KEGG   PATHWAY: rno04659
Entry
rno04659                    Pathway                                
Name
Th17 cell differentiation - Rattus norvegicus (rat)
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
rno04659  Th17 cell differentiation
rno04659

Other DBs
GO: 0072539
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
24494  Il1b; interleukin-1 beta [KO:K04519]
25663  Il1r1; interleukin-1 receptor type 1 precursor [KO:K04386]
25466  Il1rap; interleukin-1 receptor accessory protein precursor [KO:K04723]
81649  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
60352  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
29513  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
689314  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
56718  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
291100  Irf4; interferon regulatory factor 4 [KO:K09445]
59086  Tgfb1; transforming growth factor beta-1 proprotein precursor [KO:K13375]
29591  Tgfbr1; TGF-beta receptor type-1 precursor [KO:K04674] [EC:2.7.11.30]
81810  Tgfbr2; TGF-beta receptor type-2 precursor [KO:K04388] [EC:2.7.11.30]
29357  Smad2; mothers against decapentaplegic homolog 2 [KO:K04500]
25631  Smad3; mothers against decapentaplegic homolog 3 [KO:K23605]
50554  Smad4; mothers against decapentaplegic homolog 4 [KO:K04501]
365769  Il21; interleukin-21 precursor [KO:K05434]
308977  Il21r; interleukin-21 receptor precursor [KO:K05075]
140924  Il2rg; cytokine receptor common subunit gamma precursor [KO:K05070]
84598  Jak1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
25326  Jak3; tyrosine-protein kinase JAK3 [KO:K11218] [EC:2.7.10.2]
24498  Il6; interleukin-6 precursor [KO:K05405]
24499  Il6r; interleukin-6 receptor subunit alpha precursor [KO:K05055]
25205  Il6st; interleukin-6 receptor subunit beta precursor [KO:K05060]
24514  Jak2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
155140  Il23a; interleukin-23 subunit alpha precursor [KO:K05426]
689932  Il23r; interleukin-23 receptor isoform X1 [KO:K05065]
171333  Il12rb1; interleukin-12 receptor subunit beta-1 precursor [KO:K05063]
100361294  Tyk2; non-receptor tyrosine-protein kinase TYK2 [KO:K11219] [EC:2.7.10.2]
25125  Stat3; signal transducer and activator of transcription 3 [KO:K04692]
368158  Rorc; nuclear receptor ROR-gamma [KO:K08534]
300807  Rora; nuclear receptor ROR-alpha isoform X1 [KO:K08532]
29560  Hif1a; hypoxia-inducible factor 1-alpha [KO:K08268]
299331  Hsp90aa1; heat shock protein HSP 90-alpha [KO:K04079]
301252  Hsp90ab1; heat shock protein HSP 90-beta [KO:K04079]
25690  Ahr; aryl hydrocarbon receptor isoform 2 [KO:K09093]
301289  Il17a; interleukin-17A precursor [KO:K05489]
301291  Il17f; interleukin-17F precursor [KO:K05494]
500836  Il22; interleukin-22 precursor [KO:K05445]
294274  RT1-DMa; RT1 class II, DM alpha precursor [KO:K06752]
294273  RT1-DMb; RT1 class II, DM beta precursor [KO:K06752]
24984  RT1-DOa; RT1 class II, locus DOa precursor [KO:K06752]
24986  RT1-Ha; RT1 class II, locus Ha precursor [KO:K06752]
294269  RT1-Da; RT1 class II, locus Da precursor [KO:K06752]
294270  RT1-Db1; rano class II histocompatibility antigen, D-1 beta chain precursor [KO:K06752]
309621  RT1-Ba; rano class II histocompatibility antigen, B alpha chain precursor [KO:K06752]
309622  RT1-Bb; rano class II histocompatibility antigen, B-1 beta chain precursor [KO:K06752]
365542  RT1-DOb; RT1 class II, DO beta isoform 1 [KO:K06752]
24981  RT1-Db2; RT1 class II, locus Db2 precursor [KO:K06752]
24932  Cd4; T-cell surface glycoprotein CD4 precursor [KO:K06454]
313050  Lck; proto-oncogene tyrosine-protein kinase LCK [KO:K05856] [EC:2.7.10.2]
315609  Cd3e; T-cell surface glycoprotein CD3 epsilon chain precursor [KO:K06451]
300678  Cd3g; T-cell surface glycoprotein CD3 gamma chain precursor [KO:K06452]
