Q8K3I6 (IL27A_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Interleukin-27 subunit alpha
Short name=IL-27 subunit alpha
Short name=IL-27-A
Short name=IL27-A

Alternative name(s):
p28

Gene names

Name:	Il27
Synonyms:	Il27a

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	234 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Cytokine with pro- and anti-inflammatory properties, that can regulate T-helper cell development, suppress T-cell proliferation, stimulate cytotoxic T-cell activity, induce isotype switching in B-cells, and that has diverse effects on innate immune cells. Among its target cells are CD4 T-helper cells which can differentiate in type 1 effector cells (TH1), type 2 effector cells (TH2) and IL17 producing helper T-cells (TH17). It drives rapid clonal expansion of naive but not memory CD4 T-cells. It also strongly synergizes with IL-12 to trigger interferon-gamma/IFN-gamma production of naive CD4 T-cells, binds to the cytokine receptor WSX-1/TCCR which appears to be required but not sufficient for IL-27-mediated signal transduction. IL-27 potentiate the early phase of TH1 response and suppress TH2 and TH17 differentiation. It induces the differentiation of TH1 cells via two distinct pathways, p38 MAPK/TBX21- and ICAM1/ITGAL/ERK-dependent pathways. It also induces STAT1, STAT3, STAT4 and STAT5 phosphorylation and activates TBX21/T-Bet via STAT1 with resulting IL12RB2 up-regulation, an event crucial to TH1 cell commitment. It suppresses the expression of GATA3, the inhibitor TH1 cells development. In CD8 T-cells, it activates STATs as well as GZMB. IL-27 reveals to be a potent inhibitor of TH17 cell development and of IL-17 production. Indeed IL-27 subunit p28 alone is also able to inhibit the production of IL17 by CD4 and CD8 T-cells. While IL-27 suppressed the development of proinflammatory Th17 cells via STAT1, it inhibits the development of anti-inflammatory inducible regulatory T-cells, iTreg, independently of STAT1. IL-27 has also an effect on cytokine production, it suppresses proinflammatory cytokine production such as IL2, IL4, IL5 and IL6 and activates suppressors of cytokine signaling such as SOCS1 and SOCS3. Apart from suppression of cytokine production, IL-27 also antagonizes the effects of some cytokines such as IL6 through direct effects on T-cells. Another important role of IL-27 is its antitumor activity as well as its antiangiogenic activity with activation of production of antiangiogenic chemokines such as IP-10/CXCL10 and MIG/CXCL9. Ref.1 Ref.4 Ref.5 Ref.6 Ref.7 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18
Subunit structure	Heterodimer with EBI3. IL-27 is a heterodimer composed IL-27 subunit alpha and EBI3. EBI3 is also a component of the IL-12 heterodimer. Ref.1
Subcellular location	Secreted. Note: Poorly secreted without coexpression of EBI3. Ref.1
Tissue specificity	Expressed in macrophages and dendritic cells. Ref.1
Induction	By LPS and Interferon gamma in primary astrocytes and microglia. Induced by Toll-like receptor ligand in dendritic cells. Inhibited by PPAR-alpha agonist such as fenofibrate and produced by TNF-alpha in microglia. Ref.8 Ref.17 Ref.19 Ref.20 Ref.22
Post-translational modification	O-glycosylated By similarity.
Miscellaneous	In mouse models of experimental autoimmune encephalitis (EAE) induced by Toxoplasma Gondi infection, brain levels of IL-27 are massively increased. Deficiency of IL-27 receptors in this mouse model with EAE induces development of a more severe neuroinflammation than in wild-type mice with EAE. This excessive neuroinflammation is associated with increased numbers of TH17 cells in the central nervous system (CNS). Continuous administration of IL-27 to EAE mice produces a strong suppressive effect on active EAE, with reduced CNS infiltration of TH17 cells and TH17 cells activity. Mice injected with B16F10 tumor cells develop tumors and lung metastasis. In mice injected with B16F10 tumor cells stably transfected with IL-27, tumor cells grow much more slowly and the number of pulmonary metastasis is markedly reduced. IL-27 exhibits a strong antitumor activity as well as antiangiogenic activity with massive decreased of microvessels density in lung metastasis. Similarly, mice injected with C26 colon tumor cells transfected with IL-27 acquire tumor-specific protective activity and exhibit minimal tumor growth with enhanced IFN-gamma production. This antitumor activity is abolished in TBX21-deficient mice. Neuroblastoma cells overexpressing IL-27 also demonstrate markedly delayed growth; This tumor regression appears to be dependent on CD8 cells.
Sequence similarities	Belongs to the IL-6 superfamily.

