Saccharomyces spp.

Xinhua Chen; Ciarán P. Kelly

doi:10.1128/9781555815462.ch5

Chapter 5 : Saccharomyces spp.

VIEW AFFILIATIONS HIDE AFFILIATIONS

Affiliations: 1: Division of Gastroenterology, Dana 601A, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Boston, MA 02215; 2: Division of Gastroenterology, Dana 601A, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Boston, MA 02215

Content Type: Monograph

Publication Year: 2008

Category: Clinical Microbiology

Book DOI: 10.1128/9781555815462

Chapter DOI: 10.1128/9781555815462.ch5

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:

Saccharomyces spp., Page 1 of 2

< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555815462/9781555814038_Chap05-1.gif /docserver/preview/fulltext/10.1128/9781555815462/9781555814038_Chap05-2.gif

Abstract:

This chapter focuses mostly on studies carried out using the commercial strain of Saccharomyces boulardii as effector organism for probiotic and replacement therapy. It first discusses history and taxonomy of Saccharomyces species. S. boulardii utilizes multiple mechanisms to exert its beneficial effects. The mechanisms of action of Saccharomyces spp. as probiotic agents discussed are interference with bacterial adhesion, inactivation of bacterial virulence factors, enhancement of the mucosal immune response, modulating host signaling pathways, strengthening of enterocyte tight junctions, and capacity to affect immune cell redistribution. A number of animal disease models have been used to study the mechanisms of action of S. boulardii organisms as well as their potential clinical applications. S. boulardii has been used for the treatment or prevention of a variety of diarrheal diseases, such as antibiotic-associated diarrhea (AAD), acute infectious diarrhea in adults and children, traveler’s diarrhea, diarrhea in human immunodeficiency virus-infected patients, C. difficile-associated disease, and inflammatory bowel diseases including both Crohn’s disease and ulcerative colitis. Next, the chapter presents a description of some clinical trials that have shown the efficacy of S. boulardii in different diseases. Finally, it talks about adverse effects of Saccharomyces probiotic use.

Citation: Chen X, Kelly C. 2008. Saccharomyces spp., p 51-60. In Versalovic J, Wilson M (ed), Therapeutic Microbiology. ASM Press, Washington, DC. doi: 10.1128/9781555815462.ch5

Key Concept Ranking

Traveler's Diarrhea: 0.5437918
Tumor Necrosis Factor alpha: 0.4672553
Restriction Fragment Length Polymorphism: 0.42378256
Small Intestine: 0.41858286

0.5437918

Highlighted Text: Show | Hide

Full text loading...

References

/content/book/10.1128/9781555815462.ch05

1. Buts,, J. P.,, P. Bernasconi,, J. P. Vaerman, and, C. Dive. 1990. Stimulation of secretory IgA and secretory component of immunoglobulins in small intestine of rats treated with Sac- charomyces boulardii. Dig. Dis. Sci. 35: 251– 256.

2. Buts,, J. P., and, N. De Keyser. 2006. Effects of Saccharomyces boulardii on intestinal mucosa. Dig. Dis. Sci. 51: 1485– 1492.

3. Buts,, J. P.,, N. De Keyser, and, L. De Raedemaeker. 1994. Saccharomyces boulardii enhances rat intestinal enzyme expression by endoluminal release of polyamines. Pediatr. Res. 36: 522– 527.

4. Buts,, J. P.,, N. Dekeyser,, C. Stilmant,, E. Delem,, F. Smets, and, E. Sokal. 2006. Saccharomyces boulardii produces in rat small intestine a novel protein phosphatase that inhibits Escherichia coli endotoxin by dephosphorylation. Pediatr. Res. 60: 24– 29.

5. Can,, M.,, B. A. Besirbellioglu,, I. Y. Avci,, C. M. Beker, and, A. Pahsa. 2006. Prophylactic Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea: a prospective study. Med. Sci. Monit. 12:PI19–PI22.

