KEGG   PATHWAY: mlk04659
Entry
mlk04659                    Pathway                                
Name
Th17 cell differentiation - Mustela lutreola (European mink)
Description
Interleukin (IL)-17-producing helper T (Th17) cells serve as a subset of CD4+ T cells involved in epithelial cell- and neutrophil mediated immune responses against extracellular microbes and in the pathogenesis of autoimmune diseases. In vivo, Th17 differentiation requires antigen presentation and co-stimulation, and activation of antigen presenting-cells (APCs) to produce TGF-beta, IL-6, IL-1, IL-23 and IL-21. This initial activation results in the activation and up-regulation of STAT3, ROR(gamma)t and other transcriptional factors in CD4+ T cells, which bind to the promoter regions of the IL-17, IL-21 and IL-22 genes and induce IL-17, IL-21 and IL-22. In contrast, the differentiation of Th17 cells and their IL-17 expression are negatively regulated by IL-2, Th2 cytokine IL-4, IL-27 and Th1 cytokine IFN-gamma through STAT5, STAT6 and STAT1 activation, respectively. Retinoid acid and the combination of IL-2 and TGF-beta upregulate Foxp3, which also downregulates cytokines like IL-17 and IL-21. The inhibition of Th17 differentiation may serve as a protective strategy to 'fine-tune' the expression IL-17 so it does not cause excessive inflammation. Thus, balanced differentiation of Th cells is crucial for immunity and host protection.
Class
Organismal Systems; Immune system
Pathway map
mlk04659  Th17 cell differentiation
mlk04659

Other DBs
GO: 0072539
Organism
Mustela lutreola (European mink) [GN:mlk]
Gene
131840429  IL1B; interleukin-1 beta [KO:K04519]
131808468  IL1R1; interleukin-1 receptor type 1 isoform X1 [KO:K04386]
131824725  IL1RAP; interleukin-1 receptor accessory protein isoform X1 [KO:K04723]
131839655  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
131839656  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
131834189  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
131834191  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
131810411  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
131834436  IRF4; interferon regulatory factor 4 isoform X1 [KO:K09445]
131807884  LOW QUALITY PROTEIN: interferon regulatory factor 4-like [KO:K09445]
131817494  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
131812377  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
131824456  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
131811852  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
131835965  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
131810886  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
131828323  IL21; interleukin-21 [KO:K05434]
131819636  IL21R; interleukin-21 receptor isoform X1 [KO:K05075]
131821377  IL2RG; cytokine receptor common subunit gamma [KO:K05070]
131809752  JAK1; tyrosine-protein kinase JAK1 isoform X1 [KO:K11217] [EC:2.7.10.2]
131823743  JAK3; tyrosine-protein kinase JAK3 isoform X1 [KO:K11218] [EC:2.7.10.2]
131829493  IL6; interleukin-6 [KO:K05405]
131814287  IL6R; interleukin-6 receptor subunit alpha isoform X1 [KO:K05055]
131832243  IL6ST; interleukin-6 receptor subunit beta isoform X1 [KO:K05060]
131813137  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
131838601  IL23A; interleukin-23 subunit alpha isoform X1 [KO:K05426]
131810176  IL23R; interleukin-23 receptor [KO:K05065]
131823752  IL12RB1; interleukin-12 receptor subunit beta-1 [KO:K05063]
131823516  TYK2; non-receptor tyrosine-protein kinase TYK2 isoform X1 [KO:K11219] [EC:2.7.10.2]
131816590  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
131810420  RORC; nuclear receptor ROR-gamma isoform X1 [KO:K08534]
131835882  RORA; nuclear receptor ROR-alpha isoform X1 [KO:K08532]
131836655  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
131837003  HSP90AA1; heat shock protein HSP 90-alpha [KO:K04079]
131834029  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
131827404  LOW QUALITY PROTEIN: heat shock protein HSP 90-alpha-like [KO:K04079]
131832553  LOW QUALITY PROTEIN: heat shock protein HSP 90-alpha-like [KO:K04079]
131829466  AHR; aryl hydrocarbon receptor [KO:K09093]
131833211  IL17A; interleukin-17A [KO:K05489]
131833213  IL17F; interleukin-17F [KO:K05494]
131837980  IL22; interleukin-22 [KO:K05445]
131834264  HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
131834265  HLA class II histocompatibility antigen, DO alpha chain isoform X1 [KO:K06752]
131834269  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
131834270  HLA class II histocompatibility antigen, DM beta chain isoform X1 [KO:K06752]
131834274  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
131834279  HLA class II histocompatibility antigen, DQ beta 2 chain-like isoform X1 [KO:K06752]
131834280  HLA class II histocompatibility antigen, DQ beta 1 chain-like isoform X1 [KO:K06752]
131834281  HLA class II histocompatibility antigen, DQ alpha 2 chain-like [KO:K06752]
131834282  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
