Genetics of childhood-onset inflammatory bowel disease

Inflammatory Bowel Diseases

Volumn 17, Issue 1, 2011, Pages 346-361

  Henderson, Paul ^a,b   Van Limbergen, Johan E ^c   Wilson, David C ^a,b   Satsangi, Jack ^b   Russell, Richard K ^d  

^a ROYAL HOSPITAL FOR SICK CHILDREN   (United Kingdom)

^b UNIVERSITY OF EDINBURGH   (United Kingdom)

^c HOSPITAL FOR SICK CHILDREN   (Canada)

^d ROYAL HOSPITAL FOR SICK CHILDREN   (United Kingdom)

Author keywords

childhood; early onset; genetics; genome wide association study; inflammatory bowel disease

Indexed keywords

CALPAIN 10; CARRIER PROTEINS AND BINDING PROTEINS; CASPASE RECRUITMENT DOMAIN PROTEIN 15; CASPASE RECRUITMENT DOMAIN PROTEIN 9; DECOY RECEPTOR 3; DEXTRAN SULFATE; DUAL SPECIFICITY PHOSPHATASE 2; IMMUNOMODULATING AGENT; INFLIXIMAB; INTERLEUKIN 17; INTERLEUKIN 22; INTERLEUKIN 23; INTERLEUKIN 27; INTERLEUKIN 6; MYOTUBULARIN RELATED PROTEIN 3; PROBIOTIC AGENT; PROTEASOME; PROTEASOME INHIBITOR; PROTEIN PSMG1; PROTEIN TYROSINE PHOSPHATASE; RECOMBINANT INTERLEUKIN 10; SMAD3 PROTEIN; TOLL LIKE RECEPTOR 4; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR ALPHA INHIBITOR; UBIQUITIN; UNCLASSIFIED DRUG; ZINC FINGER PROTEIN; ZINC FINGER PROTEIN ZMIZ1;

ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; AUTOPHAGY; CELL DIFFERENTIATION; CHILD; CHILDHOOD DISEASE; CLINICAL TRIAL; COHORT ANALYSIS; CROHN DISEASE; DISEASE CLASSIFICATION; DISEASE SEVERITY; ENDOPLASMIC RETICULUM; ENDOPLASMIC RETICULUM STRESS; ENTERITIS; FAMILY HISTORY; GENE EXPRESSION; GENE LOCUS; GENE MUTATION; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC SUSCEPTIBILITY; HUMAN; IMMUNE DYSREGULATION; IMMUNE RESPONSE; INTESTINE SURGERY; LYMPHOCYTE PROLIFERATION; NONHUMAN; ONSET AGE; PANCREATITIS; PATHOGENESIS; PATHOPHYSIOLOGY; PATIENT SELECTION; PHARMACODYNAMICS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN DEGRADATION; REVIEW; RHEUMATOID ARTHRITIS; RISK FACTOR; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; SURGICAL TECHNIQUE; TH17 CELL; TREATMENT INDICATION; ULCERATIVE COLITIS;

ADULT; AGE OF ONSET; CHILD; GENOME-WIDE ASSOCIATION STUDY; HUMANS; INFLAMMATORY BOWEL DISEASES;

EID: 77954399830     PISSN: 10780998     EISSN: 15364844     Source Type: Journal    
DOI: 10.1002/ibd.21283     Document Type: Review

References (224)

