42)

1. C. Mowat, A. Cole, A. Windsor, T. Ahmad, I. Arnott, R. Driscoll, S. Mitton, T. Orchard, M. Rutter, L. Younge, C. Lees, G. T. Ho, J. Satsangi, S. Bloom; IBD Section of the British Society of Gastroenterology, Guidelines for the management of inflammatory bowel disease in adults. Gut 60, 571-607 (2011).
2. R. J. Xavier, D. K. Podolsky, Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427-434 (2007).
3. E. Bentley, D. Jenkins, F. Campbell, B. Warren, How could pathologists improve the initial diagnosis of colitis? Evidence from an international workshop. J. Clin. Pathol. 55, 955-960 (2002).
4. S. Vermeire, Towards a novel molecular classification of IBD. Dig. Dis. 30, 425-427 (2012).
5. J. C. Barrett, S. Hansoul, D. L. Nicolae, J. H. Cho, R. H. Duerr, J. D. Rioux, S. R. Brant, M. S. Silverberg, K. D. Taylor, M. M. Barmada, A. Bitton, T. Dassopoulos, L. W. Datta, T. Green, A. M. Griffiths, E. O. Kistner, M. T. Murtha, M. D. Regueiro, J. I. Rotter, L. P. Schumm, A. H. Steinhart, S. R. Targan, R. J. Xavier, C. Libioulle, C. Sandor, M. Lathrop, J. Belaiche, O. Dewit, I. Gut, S. Heath, D. Laukens, M. Mni, R. Rutgeerts, A. van Gossum, D. Zelenika, D. Franchimont, J. P. Hugot, M. de Vos, S. Vermeire, E. Louis; Belgian-French IBD Consortium; Wellcome Trust Case Control Consortium, L. R. Cardon, C. A. Anderson, H. Drummond, E. Nimmo, T. Ahmad, N. J. Prescott, C. M. Onnie, S. A. Fisher, J. Marchini, J. Ghori, S. Bumpstead, R. Gwilliam, M. Tremelling, P. Deloukas, J. Mansfield, D. Jewell, J. Satsangi, C. G. Mathew, M. Parkes, M. Georges, M. J. Daly, Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955-962 (2008).
6. L. Jostins, S. Ripke, R. K. Weersma, R. H. Duerr, D. P. McGovern, K. Y. Hui, J. C. Lee, L. P. Schumm, Y. Sharma, C. A. Anderson, J. Essers, M. Mitrovic, K. Ning, I. Cleynen, E. Theatre, S. L. Spain, S. Raychaudhuri, P. Goyette, Z. Wei, C. Abraham, J. P. Achkar, T. Ahmad, L. Amininejad, A. N. Ananthakrishnan, V. Andersen, J. M. Andrews, L. Baidoo, T. Balschun, P. A. Bampton, A. Bitton, G. Boucher, S. Brand, C. Büning, A. Cohain, S. Cichon, M. D'Amato, D. De Jong, K. L. Devaney, M. Dubinsky, C. Edwards, D. Ellinghaus, L. R. Ferguson, D. Franchimont, K. Fransen, R. Gearry, M. Georges, C. Gieger, J. Glas, T. Haritunians, A. Hart, C. Hawkey, M. Hedl, X. Hu, T. H. Karlsen, L. Kupcinskas, S. Kugathasan, A. Latiano, D. Laukens, I. C. Lawrance, C. W. Lees, E. Louis, G. Mahy, J. Mansfield, A. R. Morgan, C. Mowat, W. Newman, O. Palmieri, C. Y. Ponsioen, U. Potocnik, N. J. Prescott, M. Regueiro, J. I. Rotter, R. K. Russell, J. D. Sanderson, M. Sans, J. Satsangi, S. Schreiber, L. A. Simms, J. Sventoraityte, S. R. Targan, K. D. Taylor, M. Tremelling, H. W. Verspaget, M. De Vos, C. Wijmenga, D. C. Wilson, J. Winkelmann, R. J. Xavier, S. Zeissig, B. Zhang, C. K. Zhang, H. Zhao; International IBD Genetics Consortium (IIBDGC), M. S. Silverberg, V. Annese, H. Hakonarson, S. R. Brant, G. Radford-Smith, C. G. Mathew, J. D. Rioux, E. E. Schadt, M. J. Daly, A. Franke, M. Parkes, S. Vermeire, J. C. Barrett, J. H. Cho, Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119-124 (2012).
7. H. Braat, P. Stokkers, T. Hommes, D. Cohn, E. Vogels, I. Pronk, A. Spek, A. van Kampen, S. van Deventer, M. Peppelenbosch, D. Hommes, Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients. J. Mol. Med. 83, 601-609 (2005).
