KEGG   PATHWAY: hsa05321
Entry
hsa05321                    Pathway                                
Name
Inflammatory bowel disease - Homo sapiens (human)
Description
Inflammatory bowel disease (IBD), which includes Crohn disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract due to environmental and genetic factors, infectious microbes, and the dysregulated immune system. Although many environmental factors (for example, geographic locations, smoking, etc.) affect the development of IBD, the most crucial might be the luminal (external) environment of the epithelial cells. There are pathogens that are found in increasing frequency in IBD. The microbial components such as flagellin, peptidoglycan, and lipopolysaccharide are recognized by receptors such as toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) proteins, and also by antigen-presenting cells (APCs) in genetically susceptible host. The TLR recognition triggers the activation of NF-kappaB, leading to an inflammatory response. APC-expressed gene NOD2 has been associated with Crohn disease. In case of mutations of NOD2, negative regulation of IL-12 production is reduced with the stimulation of muramyl dipeptide (MDP), leading to CD. In addition, the APC mediates the differentiation of naive T cells into effector T cells (Th1, Th17, Th2) and natural killer T (NKT) cells. Th1 and Th17 cells produce high levels of IFN-gamma and IL-17, -22, respectively, both of which promote CD. In contrast, Th2 cells produce IL-4, -5, -10, which together with IL-13 from NKT induce UC.
Class
Human Diseases; Immune disease
Pathway map
hsa05321  Inflammatory bowel disease
hsa05321

Disease
H01227  Inflammatory bowel disease (IBD)
Drug
D02597  Adalimumab (USAN/INN)
D02598  Infliximab (USAN/INN)
D04358  Golimumab (USAN/INN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
7097  TLR2; toll like receptor 2 [KO:K10159]
7099  TLR4; toll like receptor 4 [KO:K10160]
7100  TLR5; toll like receptor 5 [KO:K10168]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
64127  NOD2; nucleotide binding oligomerization domain containing 2 [KO:K10165]
3108  HLA-DMA; major histocompatibility complex, class II, DM alpha [KO:K06752]
3109  HLA-DMB; major histocompatibility complex, class II, DM beta [KO:K06752]
3111  HLA-DOA; major histocompatibility complex, class II, DO alpha [KO:K06752]
3112  HLA-DOB; major histocompatibility complex, class II, DO beta [KO:K06752]
3113  HLA-DPA1; major histocompatibility complex, class II, DP alpha 1 [KO:K06752]
3115  HLA-DPB1; major histocompatibility complex, class II, DP beta 1 [KO:K06752]
3117  HLA-DQA1; major histocompatibility complex, class II, DQ alpha 1 [KO:K06752]
3118  HLA-DQA2; major histocompatibility complex, class II, DQ alpha 2 [KO:K06752]
3119  HLA-DQB1; major histocompatibility complex, class II, DQ beta 1 [KO:K06752]
3122  HLA-DRA; major histocompatibility complex, class II, DR alpha [KO:K06752]
3123  HLA-DRB1; major histocompatibility complex, class II, DR beta 1 [KO:K06752]
3125  HLA-DRB3; major histocompatibility complex, class II, DR beta 3 [KO:K06752]
3126  HLA-DRB4; major histocompatibility complex, class II, DR beta 4 [KO:K06752]
3127  HLA-DRB5; major histocompatibility complex, class II, DR beta 5 [KO:K06752]
3458  IFNG; interferon gamma [KO:K04687]
3459  IFNGR1; interferon gamma receptor 1 [KO:K05132]
3460  IFNGR2; interferon gamma receptor 2 [KO:K05133]
6772  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
30009  TBX21; T-box transcription factor 21 [KO:K10166]
3565  IL4; interleukin 4 [KO:K05430]
3567  IL5; interleukin 5 [KO:K05428]
3592  IL12A; interleukin 12A [KO:K05406]
3593  IL12B; interleukin 12B [KO:K05425]
3595  IL12RB2; interleukin 12 receptor subunit beta 2 [KO:K05064]
3594  IL12RB1; interleukin 12 receptor subunit beta 1 [KO:K05063]
6775  STAT4; signal transducer and activator of transcription 4 [KO:K11222]
3558  IL2; interleukin 2 [KO:K05429]
3606  IL18; interleukin 18 [KO:K05482]
8809  IL18R1; interleukin 18 receptor 1 [KO:K05173]
8807  IL18RAP; interleukin 18 receptor accessory protein [KO:K05174]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
7124  TNF; tumor necrosis factor [KO:K03156]
3569  IL6; interleukin 6 [KO:K05405]
3552  IL1A; interleukin 1 alpha [KO:K04383]
3553  IL1B; interleukin 1 beta [KO:K04519]
7040  TGFB1; transforming growth factor beta 1 [KO:K13375]
7042  TGFB2; transforming growth factor beta 2 [KO:K13376]
7043  TGFB3; transforming growth factor beta 3 [KO:K13377]
4087  SMAD2; SMAD family member 2 [KO:K04500]
4088  SMAD3; SMAD family member 3 [KO:K23605]
6774  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
59067  IL21; interleukin 21 [KO:K05434]
50615  IL21R; interleukin 21 receptor [KO:K05075]
51561  IL23A; interleukin 23 subunit alpha [KO:K05426]
149233  IL23R; interleukin 23 receptor [KO:K05065]
6097  RORC; RAR related orphan receptor C [KO:K08534]
6095  RORA; RAR related orphan receptor A [KO:K08532]
50943  FOXP3; forkhead box P3 [KO:K10163]
3605  IL17A; interleukin 17A [KO:K05489]
112744  IL17F; interleukin 17F [KO:K05494]
50616  IL22; interleukin 22 [KO:K05445]
3566  IL4R; interleukin 4 receptor [KO:K05071]
3561  IL2RG; interleukin 2 receptor subunit gamma [KO:K05070]
6778  STAT6; signal transducer and activator of transcription 6 [KO:K11225]
2625  GATA3; GATA binding protein 3 [KO:K17895]
3586  IL10; interleukin 10 [KO:K05443]
3596  IL13; interleukin 13 [KO:K05435]
4094  MAF; MAF bZIP transcription factor [KO:K09035]
4772  NFATC1; nuclear factor of activated T cells 1 [KO:K04446]
Reference
PMID:20134493
  Authors
Melmed GY, Targan SR
  Title
Future biologic targets for IBD: potentials and pitfalls.