1. Van Limbergen J, Wilson D, Satsangi J,. The genetics of Crohn's disease. Annu Rev Genomics Hum Genet. 2009; 10: 89-116.
2. Armitage EL, Aldhous MC, Anderson N, et al. Incidence of juvenile-onset Crohn's disease in Scotland: association with northern latitude and affluence. Gastroenterology. 2004; 127: 1051-1057.
3. Izcue A, Coombes JL, Powrie F,. Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol. 2009; 27: 313-338.
4. Loftus EV Jr,. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004; 126: 1504-1517.
5. Griffiths AM,. Specificities of inflammatory bowel disease in childhood. Best Pract Res Clin Gastroenterol. 2004; 18: 509-523.
6. Van Limbergen J, Russell RK, Drummond HE, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology. 2008; 135: 1114-1122.
7. Auvin S, Molinie F, Gower-Rousseau C, et al. Incidence, clinical presentation and location at diagnosis of pediatric inflammatory bowel disease: a prospective population-based study in northern France (1988-1999). J Pediatr Gastroenterol Nutr. 2005; 41: 49-55.
8. Hildebrand H, Finkel Y, Grahnquist L, et al. Changing pattern of paediatric inflammatory bowel disease in northern Stockholm 1990-2001. Gut. 2003; 52: 1432-1434.
9. Lindberg E, Lindquist B, Holmquist L, et al. Inflammatory bowel disease in children and adolescents in Sweden, 1984-1995. J Pediatr Gastroenterol Nutr. 2000; 30: 259-264.
10. Olafsdottir EJ, Fluge G, Haug K,. Chronic inflammatory bowel disease in children in western Norway. J Pediatr Gastroenterol Nutr. 1989; 8: 454-458.
11. Jakobsen C, Paerregaard A, Munkholm P, et al. Paediatric inflammatory bowel disease during a 44-year period in Copenhagen County: occurrence, course and prognosis-a population-based study from the Danish Crohn Colitis Database. Eur J Gastroenterol Hepatol. 2009; 21: 1291-1301.
12. Perminow G, Brackmann S, Lyckander LG, et al. A characterization in childhood inflammatory bowel disease, a new population-based inception cohort from South-Eastern Norway, 2005-07, showing increased incidence in Crohn's disease. Scand J Gastroenterol. 2009; 44: 446-456.
13. Orel R, Kamhi T, Vidmar G, et al. Epidemiology of pediatric chronic inflammatory bowel disease in central and western Slovenia, 1994-2005. J Pediatr Gastroenterol Nutr. 2009; 48: 579-586.
14. Vernier-Massouille G, Balde M, Salleron J, et al. Natural history of pediatric Crohn's disease: a population-based cohort study. Gastroenterology. 2008; 135: 1106-1113.
15. Kolek A, Janout V, Tichy M, et al. The incidence of inflammatory bowel disease is increasing among children 15 years old and younger in the Czech Republic. J Pediatr Gastroenterol Nutr. 2004; 38: 362-363.
16. Armitage E, Drummond HE, Wilson DC, et al. Increasing incidence of both juvenile-onset Crohn's disease and ulcerative colitis in Scotland. Eur J Gastroenterol Hepatol. 2001; 13: 1439-1447.
17. Barton JR, Gillon S, Ferguson A,. Incidence of inflammatory bowel disease in Scottish children between 1968 and 1983; marginal fall in ulcerative colitis, three-fold rise in Crohn's disease. Gut. 1989; 30: 618-622.
18. Sawczenko A, Sandhu BK, Logan RF, et al. Prospective survey of childhood inflammatory bowel disease in the British Isles. Lancet. 2001; 357: 1093-1094.
19. Kugathasan S, Judd RH, Hoffmann RG, et al. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr. 2003; 143: 525-531.
20. Benchimol EI, Guttmann A, Griffiths AM, et al. Increasing incidence of paediatric inflammatory bowel disease in Ontario, Canada: evidence from health administrative data. Gut. 2009; 58: 1490-1497.
21. Griffiths AM,. Growth retardation in early-onset inflammatory bowel disease: should we monitor and treat these patients differently? Dig Dis. 2009; 27: 404-411.
22. Mayberry MK, Probert C, Srivastava E, et al. Perceived discrimination in education and employment by people with Crohn's disease: a case control study of educational achievement and employment. Gut. 1992; 33: 312-314.
23. Ferguson A, Sedgwick DM, Drummond J,. Morbidity of juvenile onset inflammatory bowel disease: effects on education and employment in early adult life. Gut. 1994; 35: 665-668.
24. Kim SC, Ferry GD,. Inflammatory bowel diseases in pediatric and adolescent patients: clinical, therapeutic, and psychosocial considerations. Gastroenterology. 2004; 126: 1550-1560.
25. Brant SR, Panhuysen CI, Bailey-Wilson JE, et al. Linkage heterogeneity for the IBD1 locus in Crohn's disease pedigrees by disease onset and severity. Gastroenterology. 2000; 119: 1483-1490.
26. Akolkar PN, Gulwani-Akolkar B, Lin XY, et al. The IBD1 locus for susceptibility to Crohn's disease has a greater impact in Ashkenazi Jews with early onset disease. Am J Gastroenterol. 2001; 96: 1127-1132.
27. de Ridder L, Weersma RK, Dijkstra G, et al. Genetic susceptibility has a more important role in pediatric-onset Crohn's disease than in adult-onset Crohn's disease. Inflamm Bowel Dis. 2007; 13: 1083-1092.
28. Heyman MB, Kirschner BS, Gold BD, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr. 2005; 146: 35-40.