6. Castagliuolo, I.,, J. T. LaMont,, S. T. Nikulasson, and, C. Pothoulakis. 1996. Saccharomyces boulardii protease inhibits Clostridium difficile toxin A effects in the rat ileum. Infect. Immun. 64: 5225– 5232.

7. Castagliuolo, I.,, M. F. Riegler,, L. Valenick,, J. T. LaMont, and, C. Pothoulakis. 1999. Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infect. Immun. 67: 302– 307.

8. Chen,, X.,, E. G. Kokkotou,, N. Mustafa,, K. R. Bhaskar,, S. Sougioultzis,, M. O’Brien,, C. Pothoulakis, and, C. P. Kelly. 2006. Saccharomyces boulardii inhibits ERK1/2 mitogen-activated protein kinase activation both in vitro and in vivo and protects against Clostridium difficile toxin A-induced enteritis. J. Biol. Chem. 281: 24449– 24454.

9. Chia,, J. K.,, S. M. Chan, and, H. Goldstein. 1995. Baker’s yeast as adjunctive therapy for relapses of Clostridium difficile diarrhea. Clin. Infect. Dis. 20:1581.

10. Cohen, L.,, W. J. Henzel, and, P. A. Baeuerle. 1998. IKAP is a scaffold protein of the IkappaB kinase complex. Nature 395: 292– 296.

11. Czerucka, D.,, S. Dahan,, B. Mograbi,, B. Rossi, and, P. Rampal. 2000. Saccharomyces boulardii preserves the barrier function and modulates the signal transduction pathway induced in enteropathogenic Escherichia coli-infected T84 cells. Infect. Immun. 68: 5998– 6004.

12. Dahan,, S.,, G. Dalmasso,, V. Imbert,, J. F. Peyron,, P. Rampal, and, D. Czerucka. 2003. Saccharomyces boulardii interferes with enterohemorrhagic Escherichia coli-induced signaling pathways in T84 cells. Infect. Immun. 71: 766– 773.

13. Dalmasso,, G.,, F. Cottrez,, V. Imbert,, P. Lagadec,, J. F. Peyron,, P. Rampal,, D. Czerucka,, H. Groux,, A. Foussat, and, V. Brun. 2006. Saccharomyces boulardii inhibits inflammatory bowel disease by trapping T cells in mesenteric lymph nodes. Gastroenterology 131: 1812– 1825.

14. de Lanerolle, P., and, R. J. Paul. 1991. Myosin phosphorylation/dephosphorylation and regulation of airway smooth muscle contractility. Am. J. Physiol. 261: L1– L14.

15. Dias,, R. S.,, E. A. Bambirra,, M. E. Silva, and, J. R. Nicoli. 1995. Protective effect of Saccharomyces boulardii against the cholera toxin in rats. Braz. J. Med. Biol. Res. 28: 323– 325.

16. Dufour,, C.,, G. Dandrifosse,, P. Forget,, F. Vermesse,, N. Romain, and, P. Lepoint. 1988. Spermine and spermidine induce intestinal maturation in the rat. Gastroenterology 95: 112– 116.

17. Edwards-Ingram,, L.,, P. Gitsham,, N. Burton,, G. Warhurst,, I. Clarke,, D. Hoyle,, S. G. Oliver, and, L. Stateva. 2007. Genotypic and physiological characterization of Saccharomyces boulardii, the probiotic strain of Saccharomyces cerevisiae. Appl. Environ. Microbiol. 73: 2458– 2467.

18. Edwards-Ingram,, L. C.,, M. E. Gent,, D. C. Hoyle,, A. Hayes,, L. I. Stateva, and, S. G. Oliver. 2004. Comparative genomic hybridization provides new insights into the molecular taxonomy of the Saccharomyces sensu stricto complex. Genome Res. 14: 1043– 1051.

19. Elmer,, G. W., and, G. Corthier. 1991. Modulation of Clostridium difficile induced mortality as a function of the dose and the viability of the Saccharomyces boulardii used as a preventative agent in gnotobiotic mice. Can. J. Microbiol. 37: 315– 317.