131834285  DLA class II histocompatibility antigen, DR-1 beta chain-like isoform X1 [KO:K06752]
131834286  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
131834287  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
131830546  LOW QUALITY PROTEIN: SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
131833234  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP alpha 1 chain [KO:K06752]
131838466  CD4; T-cell surface glycoprotein CD4 isoform X1 [KO:K06454]
131809629  LCK; tyrosine-protein kinase Lck [KO:K05856] [EC:2.7.10.2]
131836598  T-cell surface glycoprotein CD3 epsilon chain isoform X1 [KO:K06451]
131836608  T-cell surface glycoprotein CD3 gamma chain [KO:K06452]
131814729  CD247; T-cell surface glycoprotein CD3 zeta chain isoform X1 [KO:K06453]
131836621  T-cell surface glycoprotein CD3 delta chain [KO:K06450]
131808568  tyrosine-protein kinase ZAP-70 isoform X1 [KO:K07360] [EC:2.7.10.2]
131819447  LAT; LOW QUALITY PROTEIN: linker for activation of T-cells family member 1 [KO:K07362]
131807620  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
131834170  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
131828824  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
131829901  PPP3CA; protein phosphatase 3 catalytic subunit alpha isoform X1 [KO:K04348] [EC:3.1.3.16]
131812695  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
131810821  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X1 [KO:K04446]
131807426  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332]
131838931  LOW QUALITY PROTEIN: nuclear factor of activated T-cells, cytoplasmic 3-like [KO:K17333]
131818512  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X1 [KO:K17333]
131838071  PRKCQ; protein kinase C theta type isoform X1 [KO:K18052] [EC:2.7.11.13]
131828549  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
131820342  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
131822182  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
131836470  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
131817751  NFKBIB; NF-kappa-B inhibitor beta isoform X1 [KO:K02581]
131834033  NFKBIE; NF-kappa-B inhibitor epsilon [KO:K05872]
131829855  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
131815578  RELA; transcription factor p65 [KO:K04735]
131811758  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
131820131  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
131836857  FOS; protein c-Fos [KO:K04379]
131828723  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
131831160  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
131832665  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
131809019  JUN; transcription factor Jun [KO:K04448]
131831369  IL4; interleukin-4 [KO:K05430]
131819330  IL4R; interleukin-4 receptor subunit alpha isoform X1 [KO:K05071]
131838572  STAT6; signal transducer and activator of transcription 6 [KO:K11225]
131838088  GATA3; trans-acting T-cell-specific transcription factor GATA-3 isoform X1 [KO:K17895]
131825345  RUNX1; runt-related transcription factor 1 isoform X1 [KO:K08367]
131819319  IL27; interleukin-27 subunit alpha [KO:K22629]
131823317  EBI3; interleukin-27 subunit beta isoform X1 [KO:K24476]
131823629  IL27RA; interleukin-27 receptor subunit alpha isoform X1 [KO:K19598]
131839127  IFNG; interferon gamma [KO:K04687]
131833755  IFNGR1; interferon gamma receptor 1 [KO:K05132]
131825325  IFNGR2; interferon gamma receptor 2 isoform X1 [KO:K05133]
131827656  STAT1; signal transducer and activator of transcription 1-alpha/beta isoform X1 [KO:K11220]
131816477  TBX21; T-box transcription factor TBX21 isoform X1 [KO:K10166]
131828386  IL2; interleukin-2 [KO:K05429]
131838068  IL2RA; interleukin-2 receptor subunit alpha isoform X1 [KO:K05068]
131839436  IL2RB; interleukin-2 receptor subunit beta isoform X1 [KO:K05069]
131816588  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
131815766  signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
131821230  FOXP3; forkhead box protein P3 isoform X1 [KO:K10163]
131816638  RARA; retinoic acid receptor alpha isoform X1 [KO:K08527]
131813243  RXRA; retinoic acid receptor RXR-alpha isoform X1 [KO:K08524]
131834260  RXRB; retinoic acid receptor RXR-beta isoform X1 [KO:K08525]
131815099  RXRG; retinoic acid receptor RXR-gamma isoform X1 [KO:K08526]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C00777  Retinoate
C01245  D-myo-Inositol 1,4,5-trisphosphate
Reference
PMID:23325835
  Authors
Muranski P, Restifo NP
  Title
Essentials of Th17 cell commitment and plasticity.
  Journal
Blood 121:2402-14 (2013)
DOI:10.1182/blood-2012-09-378653
Reference
PMID:19379825
  Authors
O'Shea JJ, Steward-Tharp SM, Laurence A, Watford WT, Wei L, Adamson AS, Fan S
  Title
Signal transduction and Th17 cell differentiation.
  Journal
Microbes Infect 11:599-611 (2009)
DOI:10.1016/j.micinf.2009.04.007
Reference
PMID:21084214
  Authors
Hirahara K, Ghoreschi K, Laurence A, Yang XP, Kanno Y, O'Shea JJ
  Title
Signal transduction pathways and transcriptional regulation in Th17 cell differentiation.