29. Imielinski M, Baldassano RN, Griffiths A, et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet. 2009; 41: 1335-1340.
30. Lakatos PL,. Environmental factors affecting inflammatory bowel disease: have we made progress? Dig Dis. 2009; 27: 215-225.
31. Hattersley AT, McCarthy MI,. What makes a good genetic association study? Lancet. 2005; 366: 1315-1323.
32. Gasche C, Scholmerich J, Brynskov J, et al. A simple classification of Crohn's disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis. 2000; 6: 8-15.
33. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005; 19 (suppl A): 5-36.
34. Pigneur B, Seksik P, Viola S, et al. Natural history of Crohn's disease: Comparison between childhood- and adult-onset disease. Inflamm Bowel Dis. 2009 [Epub ahead of print].
35. Damen GM, Hol J, de Ruiter L, et al. Chemokine production by buccal epithelium as a distinctive feature of pediatric Crohn disease. J Pediatr Gastroenterol Nutr. 2006; 42: 142-149.
36. Kugathasan S, Saubermann LJ, Smith L, et al. Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease. Gut. 2007; 56: 1696-1705.
37. Turner D, Grossman AB, Rosh J, et al. Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn's disease. Am J Gastroenterol. 2007; 102: 2804-2812.
38. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology. 2007; 132: 863-873.
39. Bhat M, Nguyen GC, Pare P, et al. Phenotypic and genotypic characteristics of inflammatory bowel disease in French Canadians: comparison with a large North American repository. Am J Gastroenterol. 2009; 104: 2233-2240.
40. Sagiv-Friedgut K, Karban A, Weiss B, et al. Early-onset Crohn disease is associated with male sex and a polymorphism in the IL-6 promoter. J Pediatr Gastroenterol Nutr. 2010; 50: 22-26.
41. Cornish JA, Tan E, Simillis C, et al. The risk of oral contraceptives in the etiology of inflammatory bowel disease: a meta-analysis. Am J Gastroenterol. 2008; 103: 2394-2400.
42. Gupta N, Bostrom AG, Kirschner BS, et al. Gender differences in presentation and course of disease in pediatric patients with Crohn disease. Pediatrics. 2007; 120: e1418-1425.
43. Baldassano RN, Bradfield JP, Monos DS, et al. Association of the T300A non-synonymous variant of the ATG16L1 gene with susceptibility to paediatric Crohn's disease. Gut. 2007; 56: 1171-1173.
44. Sawczenko A, Lynn R, Sandhu BK,. Variations in initial assessment and management of inflammatory bowel disease across Great Britain and Ireland. Arch Dis Child. 2003; 88: 990-994.
45. Henriksen M, Jahnsen J, Lygren I, et al. Ulcerative colitis and clinical course: results of a 5-year population-based follow-up study (the IBSEN study). Inflamm Bowel Dis. 2006; 12: 543-550.
46. Paul T, Birnbaum A, Pal DK, et al. Distinct phenotype of early childhood inflammatory bowel disease. J Clin Gastroenterol. 2006; 40: 583-586.
47. Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn's disease. Inflamm Bowel Dis. 2002; 8: 244-250.
48. Cannom RR, Kaiser AM, Ault GT, et al. Inflammatory bowel disease in the United States from 1998 to 2005: has infliximab affected surgical rates? Am Surg. 2009; 75: 976-980.
49. Grieci T, Butter A,. The incidence of inflammatory bowel disease in the pediatric population of Southwestern Ontario. J Pediatr Surg. 2009; 44: 977-980.
50. Perminow G, Reikvam DH, Lyckander LG, et al. Increased number and activation of colonic macrophages in pediatric patients with untreated Crohn's disease. Inflamm Bowel Dis. 2009; 15: 1368-1378.
51. Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut. 1988; 29: 990-996.
52. Russell RK, Satsangi J,. IBD: a family affair. Best Pract Res Clin Gastroenterol. 2004; 18: 525-539.
53. Orholm M, Munkholm P, Langholz E, et al. Familial occurrence of inflammatory bowel disease. N Engl J Med. 1991; 324: 84-88.
54. Peeters M, Nevens H, Baert F, et al. Familial aggregation in Crohn's disease: increased age-adjusted risk and concordance in clinical characteristics. Gastroenterology. 1996; 111: 597-603.
55. Yang H, McElree C, Roth MP, et al. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut. 1993; 34: 517-524.
56. Roth MP, Petersen GM, McElree C, et al. Familial empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews. Gastroenterology. 1989; 96: 1016-1020.
57. Liu Y, Helms C, Liao W, et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 2008; 4: e1000041.
58. Burton PR, Clayton DG, Cardon LR, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007; 39: 1329-1337.
59. Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006; 314: 1461-1463.
60. Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008; 40: 955-962.
61. Noble C, Nimmo E, Gaya D, et al. Novel susceptibility genes in inflammatory bowel disease. World J Gastroenterol. 2006; 12: 1991-1999.
62. Mathew CG,. New links to the pathogenesis of Crohn disease provided by genome-wide association scans. Nat Rev Genet. 2008; 9: 9-14.
63. Lees CW, Satsangi J,. Genetics of inflammatory bowel disease: implications for disease pathogenesis and natural history. Expert Rev Gastroenterol Hepatol. 2009; 3: 513-534.