20. Elmer,, G. W., and, L. V. McFarland. 1987. Suppression by Saccharomyces boulardii of toxigenic Clostridium difficile overgrowth after vancomycin treatment in hamsters. Anti-microb. Agents Chemother. 31: 129– 131.

21. Fekety, R., et al. 1997. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Am. J. Gastroenterol. 92: 739– 750.

22. Fiocchi, C. 2006. Probiotics in inflammatory bowel disease: yet another mechanism of action? Gastroenterology 131: 2009– 2012.

23. Gedek,, B. R. 1999. Adherence of Escherichia coli serogroup O 157 and the Salmonella typhimurium mutant DT 104 to the surface of Saccharomyces boulardii. Mycoses 42: 261– 264.

24. Gerding,, D. N.,, S. Johnson,, L. R. Peterson,, M. E. Mulligan, and, J. Silva, Jr. 1995. Clostridium difficile-associated diarrhea and colitis. Infect. Control. Hosp. Epidemiol. 16: 459– 477.

25. Guslandi, M.,, P. Giollo, and, P. A. Testoni. 2003. A pilot trial of Saccharomyces boulardii in ulcerative colitis. Eur. J. Gastroenterol. Hepatol. 15: 697– 698.

26. Guslandi, M.,, G. Mezzi,, M. Sorghi, and, P. A. Testoni. 2000. Saccharomyces boulardii in maintenance treatment of Crohn’s disease. Dig. Dis. Sci. 45: 1462– 1464.

27. Han, J.,, J. D. Lee,, L. Bibbs, and, R. J. Ulevitch. 1994. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265: 808– 811.

28. Hennequin,, C.,, C. Kauffmann-Lacroix,, A. Jobert,, J. P. Viard,, C. Ricour,, J. L. Jacquemin, and, P. Berche. 2000. Possible role of catheters in Saccharomyces boulardii fungemia. Eur. J. Clin. Microbiol. Infect. Dis. 19: 16– 20.

29. Hennequin,, C.,, A. Thierry,, G. F. Richard,, G. Lecointre,, H. V. Nguyen,, C. Gaillardin, and, B. Dujon. 2001. Microsatellite typing as a new tool for identification of Saccharomyces cerevisiae strains. J. Clin. Microbiol. 39: 551– 559.

30. Herbrecht, R., and, Y. Nivoix. 2005. Saccharomyces cerevisiae fungemia: an adverse effect of Saccharomyces boulardii pro-biotic administration. Clin. Infect. Dis. 40: 1635– 1637.

31. Hosomi,, M.,, N. H. Stace,, F. Lirussi,, S. M. Smith,, G. M. Murphy, and, R. H. Dowling. 1987. Role of polyamines in intestinal adaptation in the rat. Eur. J. Clin. Investig. 17: 375– 385.

32. Isolauri, E. 2001. Probiotics in human disease. Am. J. Clin. Nutr. 73:1142S–1146S.

33. Jobin, C., and, R. B. Sartor. 2000. The I kappa B/NF-kappa B system: a key determinant of mucosal inflammation and protection. Am. J. Physiol. Cell Physiol. 278:C451–C462.

34. Katchar,, K.,, C. P. Taylor,, S. Tummala,, X. Chen,, J. Sheikh, and, C. P. Kelly. 2007. Association between IgG2 and IgG3 subclass responses to toxin A and recurrent Clostridium difficile-associated disease. Clin. Gastroenterol. Hepatol. 5: 707– 713.

35. Keely,, S. J., and, K. E. Barrett. 2000. Regulation of chloride secretion. Novel pathways and messengers. Ann. N. Y. Acad. Sci. 915: 67– 76.

36. Kelly,, C. P.,, C. Pothoulakis, and, J. T. LaMont. 1994. Clostridium difficile colitis. N. Engl. J. Med. 330: 257– 262.

37. Kollaritsch, H.,, H. Holst,, P. Grobara, and, G. Wiedermann. 1993. [Prevention of traveler’s diarrhea with Saccharomyces boulardii. Results of a placebo controlled double-blind study]. Fortschr. Med. 111: 152– 156.