8. B. Khor, A. Gardet, R. J. Xavier, Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307-317 (2011).
9. M. Comalada, M. P. Peppelenbosch, Impaired innate immunity in Crohn's disease. Trends Mol. Med. 12, 397-399 (2006).
10. A. M. Smith, F. Z. Rahman, B. Hayee, S. J. Graham, D. J. Marks, G. W. Sewell, C. D. Palmer, J. Wilde, B. M. Foxwell, I. S. Gloger, T. Sweeting, M. Marsh, A. P. Walker, S. L. Bloom, A. W. Segal, Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn 's disease. J. Exp. Med. 206, 1883-1897 (2009).
11. S. Nuding, K. Fellermann, J. Wehkamp, E. F. Stange, Reduced mucosal antimicrobial activity in Crohn's disease of the colon. Gut 56, 1240-1247 (2007).
12. D. D. Nguyen, M. A. Wurbel, J. A. Goettel, M. A. Eston, O. S. Ahmed, R. Marin, E. K. Boden, E. J. Villablanca, H. Paidassi, V. Ahuja, H. C. Reinecker, E. Fiebiger, A. Lacy-Hulbert, B. H. Horwitz, J. R. Mora, S. B. Snapper, Wiskott-Aldrich syndrome protein deficiency in innate immune cells leads to mucosal immune dysregulation and colitis in mice. Gastroenterology 143, 719-729.e2 (2012).
13. J. W. van Baal, S. H. Diks, R. J. Wanders, A. M. Rygiel, F. Milano, J. Joore, J. J. Bergman, M. P. Peppelenbosch, K. K. Krishnadath, Comparison of kinome profiles of Barrett's esophagus with normal squamous esophagus and normal gastric cardia. Cancer Res. 66, 11605-11612 (2006).
14. H. Sikkema, S. H. Diks, W. F. den Dunnen, A. ter Elst, F. J. Scherpen, E. W. Hoving, R. Ruijtenbeek, P. J. Boender, R. de Wijn, W. A. Kamps, M. P. Peppelenbosch, E. S. de Bont, Kinome profiling in pediatric brain tumors as a new approach for target discovery. Cancer Res. 69, 5987-5995 (2009).
15. Y. Li, R. J. Arsenault, B. Trost, J. Slind, P. J. Griebel, S. Napper, A. Kusalik, A systematic approach for analysis of peptide array kinome data. Sci. Signal. 5, pl2 (2012).
16. W. J. Sandborn, S. Ghosh, J. Panes, I. Vranic, C. Su, S. Rousel, W. Niezychowski; Study A3921063 Investigators, Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N. Engl. J. Med. 367, 616-624 (2012).
17. J. P. Segain, D. Raingeard de la Blétière, V. Sauzeau, A. Bourreille, G. Hilaret, C. Cario-Toumaniantz, P. Pacaud, J. P. Galmiche, G. Loirand, Rho kinase blockade prevents inflammation via nuclear factor κB inhibition: Evidence in Crohn's disease and experimental colitis. Gastroenterology 124, 1180-1187 (2003).
18. M. Löwenberg, A. Verhaar, B. van den Blink, F. ten Kate, S. van Deventer, M. Peppelenbosch, D. Hommes, Specific inhibition of c-Raf activity by semapimod induces clinical remission in severe Crohn's disease. J. Immunol. 175, 2293-2300 (2005).
19. G. Docena, L. Rovedatti, L. Kruidenier, A. Fanning, N. A. Leakey, C. H. Knowles, K. Lee, F. Shanahan, K. Nally, P. G. McLean, A. Di Sabatino, T. T. MacDonald, Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease. Clin. Exp. Immunol. 162, 108-115 (2010).
20. K. A. Oikonomou, A. N. Kapsoritakis, A. I. Kapsoritaki, A. C. Manolakis, F. D. Tsiopoulos, A. E. Germenis, S. P. Potamianos, Downregulation of serum epidermal growth factor in patients with inflammatory bowel disease. Is there a link with mucosal damage? Growth Factors 28, 461-466 (2010).
21. A. J. Ridley, H. F. Paterson, C. L. Johnston, D. Diekmann, A. Hall, The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70, 401-410 (1992).
22. A. J. Ridley, Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol. 16, 522-529 (2006).
23. S. R. Targan, S. B. Hanauer, S. J. van Deventer, L. Mayer, D. H. Present, T. Braakman, K. L. DeWoody, T. F. Schaible, P. J. Rutgeert, A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease. Crohn 's Disease cA2 Study Group. N. Engl. J. Med. 337, 1029-1035 (1997).
24. U. G. Knaus, S. Morris, H. J. Dong, J. Chernoff, G. M. Bokoch, Regulation of human leukocyte p21-activated kinases through G protein-coupled receptors. Science 269, 221-223 (1995).
25. A. Minden, A. Lin, F. X. Claret, A. Abo, M. Karin, Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell 81, 1147-1157 (1995).