64. Kugathasan S, Baldassano RN, Bradfield JP, et al. Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet. 2008; 40: 1211-1215.
65. Polito JM, Childs B, Mellits ED, et al. Crohn's disease: influence of age at diagnosis on site and clinical type of disease. Gastroenterology. 1996; 111: 580-586.
66. Rioux JD, Silverberg MS, Daly MJ, et al. Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet. 2000; 66: 1863-1870.
67. Waller S, Tremelling M, Bredin F, et al. Evidence for association of OCTN genes and IBD5 with ulcerative colitis. Gut. 2006; 55: 809-814.
68. Noble CL, Nimmo ER, Drummond H, et al. The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease. Gastroenterology. 2005; 129: 1854-1864.
69. Russell RK, Drummond HE, Nimmo ER, et al. Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease. Gut. 2006; 55: 1114-1123.
70. Brescianini S, Trinh T, Stoll M, et al. IBD5 is associated with an extensive complicated Crohn's disease feature: implications from genotype-phenotype analysis. Gut. 2007; 56: 149-150.
71. Ferraris A, Knafelz D, Torres B, et al. Analysis of CARD15 gene variants in Italian pediatric patients with inflammatory bowel diseases. J Pediatr. 2005; 147: 272-273.
72. Sun L, Roesler J, Rosen-Wolff A, et al. CARD15 genotype and phenotype analysis in 55 pediatric patients with Crohn disease from Saxony, Germany. J Pediatr Gastroenterol Nutr. 2003; 37: 492-497.
73. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001; 411: 599-603.
74. Essers JB, Lee JJ, Kugathasan S, et al. Established genetic risk factors do not distinguish early and later onset Crohn's disease. Inflamm Bowel Dis. 2009; 15: 1508-1514.
75. Wang K, Zhang H, Kugathasan S, et al. Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn Disease. Am J Hum Genet. 2009; 84: 399-405.
76. McGreal EP,. Structural basis of pattern recognition by innate immune molecules. Adv Exp Med Biol. 2009; 653: 139-161.
77. Lala S, Ogura Y, Osborne C, et al. Crohn's disease and the NOD2 gene: a role for paneth cells. Gastroenterology. 2003; 125: 47-57.
78. Kelsall B,. Getting to the guts of NOD2. Nat Med. 2005; 11: 383-384.
79. Clark NM, Marinis JM, Cobb BA, et al. MEKK4 sequesters RIP2 to dictate NOD2 signal specificity. Curr Biol. 2008; 18: 1402-1408.
80. Rosenstiel P, Sina C, End C, et al. Regulation of DMBT1 via NOD2 and TLR4 in intestinal epithelial cells modulates bacterial recognition and invasion. J Immunol. 2007; 178: 8203-8211.
81. Rosenstiel P, Huse K, Franke A, et al. Functional characterization of two novel 5â untranslated exons reveals a complex regulation of NOD2 protein expression. BMC Genomics. 2007; 8: 472.
82. Petnicki-Ocwieja T, Hrncir T, Liu YJ, et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci U S A. 2009; 106: 15813-15818.
83. Sabbah A, Chang TH, Harnack R, et al. Activation of innate immune antiviral responses by Nod2. Nat Immunol. 2009; 10: 1073-1080.
84. Van Limbergen J, Russell RK, Nimmo ER, et al. Genetics of the innate immune response in inflammatory bowel disease. Inflamm Bowel Dis. 2007; 13: 338-355.
85. Seong SY, Matzinger P,. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004; 4: 469-478.
86. Browning BL, Huebner C, Petermann I, et al. Has toll-like receptor 4 been prematurely dismissed as an inflammatory bowel disease gene? Association study combined with meta-analysis shows strong evidence for association. Am J Gastroenterol. 2007; 102: 2504-2512.
87. De Jager PL, Franchimont D, Waliszewska A, et al. The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes Immun. 2007; 8: 387-397.
88. Labbe C, Goyette P, Lefebvre C, et al. MAST3: a novel IBD risk factor that modulates TLR4 signaling. Genes Immun. 2008; 9: 602-612.
89. Bueno de Mesquita M, Ferrante M, Henckaerts L, et al. Clustering of (auto)immune diseases with early-onset and complicated inflammatory bowel disease. Eur J Pediatr. 2009; 168: 575-583.
90. Lakatos PL, Lakatos L, Szalay F, et al. Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: phenotype-genotype correlations. World J Gastroenterol. 2005; 11: 1489-1495.
91. Palmer MT, Weaver CT,. Autoimmunity: increasing suspects in the CD4+ T cell lineup. Nat Immunol. 2010; 11: 36-40.
92. Martinez GJ, Nurieva RI, Yang XO, et al. Regulation and function of proinflammatory TH17 cells. Ann N Y Acad Sci. 2008; 1143: 188-211.
93. Fisher SA, Tremelling M, Anderson CA, et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet. 2008; 40: 710-712.
94. Glas J, Seiderer J, Wetzke M, et al. rs1004819 is the main disease-associated IL23R variant in German Crohn's disease patients: combined analysis of IL23R, CARD15, and OCTN1/2 variants. PLoS One. 2007; 2: e819.
95. Tremelling M, Cummings F, Fisher SA, et al. IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease. Gastroenterology. 2007; 132: 1657-1664.
96. Van Limbergen J, Russell RK, Nimmo ER, et al. IL23R Arg381Gln is associated with childhood onset inflammatory bowel disease in Scotland. Gut. 2007; 56: 1173-1174.