38. Kotowska, M.,, P. Albrecht, and, H. Szajewska. 2005. Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: a randomized double-blind placebo-controlled trial. Aliment. Pharmacol. Ther. 21: 583– 590.

39. Kovacs,, D. J., and, T. Berk. 2000. Recurrent Clostridium difficile-associated diarrhea and colitis treated with Saccharomyces cerevisiae (baker’s yeast) in combination with antibiotic therapy: a case report. J. Am. Board Fam. Pract. 13: 138– 140.

40. Kumura, H.,, Y. Tanoue,, M. Tsukahara,, T. Tanaka, and, K. Shimazaki. 2004. Screening of dairy yeast strains for probiotic applications. J. Dairy Sci. 87: 4050– 4056.

41. Kyne, L., and, C. P. Kelly. 2001. Recurrent Clostridium difficile diarrhoea. Gut 49: 152– 153.

42. Kyne, L.,, M. Warny,, A. Qamar, and, C. P. Kelly. 2001. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 357: 189– 193.

43. Kyriakis,, J. M.,, P. Banerjee,, E. Nikolakaki,, T. Dai,, E. A. Rubie,, M. F. Ahmad,, J. Avruch, and, J. R. Woodgett. 1994. The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369: 156– 160.

44. Lee,, J. C.,, J. T. Laydon,, P. C. McDonnell,, T. F. Gallagher,, S. Kumar,, D. Green,, D. McNulty,, M. J. Blumenthal,, J. R. Heys,, S. W. Landvatter, et al. 1994. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372: 739– 746.

45. Lee,, S. K.,, H. J. Kim,, S. G. Chi,, J. Y. Jang,, K. D. Nam,, N. H. Kim,, K. R. Joo,, S. H. Dong,, B. H. Kim,, Y. W. Chang,, J. I. Lee, and, R. Chang. 2005. [ Saccharomyces boulardii activates expression of peroxisome proliferator-activated receptor-gamma in HT-29 cells]. Korean J. Gastroenterol. 45: 328– 334.

46. Malgoire,, J. Y.,, S. Bertout,, F. Renaud,, J. M. Bastide, and, M. Mallie. 2005. Typing of Saccharomyces cerevisiae clinical strains by using microsatellite sequence polymorphism. J. Clin. Microbiol. 43: 1133– 1137.

47. Martins,, F. S.,, A. C. Rodrigues,, F. C. Tiago,, F. J. Penna,, C. A. Rosa,, R. M. Arantes,, R. M. Nardi,, M. J. Neves, and, J. R. Nicoli. 2007. Saccharomyces cerevisiae strain 905 reduces the translocation of Salmonella enterica serotype Typhimurium and stimulates the immune system in gnotobiotic and conventional mice. J. Med. Microbiol. 56: 352– 359.

48. McCullough,, M. J.,, K. V. Clemons,, J. H. McCusker, and, D. A. Stevens. 1998. Species identification and virulence attributes of Saccharomyces boulardii (nom. inval.). J. Clin. Microbiol. 36: 2613– 2617.

49. McFarland,, L. V. 1998. Epidemiology, risk factors and treatments for antibiotic-associated diarrhea. Dig. Dis. 16: 292– 307.

50. McFarland,, L. V. 2006. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am. J. Gastroenterol. 101: 812– 822.

51. McFarland,, L. V. 2007. Meta-analysis of probiotics for the prevention of traveler’s diarrhea. Travel Med. Infect. Dis. 5: 97– 105.

52. McFarland,, L. V. 1996. Saccharomyces boulardii is not Saccharomyces cerevisiae. Clin. Infect. Dis. 22: 200– 201.

53. McFarland,, L. V.,, C. M. Surawicz,, R. N. Greenberg,, R. Fekety,, G. W. Elmer,, K. A. Moyer,, S. A. Melcher,, K. E. Bowen,, J. L. Cox,, Z. Noorani, et al. 1994. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 271: 1913– 1918.