  Journal
Cytokine Growth Factor Rev 21:425-34 (2010)
DOI:10.1016/j.cytogfr.2010.10.006
Reference
PMID:18166487
  Authors
Chen Z, Laurence A, O'Shea JJ
  Title
Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation.
  Journal
Semin Immunol 19:400-8 (2007)
DOI:10.1016/j.smim.2007.10.015
Reference
PMID:22640807
  Authors
Maddur MS, Miossec P, Kaveri SV, Bayry J
  Title
Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies.
  Journal
Am J Pathol 181:8-18 (2012)
DOI:10.1016/j.ajpath.2012.03.044
Reference
PMID:23036716
  Authors
Hemdan NY, Birkenmeier G, Wichmann G
  Title
Key molecules in the differentiation and commitment program of T helper 17 (Th17) cells up-to-date.
  Journal
Immunol Lett 148:97-109 (2012)
DOI:10.1016/j.imlet.2012.09.007
Reference
PMID:18408735
  Authors
Dong C
  Title
TH17 cells in development: an updated view of their molecular identity and genetic programming.
  Journal
Nat Rev Immunol 8:337-48 (2008)
DOI:10.1038/nri2295
Reference
PMID:20054607
  Authors
Torchinsky MB, Blander JM
  Title
T helper 17 cells: discovery, function, and physiological trigger.
  Journal
Cell Mol Life Sci 67:1407-21 (2010)
DOI:10.1007/s00018-009-0248-3
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:22133865
  Authors
Oestreich KJ, Weinmann AS
  Title
T-bet employs diverse regulatory mechanisms to repress transcription.
  Journal
Trends Immunol 33:78-83 (2012)
DOI:10.1016/j.it.2011.10.005
Reference
PMID:24325586
  Authors
Manni ML, Robinson KM, Alcorn JF
  Title
A tale of two cytokines: IL-17 and IL-22 in asthma and infection.
  Journal
Expert Rev Respir Med 8:25-42 (2014)
DOI:10.1586/17476348.2014.854167
Reference
PMID:21776333
  Authors
Sha Y, Markovic-Plese S
  Title
A role of IL-1R1 signaling in the differentiation of Th17 cells and the development of autoimmune diseases.
  Journal
Self Nonself 2:35-42 (2011)
DOI:10.4161/self.2.1.15639
Reference
PMID:20488727
  Authors
Nakayama T, Yamashita M
  Title
The TCR-mediated signaling pathways that control the direction of helper T cell differentiation.
  Journal
Semin Immunol 22:303-9 (2010)
DOI:10.1016/j.smim.2010.04.010
Reference
PMID:21151104
  Authors
Lazarevic V, Chen X, Shim JH, Hwang ES, Jang E, Bolm AN, Oukka M, Kuchroo VK, Glimcher LH
  Title
T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORgammat.
  Journal
Nat Immunol 12:96-104 (2011)
DOI:10.1038/ni.1969
Reference
PMID:22754770
  Authors
Pan F, Barbi J, Pardoll DM
  Title
Hypoxia-inducible factor 1: A link between metabolism and T cell differentiation and a potential therapeutic target.
  Journal
Oncoimmunology 1:510-515 (2012)
DOI:10.4161/onci.19457
Reference
PMID:18362914
  Authors
Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B
  Title
The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins.
  Journal
Nature 453:106-9 (2008)
DOI:10.1038/nature06881
Reference
PMID:17768419
  Authors
Deenick EK, Tangye SG
  Title
Autoimmunity: IL-21: a new player in Th17-cell differentiation.
  Journal
Immunol Cell Biol 85:503-5 (2007)
DOI:10.1038/sj.icb.7100114
Reference
PMID:26253381
  Authors
Meka RR, Venkatesha SH, Dudics S, Acharya B, Moudgil KD
  Title
IL-27-induced modulation of autoimmunity and its therapeutic potential.
  Journal
Autoimmun Rev 14:1131-41 (2015)
DOI:10.1016/j.autrev.2015.08.001
Reference
PMID:16200068
  Authors
Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C
  Title
A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
  Journal
Nat Immunol 6:1133-41 (2005)
DOI:10.1038/ni1261
Reference
PMID:22324470
  Authors
Zhu S, Qian Y
  Title
IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential.
  Journal
Clin Sci (Lond) 122:487-511 (2012)
DOI:10.1042/CS20110496
Related
pathway
mlk04010  MAPK signaling pathway
mlk04020  Calcium signaling pathway
mlk04064  NF-kappa B signaling pathway
mlk04066  HIF-1 signaling pathway
mlk04350  TGF-beta signaling pathway
mlk04514  Cell adhesion molecules
mlk04620  Toll-like receptor signaling pathway
mlk04630  JAK-STAT signaling pathway
mlk04660  T cell receptor signaling pathway
mlk05321  Inflammatory bowel disease
mlk05323  Rheumatoid arthritis
KO pathway
ko04659   
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