97. Dubinsky MC, Wang D, Picornell Y, et al. IL-23 receptor (IL-23R) gene protects against pediatric Crohn's disease. Inflamm Bowel Dis. 2007; 13: 511-515.
98. Peterson N, Guthery S, Denson L, et al. Genetic variants in the autophagy pathway contribute to paediatric Crohn's disease. Gut. 2008; 57: 1336-1337; author reply 7.
99. Newman WG, Zhang Q, Liu X, et al. Genetic variants in IL-23R and ATG16L1 independently predispose to increased susceptibility to Crohn's disease in a Canadian population. J Clin Gastroenterol. 2009; 43: 444-447.
100. Taylor KD, Targan SR, Mei L, et al. IL23R haplotypes provide a large population attributable risk for Crohn's disease. Inflamm Bowel Dis. 2008; 14: 1185-1191.
101. Raelson JV, Little RD, Ruether A, et al. Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci. Proc Natl Acad Sci U S A. 2007; 104: 14747-14752.
102. Brand S,. Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut. 2009; 58: 1152-1167.
103. Bauquet AT, Jin H, Paterson AM, et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol. 2009; 10: 167-175.
104. Takahashi N, Matsumoto K, Saito H, et al. Impaired CD4 and CD8 effector function and decreased memory T cell populations in ICOS-deficient patients. J Immunol. 2009; 182: 5515-5527.
105. Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003; 52: 65-70. (Pubitemid 36020767)
106. Schmechel S, Konrad A, Diegelmann J, et al. Linking genetic susceptibility to Crohn's disease with Th17 cell function: IL-22 serum levels are increased in Crohn's disease and correlate with disease activity and IL23R genotype status. Inflamm Bowel Dis. 2008; 14: 204-212.
107. Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease. Gut. 2008; 57: 1682-1689.
108. Leppkes M, Becker C, Ivanov, II, et al. RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology. 2009; 136: 257-267.
109. El-Behi M, Rostami A, Ciric B,. Current views on the roles of th1 and th17 cells in experimental autoimmune encephalomyelitis. J Neuroimmune Pharmacol. 2010 [Epub ahead of print].
110. van Beelen AJ, Zelinkova Z, Taanman-Kueter EW, et al. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity. 2007; 27: 660-669.
111. LeibundGut-Landmann S, Gross O, Robinson MJ, et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol. 2007; 8: 630-638.
112. de Vries HS, Plantinga TS, van Krieken JH, et al. Genetic association analysis of the functional c.714T>G polymorphism and mucosal expression of dectin-1 in inflammatory bowel disease. PLoS One. 2009; 4: e7818.
113. Neufert C, Becker C, Wirtz S, et al. IL-27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1. Eur J Immunol. 2007; 37: 1809-1816.
114. Pflanz S, Timans JC, Cheung J, et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4 (+) T cells. Immunity. 2002; 16: 779-790.
115. Furukawa M, Takaishi H, Takito J, et al. IL-27 abrogates receptor activator of NF-kappa B ligand-mediated osteoclastogenesis of human granulocyte-macrophage colony-forming unit cells through STAT1-dependent inhibition of c-Fos. J Immunol. 2009; 183: 2397-2406.
116. Yoshimura T, Takeda A, Hamano S, et al. Two-sided roles of IL-27: induction of Th1 differentiation on naive CD4+ T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4+ T cells partially through STAT3-dependent mechanism. J Immunol. 2006; 177: 5377-5385.
117. Yoshida H, Nakaya M, Miyazaki Y,. Interleukin 27: a double-edged sword for offense and defense. J Leukoc Biol. 2009; 86: 1295-1303.
118. Takeda A, Hamano S, Yamanaka A, et al. Cutting edge: role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment. J Immunol. 2003; 170: 4886-4890.
119. Lucas S, Ghilardi N, Li J, et al. IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc Natl Acad Sci U S A. 2003; 100: 15047-15052.
120. Murugaiyan G, Mittal A, Lopez-Diego R, et al. IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J Immunol. 2009; 183: 2435-2443.
121. Yoshida H, Yoshiyuki M,. Regulation of immune responses by interleukin-27. Immunol Rev. 2008; 226: 234-247.
122. Troy AE, Zaph C, Du Y, et al. IL-27 regulates homeostasis of the intestinal CD4+ effector T cell pool and limits intestinal inflammation in a murine model of colitis. J Immunol. 2009; 183: 2037-2044.
123. Stumhofer JS, Silver JS, Laurence A, et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol. 2007; 8: 1363-1371.
124. Pot C, Jin H, Awasthi A, et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol. 2009; 183: 797-801.
125. Yoshimoto T, Okada K, Morishima N, et al. Induction of IgG2a class switching in B cells by IL-27. J Immunol. 2004; 173: 2479-2485.
126. Feng XM, Liu N, Yang SG, et al. Regulation of the class II and class I MHC pathways in human THP-1 monocytic cells by interleukin-27. Biochem Biophys Res Commun. 2008; 367: 553-559.
127. Sanjuan MA, Dillon CP, Tait SW, et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature. 2007; 450: 1253-1257.
128. Travassos LH, Carneiro LA, Ramjeet M, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol. 2010; 11: 55-62.