25300  Cd247; T-cell surface glycoprotein CD3 zeta chain isoform 2 precursor [KO:K06453]
25710  Cd3d; T-cell surface glycoprotein CD3 delta chain precursor [KO:K06450]
301348  Zap70; tyrosine-protein kinase ZAP-70 [KO:K07360] [EC:2.7.10.2]
81511  Lat; linker for activation of T-cells family member 1 [KO:K07362]
25738  Plcg1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
24674  Ppp3ca; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
24675  Ppp3cb; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform [KO:K04348] [EC:3.1.3.16]
171378  Ppp3cc; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform [KO:K04348] [EC:3.1.3.16]
29748  Ppp3r1; calcineurin subunit B type 1 [KO:K06268]
29749  Ppp3r2; calcineurin subunit B type 2 [KO:K06268]
100361818  Nfatc1; nuclear factor of activated T-cells, cytoplasmic 1 isoform 1 [KO:K04446]
311658  Nfatc2; nuclear factor of activated T-cells, cytoplasmic 2 [KO:K17332]
361400  Nfatc3; nuclear factor of activated T-cells, cytoplasmic 3 [KO:K17333]
85420  Prkcq; protein kinase C theta type [KO:K18052] [EC:2.7.11.13]
309361  Chuk; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
84351  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
309295  Ikbkg; NF-kappa-B essential modulator [KO:K07210]
25493  Nfkbia; NF-kappa-B inhibitor alpha [KO:K04734]
81525  Nfkbib; NF-kappa-B inhibitor beta [KO:K02581]
316241  Nfkbie; NF-kappa-B inhibitor epsilon [KO:K05872]
81736  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580]
309165  Rela; transcription factor p65 [KO:K04735]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
314322  Fos; protein c-Fos [KO:K04379]
25272  Mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
50658  Mapk9; mitogen-activated protein kinase 9 isoform 2 [KO:K04440] [EC:2.7.11.24]
116554  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
24516  Jun; transcription factor Jun [KO:K04448]
287287  Il4; interleukin-4 precursor [KO:K05430]
25084  Il4r; interleukin-4 receptor subunit alpha precursor [KO:K05071]
362896  Stat6; signal transducer and activator of transcription 6 [KO:K11225]
85471  Gata3; trans-acting T-cell-specific transcription factor GATA-3 [KO:K17895]
50662  Runx1; runt-related transcription factor 1 [KO:K08367]
365368  Il27; interleukin-27 subunit alpha [KO:K22629]
680609  Ebi3; interleukin-27 subunit beta precursor [KO:K24476]
288905  Il27ra; interleukin-27 receptor subunit alpha precursor [KO:K19598]
25712  Ifng; interferon gamma precursor [KO:K04687]
116465  Ifngr1; interferon gamma receptor 1 precursor [KO:K05132]
360697  Ifngr2; interferon gamma receptor 2 precursor [KO:K05133]
25124  Stat1; signal transducer and activator of transcription 1-alpha/beta isoform beta [KO:K11220]
303496  Tbx21; T-box transcription factor TBX21 [KO:K10166]
116562  Il2; interleukin-2 precursor [KO:K05429]
25704  Il2ra; interleukin-2 receptor subunit alpha precursor [KO:K05068]
25746  Il2rb; interleukin-2 receptor subunit beta precursor [KO:K05069]
24918  Stat5a; signal transducer and activator of transcription 5A [KO:K11223]
25126  Stat5b; signal transducer and activator of transcription 5B [KO:K11224]
317382  Foxp3; forkhead box protein P3 [KO:K10163]
24705  Rara; retinoic acid receptor alpha [KO:K08527]
25271  Rxra; retinoic acid receptor RXR-alpha [KO:K08524]
361801  Rxrb; retinoic acid receptor RXR-beta [KO:K08525]
83574  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
rno04010  MAPK signaling pathway
rno04020  Calcium signaling pathway
rno04064  NF-kappa B signaling pathway
rno04066  HIF-1 signaling pathway
rno04350  TGF-beta signaling pathway
rno04514  Cell adhesion molecules
rno04620  Toll-like receptor signaling pathway
rno04630  JAK-STAT signaling pathway
rno04660  T cell receptor signaling pathway
rno05321  Inflammatory bowel disease
rno05323  Rheumatoid arthritis
KO pathway
ko04659   
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