54. Mitterdorfer, G.,, W. Kneifel, and, H. Viernstein. 2001. Utilization of prebiotic carbohydrates by yeasts of therapeutic relevance. Lett. Appl. Microbiol. 33: 251– 255.

55. Mitterdorfer, G.,, H. K. Mayer,, W. Kneifel, and, H. Viernstein. 2002a. Clustering of Saccharomyces boulardii strains within the species S. cerevisiae using molecular typing techniques. J. Appl. Microbiol. 93: 521– 530.

56. Mitterdorfer, G.,, H. K. Mayer,, W. Kneifel, and, H. Viernstein. 2002b. Protein fingerprinting of Saccharomyces isolates with therapeutic relevance using one- and two-dimensional electrophoresis. Proteomics 2: 1532– 1538.

57. Munoz,, P.,, E. Bouza,, M. Cuenca-Estrella,, J. M. Eiros,, M. J. Perez,, M. Sanchez-Somolinos,, C. Rincon,, J. Hortal, and, T. Pelaez. 2005. Saccharomyces cerevisiae fungemia: an emerging infectious disease. Clin. Infect. Dis. 40: 1625– 1634.

58. Penna,, F. J.,, L. A. Filho,, A. C. Calcado,, H. R. Junior, and, J. R. Nicolli. 2000. [Up-to-date clinical and experimental basis for the use of probiotics]. J. Pediatr. (Rio de Janeiro) 76(Suppl. 1): S209– S217. (In Portuguese.)

59. Perapoch,, J.,, A. M. Planes,, A. Querol,, V. Lopez,, I. Martinez-Bendayan,, R. Tormo,, F. Fernandez,, G. Peguero, and, S. Salcedo. 2000. Fungemia with Saccharomyces cerevisiae in two newborns, only one of whom had been treated with ultra-levura. Eur. J. Clin. Microbiol. Infect. Dis. 19: 468– 470.

60. Philpott,, D. J.,, D. M. McKay,, P. M. Sherman, and, M. H. Perdue. 1996. Infection of T84 cells with enteropathogenic Escherichia coli alters barrier and transport functions. Am. J. Physiol. 270:G634–G645.

61. Pothoulakis,, C.,, C. P. Kelly,, M. A. Joshi,, N. Gao,, C. J. O’Keane,, I. Castagliuolo, and, J. T. Lamont. 1993. Saccharomyces boulardii inhibits Clostridium difficile toxin A binding and enterotoxicity in rat ileum. Gastroenterology 104: 1108– 1115.

62. Qamar,, A.,, S. Aboudola,, M. Warny,, P. Michetti,, C. Pothoulakis,, J. T. LaMont, and, C. P. Kelly. 2001. Saccharomyces boulardii stimulates intestinal immunoglobulin A immune response to Clostridium difficile toxin A in mice. Infect. Immun. 69: 2762– 2765.

63. Richmond, A. 2002. Nf-kappa B, chemokine gene transcription and tumour growth. Nat. Rev. Immunol. 2: 664– 674.

64. Rigothier,, M. C.,, J. Maccario, and, P. Gayral. 1994. Inhibitory activity of saccharomyces yeasts on the adhesion of Entamoeba histolytica trophozoites to human erythrocytes in vitro. Parasitol. Res. 80: 10– 15.

65. Rigothier,, M. C.,, J. Maccario,, P. N. Vuong, and, P. Gayral. 1990. [Effects of Saccharomyces boulardii yeast on trophozoites of Entamoeba histolytica in vitro and in cecal amebiasis in young rats]. Ann. Parasitol. Hum. Comp. 65: 51– 60. (In French.)

66. Riquelme,, A. J.,, M. A. Calvo,, A. M. Guzman,, M. S. Depix,, P. Garcia,, C. Perez,, M. Arrese, and, J. A. Labarca. 2003. Saccharomyces cerevisiae fungemia after Saccharomyces boulardii treatment in immunocompromised patients. J. Clin. Gastroenterol. 36: 41– 43.