129. Cooney R, Baker J, Brain O, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010; 16: 90-97.
130. Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007; 39: 207-211. (Pubitemid 46184351)
131. Parkes M, Barrett JC, Prescott NJ, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet. 2007; 39: 830-832.
132. Glas J, Konrad A, Schmechel S, et al. The ATG16L1 gene variants rs2241879 and rs2241880 (T300A) are strongly associated with susceptibility to Crohn's disease in the German population. Am J Gastroenterol. 2008; 103: 682-691.
133. Weersma RK, Zhernakova A, Nolte IM, et al. ATG16L1 and IL23R are associated with inflammatory bowel diseases but not with celiac disease in the Netherlands. Am J Gastroenterol. 2008; 103: 621-627.
134. Lacher M, Schroepf S, Ballauff A, et al. Autophagy 16-like 1 rs2241880 G allele is associated with Crohn's disease in German children. Acta Paediatr. 2009; 98: 1835-1840.
135. Van Limbergen J, Russell RK, Nimmo ER, et al. Autophagy gene ATG16L1 influences susceptibility and disease location but not childhood-onset in Crohn's disease in Northern Europe. Inflamm Bowel Dis. 2008; 14: 338-346.
136. Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008; 456: 259-263.
137. Fowler EV, Doecke J, Simms LA, et al. ATG16L1 T300A shows strong associations with disease subgroups in a large Australian IBD population: further support for significant disease heterogeneity. Am J Gastroenterol. 2008; 103: 2519-2526.
138. Greggio E, Zambrano I, Kaganovich A, et al. The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem. 2008; 283: 16906-16914.
139. Alegre-Abarrategui J, Wade-Martins R,. Parkinson disease, LRRK2 and the endocytic-autophagic pathway. Autophagy. 2009; 5: 1208-1210.
140. Palomino-Morales RJ, Oliver J, Gomez-Garcia M, et al. Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach. Genes Immun. 2009; 10: 356-364.
141. McCarroll SA, Huett A, Kuballa P, et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet. 2008; 40: 1107-1112.
142. Van Limbergen J, Russell RK, Nimmo ER, et al. Germline variants of IRGM in childhood-onset Crohn's disease. Gut. 2009; 58: 610-611.
143. Jackson MD, Denu JM,. Molecular reactions of protein phosphatases- insights from structure and chemistry. Chem Rev. 2001; 101: 2313-2340.
144. Robinson FL, Dixon JE,. Myotubularin phosphatases: policing 3-phosphoinositides. Trends Cell Biol. 2006; 16: 403-412.
145. Zhao R, Qi Y, Chen J, et al. FYVE-DSP2, a FYVE domain-containing dual specificity protein phosphatase that dephosphorylates phosphotidylinositol 3-phosphate. Exp Cell Res. 2001; 265: 329-338.
146. Obara K, Ohsumi Y,. Dynamics and function of PtdIns (3)P in autophagy. Autophagy. 2008; 4: 952-954.
147. Dove SK, Piper RC, McEwen RK, et al. Svp1p defines a family of phosphatidylinositol 3,5-bisphosphate effectors. EMBO J. 2004; 23: 1922-1933.
148. Stromhaug PE, Reggiori F, Guan J, et al. Atg21 is a phosphoinositide binding protein required for efficient lipidation and localization of Atg8 during uptake of aminopeptidase I by selective autophagy. Mol Biol Cell. 2004; 15: 3553-3566.
149. Krick R, Tolstrup J, Appelles A, et al. The relevance of the phosphatidylinositolphosphat-binding motif FRRGT of Atg18 and Atg21 for the Cvt pathway and autophagy. FEBS Lett. 2006; 580: 4632-4638.
150. Levine B, Deretic V,. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol. 2007; 7: 767-777.
151. Vidal-Taboada JM, Sanz S, Egeo A, et al. Identification and characterization of a new gene from human chromosome 21 between markers D21S343 and D21S268 encoding a leucine-rich protein. Biochem Biophys Res Commun. 1998; 250: 547-554. (Pubitemid 28484762)
152. Vidal-Taboada JM, Lu A, Pique M, et al. Down syndrome critical region gene 2: expression during mouse development and in human cell lines indicates a function related to cell proliferation. Biochem Biophys Res Commun. 2000; 272: 156-163.
153. Hirano Y, Hendil KB, Yashiroda H, et al. A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes. Nature. 2005; 437: 1381-1385.
154. Wang J, Maldonado MA,. The ubiquitin-proteasome system and its role in inflammatory and autoimmune diseases. Cell Mol Immunol. 2006; 3: 255-261.
155. Qureshi N, Vogel SN, Van Way C, 3rd, et al. The proteasome: a central regulator of inflammation and macrophage function. Immunol Res. 2005; 31: 243-260.
156. Rock KL, Gramm C, Rothstein L, et al. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell. 1994; 78: 761-771.
157. Zhang J, Bardos T, Li D, et al. Cutting edge: regulation of T cell activation threshold by CD28 costimulation through targeting Cbl-b for ubiquitination. J Immunol. 2002; 169: 2236-2240.
158. Dong X, Zhan YC, Jiang RY, et al. The potential effect of proteasome inhibitor PS-341 on severe acute pancreatitis detected by positron emission tomography in ICR mice. J Surg Res. 2009 [Epub ahead of print].
