KEGG   PATHWAY: uah05321
Entry
uah05321                    Pathway                                

Name
Inflammatory bowel disease (IBD) - Ursus arctos horribilis
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
uah05321  Inflammatory bowel disease (IBD)
uah05321

Organism
Ursus arctos horribilis [GN:uah]
Gene
113255769  TLR2; toll-like receptor 2 [KO:K10159]
113266343  TLR4; toll-like receptor 4 [KO:K10160]
113262895  TLR5; toll-like receptor 5 isoform X1 [KO:K10168]
113263101  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
113244102  RELA; transcription factor p65 [KO:K04735]
113252225  NOD2; nucleotide-binding oligomerization domain-containing protein 2 isoform X1 [KO:K10165]
113243684  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP alpha 1 chain-like [KO:K06752]
113243685  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
113243774  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
113243775  DLA class II histocompatibility antigen, DR-1 beta chain [KO:K06752]
113243776  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
113243777  HLA class II histocompatibility antigen, DQ beta 1 chain-like [KO:K06752]
113243778  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
113243779  HLA class II histocompatibility antigen, DO beta chain isoform X1 [KO:K06752]
113243784  HLA class II histocompatibility antigen, DM beta chain isoform X1 [KO:K06752]
113243786  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
113243788  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
113265359  uncharacterized protein LOC113265359 [KO:K10785]
113256304  IFNG; interferon gamma [KO:K04687]
113259485  IFNGR1; interferon gamma receptor 1 [KO:K05132]
113264675  IFNGR2; interferon gamma receptor 2 [KO:K05133]
113250654  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
113265555  TBX21; T-box transcription factor TBX21 [KO:K10166]
113261716  IL4; interleukin-4 [KO:K05430]
113261714  IL5; interleukin-5 [KO:K05428]
113254130  IL12A; interleukin-12 subunit alpha [KO:K05406]
113263879  IL12B; interleukin-12 subunit beta [KO:K05425]
113254551  IL12RB2; interleukin-12 receptor subunit beta-2 [KO:K05064]
113256701  IL12RB1; interleukin-12 receptor subunit beta-1 isoform X1 [KO:K05063]
113250651  STAT4; signal transducer and activator of transcription 4 [KO:K11222]
113255635  IL2; interleukin-2 [KO:K05429]
113260053  IL18; interleukin-18 [KO:K05482]
113247412  IL18R1; interleukin-18 receptor 1 isoform X1 [KO:K05173]
113247431  IL18RAP; interleukin-18 receptor accessory protein isoform X1 [KO:K05174]
113254611  JUN; transcription factor AP-1 [KO:K04448]
113243711  TNF; tumor necrosis factor [KO:K03156]
113261280  IL6; interleukin-6 [KO:K05405]
113268160  IL1A; interleukin-1 alpha [KO:K04383]
113242506  IL1B; interleukin-1 beta [KO:K04519]
113243540  TGFB1; transforming growth factor beta-1 isoform X1 [KO:K13375]
113268733  TGFB2; transforming growth factor beta-2 isoform X1 [KO:K13376]
113270312  TGFB3; transforming growth factor beta-3 [KO:K13377]
113253394  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
113240893  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
113265422  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
113255465  IL21; interleukin-21 [KO:K05434]
113267611  IL21R; interleukin-21 receptor [KO:K05075]
113256421  IL23A; interleukin-23 subunit alpha [KO:K05426]
113254554  IL23R; interleukin-23 receptor [KO:K05065]
113246193  RORC; nuclear receptor ROR-gamma isoform X1 [KO:K08534]
113269696  RORA; nuclear receptor ROR-alpha isoform X1 [KO:K08532]
113265955  FOXP3; forkhead box protein P3 isoform X1 [KO:K10163]
113261362  IL17A; interleukin-17A [KO:K05489]
113261197  IL17F; interleukin-17F isoform X1 [KO:K05494]
113255914  IL22; interleukin-22 [KO:K05445]
113267608  IL4R; interleukin-4 receptor subunit alpha isoform X1 [KO:K05071]
113245610  IL2RG; cytokine receptor common subunit gamma isoform X1 [KO:K05070]
113256394  STAT6; signal transducer and activator of transcription 6 isoform X1 [KO:K11225]
113241157  GATA3; trans-acting T-cell-specific transcription factor GATA-3 isoform X1 [KO:K17895]
113242596  IL10; interleukin-10 [KO:K05443]
113261717  IL13; interleukin-13 [KO:K05435]
113251743  MAF; transcription factor Maf [KO:K09035]
113253544  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X1 [KO:K04446]
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
uah04060  Cytokine-cytokine receptor interaction
uah04612  Antigen processing and presentation
uah04620  Toll-like receptor signaling pathway
uah04621  NOD-like receptor signaling pathway
uah04630  JAK-STAT signaling pathway
uah04659  Th17 cell differentiation
uah04660  T cell receptor signaling pathway
KO pathway
ko05321   
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