67. Rodrigues,, A. C.,, D. C. Cara,, S. H. Fretez,, F. Q. Cunha,, E. C. Vieira,, J. R. Nicoli, and, L. Q. Vieira. 2000. Saccharomyces boulardii stimulates sIgA production and the phagocytic system of gnotobiotic mice. J. Appl. Microbiol. 89: 404– 414.

68. Rodrigues,, A. C. P.,, R. M. Nardi,, E. A. Bambirra,, E. C. Vieira, and, J. R. Nicoli. 1996. Effect of Saccharomyces boulardii against experimental oral infection with Salmonella typhimurium and Shigella flexneri in conventional and gnotobiotic mice. J. Appl. Bacteriol. 81: 251– 256.

69. Saint-Marc, T.,, L. Rossello-Prats, and, J. L. Touraine. 1991. [Efficacy of Saccharomyces boulardii in the treatment of diarrhea in AIDS]. Ann. Med. Interne (Paris) 142: 64– 65.

70. Sazawal,, S.,, G. Hiremath,, U. Dhingra,, P. Malik,, S. Deb, and, R. E. Black. 2006. Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials. Lancet Infect. Dis. 6: 374– 382.

71. Simeonidis,, S.,, I. Castagliuolo,, A. Pan,, J. Liu,, C. C. Wang,, A. Mykoniatis,, A. Pasha,, L. Valenick,, S. Sougioultzis,, D. Zhao, and, C. Pothoulakis. 2003. Regulation of the NK-1 receptor gene expression in human macrophage cells via an NF-kappa B site on its promoter. Proc. Natl. Acad. Sci. USA 100: 2957– 2962.

72. Simeonidis, S.,, D. Stauber,, G. Chen,, W. A. Hendrickson, and, D. Thanos. 1999. Mechanisms by which IkappaB proteins control NF-kappaB activity. Proc. Natl. Acad. Sci. USA 96: 49– 54.

73. Sougioultzis,, S.,, S. Simeonidis,, K. R. Bhaskar,, X. Chen,, P. M. Anton,, S. Keates,, C. Pothoulakis, and, C. P. Kelly. 2006. Saccharomyces boulardii produces a soluble anti-inflammatory factor that inhibits NF-kappaB-mediated IL-8 gene expression. Biochem. Biophys. Res. Commun. 343: 69– 76.

74. Spitz,, J.,, R. Yuhan,, A. Koutsouris,, C. Blatt,, J. Alverdy, and, G. Hecht. 1995. Enteropathogenic Escherichia coli adherence to intestinal epithelial monolayers diminishes barrier function. Am. J. Physiol. 268:G374–G379.

75. Surawicz,, C. M.,, G. W. Elmer,, P. Speelman,, L. V. McFarland,, J. Chinn, and, G. van Belle. 1989. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterology 96: 981– 988.

76. Surawicz,, C. M.,, L. V. McFarland,, R. N. Greenberg,, M. Rubin,, R. Fekety,, M. E. Mulligan,, R. J. Garcia,, S. Brandmarker,, K. Bowen,, D. Borjal, and, G. W. Elmer. 2000. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin. Infect. Dis. 31: 1012– 1017.

77. Szajewska, H.,, A. Skorka, and, M. Dylag. 2007. Meta-analysis: Saccharomyces boulardii for treating acute diarrhoea in children. Aliment. Pharmacol. Ther. 25: 257– 264.

78. Villarruel,, G.,, D. M. Rubio,, F. Lopez,, J. Cintioni,, R. Gurevech,, G. Romero, and, Y. Vandenplas. 2007. Saccharomyces boulardii in acute childhood diarrhoea: a randomized, placebo-controlled study. Acta Paediatr. 96: 538– 541.

79. Wilson,, A. K.,, G. Gorgas,, W. D. Claypool, and, P. de Lanerolle. 1991. An increase or a decrease in myosin II phosphorylation inhibits macrophage motility. J. Cell Biol. 114: 277– 283.

80. Woronicz,, J. D.,, X. Gao,, Z. Cao,, M. Rothe, and, D. V. Goeddel. 1997. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science 278: 866– 869.