159. van der Heijden JW, Oerlemans R, Lems WF, et al. The proteasome inhibitor bortezomib inhibits the release of NFkappaB-inducible cytokines and induces apoptosis of activated T cells from rheumatoid arthritis patients. Clin Exp Rheumatol. 2009; 27: 92-98.
160. Visekruna A, Joeris T, Schmidt N, et al. Comparative expression analysis and characterization of 20S proteasomes in human intestinal tissues: The proteasome pattern as diagnostic tool for IBD patients. Inflamm Bowel Dis. 2009; 15: 526-533.
161. Petrof EO, Claud EC, Sun J, et al. Bacteria-free solution derived from Lactobacillus plantarum inhibits multiple NF-kappaB pathways and inhibits proteasome function. Inflamm Bowel Dis. 2009; 15: 1537-1547.
162. van Heel DA, Fisher SA, Kirby A, et al. Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs. Hum Mol Genet. 2004; 13: 763-770.
163. Festen EA, Stokkers PC, van Diemen CC, et al. Genetic analysis in a Dutch study sample identifies more ulcerative colitis susceptibility loci and shows their additive role in disease risk. Am J Gastroenterol. 2009; 105: 395-402.
164. Goyette P, Lefebvre C, Ng A, et al. Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal Immunol. 2008; 1: 131-138.
165. Pizarro TT, Michie MH, Bentz M, et al. IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization in intestinal mucosal cells. J Immunol. 1999; 162: 6829-6835.
166. Ten Hove T, Corbaz A, Amitai H, et al. Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-alpha production in mice. Gastroenterology. 2001; 121: 1372-1379.
167. Tremelling M, Berzuini C, Massey D, et al. Contribution of TNFSF15 gene variants to Crohn's disease susceptibility confirmed in UK population. Inflamm Bowel Dis. 2008; 14: 733-737.
168. Kakuta Y, Kinouchi Y, Negoro K, et al. Association study of TNFSF15 polymorphisms in Japanese patients with inflammatory bowel disease. Gut. 2006; 55: 1527-1528.
169. Thiebaut R, Kotti S, Jung C, et al. TNFSF15 polymorphisms are associated with susceptibility to inflammatory bowel disease in a new European cohort. Am J Gastroenterol. 2009; 104: 384-391.
170. Bamias G, Mishina M, Nyce M, et al. Role of TL1A and its receptor DR3 in two models of chronic murine ileitis. Proc Natl Acad Sci U S A. 2006; 103: 8441-8446.
171. Pappu BP, Borodovsky A, Zheng TS, et al. TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease. J Exp Med. 2008; 205: 1049-1062.
172. Amre DK, Mack DR, Morgan K, et al. Investigation of reported associations between the 20q13 and 21q22 loci and pediatric-onset Crohn's disease in Canadian children. Am J Gastroenterol. 2009; 104: 2824-2848.
173. Shi G, Wu Y, Zhang J, et al. Death decoy receptor TR6/DcR3 inhibits T cell chemotaxis in vitro and in vivo. J Immunol. 2003; 171: 3407-3414.
174. Pitti RM, Marsters SA, Lawrence DA, et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature. 1998; 396: 699-703.
175. Migone TS, Zhang J, Luo X, et al. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity. 2002; 16: 479-492.
176. Zhang J, Salcedo TW, Wan X, et al. Modulation of T-cell responses to alloantigens by TR6/DcR3. J Clin Invest. 2001; 107: 1459-1468.
177. Wan X, Zhang J, Luo H, et al. A TNF family member LIGHT transduces costimulatory signals into human T cells. J Immunol. 2002; 169: 6813-6821. (Pubitemid 36899266)
178. Shi G, Luo H, Wan X, et al. Mouse T cells receive costimulatory signals from LIGHT, a TNF family member. Blood. 2002; 100: 3279-3286. (Pubitemid 35217078)
179. Funke B, Autschbach F, Kim S, et al. Functional characterisation of decoy receptor 3 in Crohn's disease. Gut. 2009; 58: 483-491.
180. Bamias G, Siakavellas SI, Stamatelopoulos KS, et al. Circulating levels of TNF-like cytokine 1A (TL1A) and its decoy receptor 3 (DcR3) in rheumatoid arthritis. Clin Immunol. 2008; 129: 249-255.
181. Han B, Bojalil R, Amezcua-Guerra LM, et al. DcR3 as a diagnostic parameter and risk factor for systemic lupus erythematosus. Int Immunol. 2008; 20: 1067-1075.
182. Fayad R, Brand MI, Stone D, et al. Apoptosis resistance in ulcerative colitis: high expression of decoy receptors by lamina propria T cells. Eur J Immunol. 2006; 36: 2215-2222.
183. Ina K, Itoh J, Fukushima K, et al. Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. J Immunol. 1999; 163: 1081-1090.
184. Rigby WF,. Drug insight: different mechanisms of action of tumor necrosis factor antagonists-passive-aggressive behavior? Nat Clin Pract Rheumatol. 2007; 3: 227-333.
185. Di Sabatino A, Ciccocioppo R, Cinque B, et al. Defective mucosal T cell death is sustainably reverted by infliximab in a caspase dependent pathway in Crohn's disease. Gut. 2004; 53: 70-77.
186. ten Hove T, van Montfrans C, Peppelenbosch MP, et al. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease. Gut. 2002; 50: 206-211.
187. Lugering A, Schmidt M, Lugering N, et al. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway. Gastroenterology. 2001; 121: 1145-1157.
188. Sharma M, Li X, Wang Y, et al. hZimp10 is an androgen receptor co-activator and forms a complex with SUMO-1 at replication foci. EMBO J. 2003; 22: 6101-6114.