26. A. M. Muise, T. Walters, W. Xu, G. Shen-Tu, C. H. Guo, R. Fattouh, G. Y. Lam, V. M. Wolters, J. Bennitz, J. van Limbergen, P. Renbaum, Y. Kasirer, B. Y. Ngan, D. Turner, L. A. Denson, P. M. Sherman, R. H. Duerr, J. Cho, C. W. Lees, J. Satsang, D. C. Wilson, A. D. Paterson, A. M. Griffiths, M. Glogauer, M. S. Silverberg, J. H. Brumell, Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis. Gastroenterology 141, 633-641 (2011).
27. Z. Dong, D. Davidson, L. A. Pérez-Quintero, T. Kurosaki, W. Swat, A. Veillette, The adaptor SAP controls NK cell activation by regulating the enzymes Vav-1 and SHIP-1 and by enhancing conjugates with target cells. Immunity 36, 974-985 (2012).
28. Y. Gao, J. B. Dickerson, F. Guo, J. Zheng, Y. Zheng, Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc. Natl. Acad. Sci. U.S.A. 101, 7618-7623 (2004).
29. M. Nakaya, M. Kitano, M. Matsuda, S. Nagata, Spatiotemporal activation of Rac1 for engulfment of apoptotic cells. Proc. Natl. Acad. Sci. U.S.A. 105, 9198-9203 (2008).
30. L. Lennard, The clinical pharmacology of 6-mercaptopurine. Eur. J. Clin. Pharmacol. 43, 329-339 (1992).
31. G. D'Haens, F. Baert, G. van Assche, P. Caenepeel, P. Vergauwe, H. Tuynman, M. De Vos, S. van Deventer, L. Stitt, A. Donner, S. Vermeire, F. J. Van de Mierop, J. C. Coche, J. van der Woude, T. Ochsenkühn, A. A. van Bodegraven, P. P. Van Hootegem, G. L. Lambrecht, F. Mana, P. Rutgeerts, B. G. Feagan, D. Hommes; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club, Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: An open randomised trial. Lancet 371, 660-667 (2008).
32. + T lymphocytes. J. Clin. Invest. 111, 1133-1145 (2003).
33. J. Wehkamp, J. Harder, M. Weichenthal, M. Schwab, E. Schäffeler, M. Schlee, K. R. Herrlinger, A. Stallmach, F. Noack, P. Fritz, J. M. Schröder, C. L. Bevins, K. Fellermann, E. F. Stange, NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression. Gut 53, 1658-1664 (2004).
34. L. A. Simms, J. D. Doecke, M. D. Walsh, N. Huang, E. V. Fowler, G. L. Radford-Smith, Reduced α-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn's disease. Gut 57, 903-910 (2008).
35. C. Gasche, P. Grundtner, Genotypes and phenotypes in Crohn's disease: Do they help in clinical management? Gut 54, 162-167 (2005).
36. T. Bosse, J. Ehinger, A. Czuchra, S. Benesch, A. Steffen, X. Wu, K. Schloen, H. H. Niemann, G. Scita, T. E. Stradal, C. Brakebusch, K. Rottner, Cdc42 and phosphoinositide 3-kinase drive Rac-mediated actin polymerization downstream of c-Met in distinct and common pathways. Mol. Cell. Biol. 27, 6615-6628 (2007).
37. I. Oancea, C. W. Png, I. Das, R. Lourie, I. G. Winkler, R. Eri, N. Subramaniam, H. A. Jinnah, B. C. McWhinney, J. P. Levesque, M. A. McGuckin, J. A. Duley, T. H. J. Florin, A novel mouse model of veno-occlusive disease provides strategies to prevent thioguanine-induced hepatic toxicity. Gut 62, 594-605 (2013).
38. K. Parikh, M. P. Peppelenbosch, T. Ritsema, Kinome profiling using peptide arrays in eukaryotic cells. Methods Mol. Biol. 527, 269-280 (2009).
39. G. M. Fuhler, S. H. Diks, M. P. Peppelenbosch, W. G. Kerr, Widespread deregulation of phosphorylation-based signaling pathways in multiple myeloma cells: Opportunities for therapeutic intervention. Mol. Med. 17, 790-798 (2011).
40. H. H. Versteeg, B. B. Sørensen, S. H. Slofstra, J. H. Van den Brande, J. C. Stam, P. M. van Bergen en Henegouwen, D. J. Richel, L. C. Petersen, M. P. Peppelenbosch, VIIa/tissue factor interaction results in a tissue factor cytoplasmic domain-independent activation of protein synthesis, p70, and p90 S6 kinase phosphorylation. J. Biol. Chem. 277, 27065-27072 (2002).
41. G. M. Fuhler, A. L. Drayer, E. Vellenga, Decreased phosphorylation of protein kinase B and extracellular signal-regulated kinase in neutrophils from patients with myelodysplasia. Blood 101, 1172-1180 (2003).
42. L. Zhou, R. Somasundaram, R. F. Nederhof, G. Dijkstra, K. N. Faber, M. P. Peppelenbosch, G. M. Fuhler, Impact of human granulocyte and monocyte isolation procedures on functional studies. Clin. Vaccine Immunol. 19, 1065-1074 (2012).