  Journal
Nat Rev Gastroenterol Hepatol 7:110-7 (2010)
DOI:10.1038/nrgastro.2009.218
Reference
PMID:18200661
  Authors
Shih DQ, Targan SR
  Title
Immunopathogenesis of inflammatory bowel disease.
  Journal
World J Gastroenterol 14:390-400 (2008)
DOI:10.3748/wjg.14.390
Reference
PMID:17499605
  Authors
Baumgart DC, Carding SR
  Title
Inflammatory bowel disease: cause and immunobiology.
  Journal
Lancet 369:1627-40 (2007)
DOI:10.1016/S0140-6736(07)60750-8
Reference
PMID:16493424
  Authors
Strober W, Murray PJ, Kitani A, Watanabe T
  Title
Signalling pathways and molecular interactions of NOD1 and NOD2.
  Journal
Nat Rev Immunol 6:9-20 (2006)
DOI:10.1038/nri1747
Reference
PMID:21487504
  Authors
Matricon J, Barnich N, Ardid D
  Title
Immunopathogenesis of inflammatory bowel disease.
  Journal
Self Nonself 1:299-309 (2010)
DOI:10.4161/self.1.4.13560
Reference
PMID:12797537
  Authors
Agnello D, Lankford CS, Bream J, Morinobu A, Gadina M, O'Shea JJ, Frucht DM
  Title
Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights.
  Journal
J Clin Immunol 23:147-61 (2003)
DOI:10.1023/A:1023381027062
Reference
PMID:10898785
  Authors
Glimcher LH, Murphy KM
  Title
Lineage commitment in the immune system: the T helper lymphocyte grows up.
  Journal
Genes Dev 14:1693-711 (2000)
DOI:10.1101/gad.14.14.1693
Reference
PMID:12042806
  Authors
Neurath MF, Finotto S, Glimcher LH
  Title
The role of Th1/Th2 polarization in mucosal immunity.
  Journal
Nat Med 8:567-73 (2002)
DOI:10.1038/nm0602-567
Reference
PMID:12006974
  Authors
Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, Murphy TL, Murphy KM
  Title
T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells.
  Journal
Nat Immunol 3:549-57 (2002)
DOI:10.1038/ni794
Reference
PMID:18242222
  Authors
Sartor RB
  Title
Microbial influences in inflammatory bowel diseases.
  Journal
Gastroenterology 134:577-94 (2008)
DOI:10.1053/j.gastro.2007.11.059
Reference
PMID:9759857
  Authors
Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, Akira S, Nakanishi K
  Title
IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production.
  Journal
J Immunol 161:3400-7 (1998)
Reference
PMID:23176791
  Authors
Hur SJ, Kang SH, Jung HS, Kim SC, Jeon HS, Kim IH, Lee JD
  Title
Review of natural products actions on cytokines in inflammatory bowel disease.
  Journal
Nutr Res 32:801-16 (2012)
DOI:10.1016/j.nutres.2012.09.013
Reference
PMID:18563156
  Authors
Bettelli E, Korn T, Oukka M, Kuchroo VK
  Title
Induction and effector functions of T(H)17 cells.
  Journal
Nature 453:1051-7 (2008)
DOI:10.1038/nature07036
Reference
PMID:18053739
  Authors
Ivanov II, Zhou L, Littman DR
  Title
Transcriptional regulation of Th17 cell differentiation.
  Journal
Semin Immunol 19:409-17 (2007)
DOI:10.1016/j.smim.2007.10.011
Reference
PMID:19322214
  Authors
Di Cesare A, Di Meglio P, Nestle FO
  Title
The IL-23/Th17 axis in the immunopathogenesis of psoriasis.
  Journal
J Invest Dermatol 129:1339-50 (2009)
DOI:10.1038/jid.2009.59
Reference
PMID:19381306
  Authors
Jetten AM
  Title
Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism.
  Journal
Nucl Recept Signal 7:e003 (2009)
DOI:10.1621/nrs.07003
Reference
PMID:21681604
  Authors
Bene L, Falus A, Baffy N, Fulop AK
  Title
Cellular and molecular mechanisms in the two major forms of inflammatory bowel disease.
  Journal
Pathol Oncol Res 17:463-72 (2011)
DOI:10.1007/s12253-011-9397-4
Related
pathway
hsa04060  Cytokine-cytokine receptor interaction
hsa04612  Antigen processing and presentation
hsa04620  Toll-like receptor signaling pathway
hsa04621  NOD-like receptor signaling pathway
hsa04630  JAK-STAT signaling pathway
hsa04659  Th17 cell differentiation
hsa04660  T cell receptor signaling pathway
KO pathway
ko05321   
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