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KEGG   PATHWAY: hsa05321
hsa05321                    Pathway                                
Inflammatory bowel disease - Homo sapiens (human)
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.
Human Diseases; Immune disease
Pathway map
hsa05321  Inflammatory bowel disease

H01227  Inflammatory bowel disease (IBD)
D02597  Adalimumab (USAN/INN)
D02598  Infliximab (USAN/INN)
D04358  Golimumab (USAN/INN)
Homo sapiens (human) [GN:hsa]
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]
Melmed GY, Targan SR
Future biologic targets for IBD: potentials and pitfalls.
Nat Rev Gastroenterol Hepatol 7:110-7 (2010)
Shih DQ, Targan SR
Immunopathogenesis of inflammatory bowel disease.
World J Gastroenterol 14:390-400 (2008)
Baumgart DC, Carding SR
Inflammatory bowel disease: cause and immunobiology.
Lancet 369:1627-40 (2007)
Strober W, Murray PJ, Kitani A, Watanabe T
Signalling pathways and molecular interactions of NOD1 and NOD2.
Nat Rev Immunol 6:9-20 (2006)
Matricon J, Barnich N, Ardid D
Immunopathogenesis of inflammatory bowel disease.
Self Nonself 1:299-309 (2010)
Agnello D, Lankford CS, Bream J, Morinobu A, Gadina M, O'Shea JJ, Frucht DM
Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights.
J Clin Immunol 23:147-61 (2003)
Glimcher LH, Murphy KM
Lineage commitment in the immune system: the T helper lymphocyte grows up.
Genes Dev 14:1693-711 (2000)
Neurath MF, Finotto S, Glimcher LH
The role of Th1/Th2 polarization in mucosal immunity.
Nat Med 8:567-73 (2002)
Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, Murphy TL, Murphy KM
T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells.
Nat Immunol 3:549-57 (2002)
Sartor RB
Microbial influences in inflammatory bowel diseases.
Gastroenterology 134:577-94 (2008)
Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, Akira S, Nakanishi K
IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production.
J Immunol 161:3400-7 (1998)
Hur SJ, Kang SH, Jung HS, Kim SC, Jeon HS, Kim IH, Lee JD
Review of natural products actions on cytokines in inflammatory bowel disease.
Nutr Res 32:801-16 (2012)
Bettelli E, Korn T, Oukka M, Kuchroo VK
Induction and effector functions of T(H)17 cells.
Nature 453:1051-7 (2008)
Ivanov II, Zhou L, Littman DR
Transcriptional regulation of Th17 cell differentiation.
Semin Immunol 19:409-17 (2007)
Di Cesare A, Di Meglio P, Nestle FO
The IL-23/Th17 axis in the immunopathogenesis of psoriasis.
J Invest Dermatol 129:1339-50 (2009)
Jetten AM
Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism.
Nucl Recept Signal 7:e003 (2009)
Bene L, Falus A, Baffy N, Fulop AK
Cellular and molecular mechanisms in the two major forms of inflammatory bowel disease.
Pathol Oncol Res 17:463-72 (2011)
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

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