189. Gutierrez L, Zurita M, Kennison JA, et al. The Drosophila trithorax group gene tonalli (tna) interacts genetically with the Brahma remodeling complex and encodes an SP-RING finger protein. Development. 2003; 130: 343-354.
190. Lee J, Beliakoff J, Sun Z,. The novel PIAS-like protein hZimp10 is a transcriptional co-activator of the p53 tumor suppressor. Nucleic Acids Res. 2007; 35: 4523-4534.
191. Beliakoff J, Lee J, Ueno H, et al. The PIAS-like protein Zimp10 is essential for embryonic viability and proper vascular development. Mol Cell Biol. 2008; 28: 282-292.
192. Li X, Thyssen G, Beliakoff J, et al. The novel PIAS-like protein hZimp10 enhances Smad transcriptional activity. J Biol Chem. 2006; 281: 23748-23756.
193. Heldin CH, Miyazono K, ten Dijke P,. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997; 390: 465-571.
194. Monteleone G, Boirivant M, Pallone F, et al. TGF-beta1 and Smad7 in the regulation of IBD. Mucosal Immunol. 2008; 1 (suppl 1): S50-53.
195. Yang X, Letterio JJ, Lechleider RJ, et al. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J. 1999; 18: 1280-1291.
196. Owen CR, Yuan L, Basson MD,. Smad3 knockout mice exhibit impaired intestinal mucosal healing. Lab Invest. 2008; 88: 1101-1109.
197. Monteleone G, Kumberova A, Croft NM, et al. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest. 2001; 108: 601-69.
198. Fantini MC, Rizzo A, Fina D, et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology. 2009; 136: 1308-1316, e1-3.
199. Lutz MB, Kurts C,. Induction of peripheral CD4+ T-cell tolerance and CD8+ T-cell cross-tolerance by dendritic cells. Eur J Immunol. 2009; 39: 2325-2330.
200. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008; 134: 743-756.
201. Hetz C, Glimcher LH,. Fine-tuning of the unfolded protein response: Assembling the IRE1alpha interactome. Mol Cell. 2009; 35: 551-561.
202. Todd DJ, Lee AH, Glimcher LH,. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol. 2008; 8: 663-674.
203. Zhang K, Kaufman RJ,. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008; 454: 455-462.
204. Kaser A, Blumberg RS,. Endoplasmic reticulum stress and intestinal inflammation. Mucosal Immunol. 2010; 3: 11-16.
205. Harding HP, Zhang Y, Zeng H, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003; 11: 619-633.
206. Shkoda A, Ruiz PA, Daniel H, et al. Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology. 2007; 132: 190-207.
207. Brandl K, Rutschmann S, Li X, et al. Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response. Proc Natl Acad Sci U S A. 2009; 106: 3300-3305.
208. Heazlewood CK, Cook MC, Eri R, et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 2008; 5: e54.
209. Hjelmqvist L, Tuson M, Marfany G, et al. ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol. 2002; 3: RESEARCH0027.
210. Cantero-Recasens G, Fandos C, Rubio-Moscardo F, et al. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum Mol Genet. 2010; 19: 111-121.
211. Sorimachi H, Suzuki K,. The structure of calpain. J Biochem. 2001; 129: 653-664.
212. Horikawa Y, Oda N, Cox NJ, et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet. 2000; 26: 163-175.
213. Suzuki K, Hata S, Kawabata Y, et al. Structure, activation, and biology of calpain. Diabetes. 2004; 53 (suppl 1): S12-18.
214. Huang Y, Wang KK,. The calpain family and human disease. Trends Mol Med. 2001; 7: 355-362.
215. Frayling TM,. Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev Genet. 2007; 8: 657-662.
216. Gonzalez A, Abril E, Roca A, et al. Comment: CAPN10 alleles are associated with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002; 87: 3971-3976.
217. Daimon M, Oizumi T, Saitoh T, et al. Calpain 10 gene polymorphisms are related, not to type 2 diabetes, but to increased serum cholesterol in Japanese. Diabetes Res Clin Pract. 2002; 56: 147-152.
218. Frances CP, Conde MC, Saez ME, et al. Identification of a protective haplogenotype within CAPN10 gene influencing colorectal cancer susceptibility. J Gastroenterol Hepatol. 2007; 22: 2298-2302.
219. Santella L, Kyozuka K, De Riso L, et al. Calcium, protease action, and the regulation of the cell cycle. Cell Calcium. 1998; 23: 123-130.
220. Wang KK,. Calpain and caspase: can you tell the difference? Trends Neurosci. 2000; 23: 20-26.
221. Arrington DD, Schnellmann RG,. Targeting of the molecular chaperone oxygen-regulated protein 150 (ORP150) to mitochondria and its induction by cellular stress. Am J Physiol Cell Physiol. 2008; 294: C641-650.
222. Zhao L, Rosales C, Seburn K, et al. Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjogren syndrome. Hum Mol Genet. 2010; 19: 25-35.
223. Weitzmann A, Volkmer J, Zimmermann R,. The nucleotide exchange factor activity of Grp170 may explain the non-lethal phenotype of loss of Sil1 function in man and mouse. FEBS Lett. 2006; 580: 5237-5240.
224. Tagawa Y, Hiramatsu N, Kasai A, et al. Induction of apoptosis by cigarette smoke via ROS-dependent endoplasmic reticulum stress and CCAAT/enhancer-binding protein-homologous protein (CHOP). Free Radic Biol Med. 2008; 45: 50-59.