KEGG   PATHWAY: pcoo04659
Entry
pcoo04659                   Pathway                                
Name
Th17 cell differentiation - Puma concolor (puma)
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
pcoo04659  Th17 cell differentiation
pcoo04659

Other DBs
GO: 0072539
Organism
Puma concolor (puma) [GN:pcoo]
Gene
112864068  IL1B; interleukin-1 beta [KO:K04519]
112868908  IL1R1; interleukin-1 receptor type 1 isoform X1 [KO:K04386]
112849639  IL1RAP; interleukin-1 receptor accessory protein [KO:K04723]
112862836  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
112862837  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
112863384  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
112848905  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
112853664  IRF4; interferon regulatory factor 4 isoform X1 [KO:K09445]
112850697  TGFB1; transforming growth factor beta-1 [KO:K13375]
112851426  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
112850049  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
112868176  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
112855310  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
112868129  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
112858959  IL21; interleukin-21 [KO:K05434]
112856544  IL21R; interleukin-21 receptor [KO:K05075]
112871236  IL2RG; cytokine receptor common subunit gamma [KO:K05070]
112871857  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
112852387  JAK3; LOW QUALITY PROTEIN: tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
112866659  IL6; interleukin-6 [KO:K05405]
112851720  IL6R; LOW QUALITY PROTEIN: interleukin-6 receptor subunit alpha [KO:K05055]
112860883  IL6ST; interleukin-6 receptor subunit beta isoform X1 [KO:K05060]
112868696  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
112863908  IL23A; interleukin-23 subunit alpha [KO:K05426]
112872049  IL23R; interleukin-23 receptor [KO:K05065]
112852391  IL12RB1; interleukin-12 receptor subunit beta-1 [KO:K05063]
112852708  TYK2; non-receptor tyrosine-protein kinase TYK2 [KO:K11219] [EC:2.7.10.2]
112853996  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
112865340  RORC; nuclear receptor ROR-gamma [KO:K08534]
112855559  RORA; nuclear receptor ROR-alpha [KO:K08532]
112855387  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
112855434  HSP90AA1; heat shock protein HSP 90-alpha isoform X1 [KO:K04079]
112862791  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
112866720  AHR; aryl hydrocarbon receptor [KO:K09093]
112862764  IL17A; interleukin-17A [KO:K05489]
112862543  IL17F; interleukin-17F [KO:K05494]
112863817  IL22; interleukin-22 [KO:K05445]
112862042  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
112862071  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
112862094  HLA class II histocompatibility antigen, DM alpha chain [KO:K06752]
112862131  HLA class II histocompatibility antigen, DP beta 1 chain [KO:K06752]
112862364  HLA class II histocompatibility antigen, DO beta chain-like [KO:K06752]
112862858  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP alpha 1 chain-like [KO:K06752]
112862859  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DRB1-10 beta chain-like [KO:K06752]
112862863  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
112867903  CD4; LOW QUALITY PROTEIN: T-cell surface glycoprotein CD4 [KO:K06454]
112871853  LCK; tyrosine-protein kinase Lck [KO:K05856] [EC:2.7.10.2]
112865851  CD3E; T-cell surface glycoprotein CD3 epsilon chain [KO:K06451]
112865849  CD3G; LOW QUALITY PROTEIN: T-cell surface glycoprotein CD3 gamma chain [KO:K06452]
112863153  CD247; LOW QUALITY PROTEIN: T-cell surface glycoprotein CD3 zeta chain [KO:K06453]
112865955  CD3D; T-cell surface glycoprotein CD3 delta chain isoform X1 [KO:K06450]
112868941  tyrosine-protein kinase ZAP-70 [KO:K07360] [EC:2.7.10.2]
112857361  LAT; linker for activation of T-cells family member 1 isoform X1 [KO:K07362]
112869500  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
112869884  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform [KO:K04348] [EC:3.1.3.16]
112858792  PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform [KO:K04348] [EC:3.1.3.16]
112854258  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
112861555  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
112869328  PPP3R1; calcineurin subunit B type 1 [KO:K06268]
112869109  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 [KO:K17332]
112857223  NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X1 [KO:K17333]
112867481  PRKCQ; protein kinase C theta type isoform X1 [KO:K18052] [EC:2.7.11.13]
112854253  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
112858003  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
112871176  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
112855073  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
112851076  NFKBIB; NF-kappa-B inhibitor beta [KO:K02581]
112862790  NFKBIE; LOW QUALITY PROTEIN: NF-kappa-B inhibitor epsilon [KO:K05872]
112858048  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
112851941  RELA; transcription factor p65 [KO:K04735]
112856394  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
112870302  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
112854981  FOS; proto-oncogene c-Fos [KO:K04379]
112859092  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
112854846  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
112861322  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
112872218  JUN; transcription factor AP-1 [KO:K04448]
112861021  IL4; interleukin-4 [KO:K05430]
112856560  IL4R; interleukin-4 receptor subunit alpha [KO:K05071]
112863244  STAT6; signal transducer and activator of transcription 6 isoform X1 [KO:K11225]
112849752  RUNX1; runt-related transcription factor 1 [KO:K08367]
112856416  IL27; interleukin-27 subunit alpha [KO:K22629]
112852830  EBI3; interleukin-27 subunit beta [KO:K24476]
112852311  IL27RA; LOW QUALITY PROTEIN: interleukin-27 receptor subunit alpha [KO:K19598]
112863468  IFNG; interferon gamma [KO:K04687]
112861963  IFNGR1; interferon gamma receptor 1 [KO:K05132]
112849760  IFNGR2; interferon gamma receptor 2 [KO:K05133]
112869860  STAT1; signal transducer and activator of transcription 1-alpha/beta isoform X1 [KO:K11220]
112858002  IL2; interleukin-2 [KO:K05429]
112867999  IL2RA; interleukin-2 receptor subunit alpha [KO:K05068]
112863752  IL2RB; LOW QUALITY PROTEIN: interleukin-2 receptor subunit beta [KO:K05069]
112853998  signal transducer and activator of transcription 5A [KO:K11223]
112870983  FOXP3; forkhead box protein P3 isoform X1 [KO:K10163]
112854085  RARA; retinoic acid receptor alpha [KO:K08527]
112860381  RXRA; retinoic acid receptor RXR-alpha [KO:K08524]
112862195  RXRB; retinoic acid receptor RXR-beta isoform X1 [KO:K08525]
112864769  RXRG; retinoic acid receptor RXR-gamma [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
pcoo04010  MAPK signaling pathway
pcoo04020  Calcium signaling pathway
pcoo04064  NF-kappa B signaling pathway
pcoo04066  HIF-1 signaling pathway
pcoo04350  TGF-beta signaling pathway
pcoo04514  Cell adhesion molecules
pcoo04620  Toll-like receptor signaling pathway
pcoo04630  JAK-STAT signaling pathway
pcoo04660  T cell receptor signaling pathway
pcoo05321  Inflammatory bowel disease
pcoo05323  Rheumatoid arthritis
KO pathway
ko04659   
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