Ontologies

Keywords
Biological process	Immunity Inflammatory response Innate immunity
Cellular component	Secreted
Domain	Signal
Molecular function	Cytokine
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of interferon-gamma biosynthetic process Inferred from electronic annotation. Source: Compara regulation of T cell proliferation Inferred from direct assay Ref.1. Source: MGI regulation of T-helper 1 cell differentiation Inferred from electronic annotation. Source: Compara response to bacterium Inferred from electronic annotation. Source: Compara
Cellular_component	extracellular space Inferred from direct assay Ref.1. Source: MGI
Molecular_function	interleukin-27 receptor binding Inferred from direct assay Ref.1. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 28	28	Potential
	Chain	29 – 234	206	Interleukin-27 subunit alpha		PRO_0000320140
Regions
	Compositional bias	161 – 175	15	Glu-rich
Amino acid modifications
	Glycosylation	85	1	N-linked (GlcNAc...) Potential

Sequences

	Sequence		Length	Mass (Da)
	Q8K3I6 [UniParc]. Last modified October 1, 2002. Version 1. Checksum: DB33E7EC8AB4D0DA	FASTA	234	26,542
	10 20 30 40 50 60 MGQVTGDLGW RLSLLLLPLL LVQAGSWGFP TDPLSLQELR REFTVSLYLA RKLLSEVQGY 70 80 90 100 110 120 VHSFAESRLP GVNLDLLPLG YHLPNVSLTF QAWHHLSDSE RLCFLATTLR PFPAMLGGLG 130 140 150 160 170 180 TQGTWTSSER EQLWAMRLDL RDLHRHLRFQ VLAAGFKCSK EEEDKEEEEE EEEEEKKLPL 190 200 210 220 230 GALGGPNQVS SQVSWPQLLY TYQLLHSLEL VLSRAVRDLL LLSLPRRPGS AWDS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells." Pflanz S., Timans J.C., Cheung J., Rosales R., Kanzler H., Gilbert J., Hibbert L., Churakova T., Travis M., Vaisberg E., Blumenschein W.M., Mattson J.D., Wagner J.L., To W., Zurawski S., McClanahan T.K., Gorman D.M., Bazan J.F. , de Waal Malefyt R., Rennick D., Kastelein R.A. Immunity 16:779-790(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, SUBUNIT. Strain: NZB.
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J. Tissue: Bone marrow.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[4]	"IL-27 and IFN-alpha signal via Stat1 and Stat3 and induce T-Bet and IL-12Rbeta2 in naive T cells." Hibbert L., Pflanz S., De Waal Malefyt R., Kastelein R.A. J. Interferon Cytokine Res. 23:513-522(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[5]	"IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms." Lucas S., Ghilardi N., Li J., de Sauvage F.J. Proc. Natl. Acad. Sci. U.S.A. 100:15047-15052(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[6]	"Potent antitumor activity of interleukin-27." Hisada M., Kamiya S., Fujita K., Belladonna M.L., Aoki T., Koyanagi Y., Mizuguchi J., Yoshimoto T. Cancer Res. 64:1152-1156(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[7]	"IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors: role for CD8+ T cells." Salcedo R., Stauffer J.K., Lincoln E., Back T.C., Hixon J.A., Hahn C., Shafer-Weaver K., Malyguine A., Kastelein R., Wigginton J.M. J. Immunol. 173:7170-7182(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[8]	"Production of IL-27 and other IL-12 family cytokines by microglia and their subpopulations." Sonobe Y., Yawata I., Kawanokuchi J., Takeuchi H., Mizuno T., Suzumura A. Brain Res. 1040:202-207(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[9]	"Expression of IL-27 in murine carcinoma cells produces antitumor effects and induces protective immunity in inoculated host animals." Chiyo M., Shimozato O., Yu L., Kawamura K., Iizasa T., Fujisawa T., Tagawa M. Int. J. Cancer 115:437-442(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[10]	"Augmentation of effector CD8+ T cell generation with enhanced granzyme B expression by IL-27." Morishima N., Owaki T., Asakawa M., Kamiya S., Mizuguchi J., Yoshimoto T. J. Immunol. 175:1686-1693(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[11]	"IL-27 limits IL-2 production during Th1 differentiation." Villarino A.V., Stumhofer J.S., Saris C.J.M., Kastelein R.A., de Sauvage F.J., Hunter C.A. J. Immunol. 176:237-247(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[12]	"IL-27 suppresses CD28-mediated IL-2 production through suppressor of cytokine signaling 3." Owaki T., Asakawa M., Kamiya S., Takeda K., Fukai F., Mizuguchi J., Yoshimoto T. J. Immunol. 176:2773-2780(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[13]	"Antiangiogenic and antitumor activities of IL-27." Shimizu M., Shimamura M., Owaki T., Asakawa M., Fujita K., Kudo M., Iwakura Y., Takeda Y., Luster A.D., Mizuguchi J., Yoshimoto T. J. Immunol. 176:7317-7324(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[14]	"Two-sided roles of IL-27: induction of Th1 differentiation on naive CD4+ T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4+ T cells partially through STAT3-dependent mechanism." Yoshimura T., Takeda A., Hamano S., Miyazaki Y., Kinjyo I., Ishibashi T., Yoshimura A., Yoshida H. J. Immunol. 177:5377-5385(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[15]	"IL-27 induces Th1 differentiation via p38 MAPK/T-bet- and intercellular adhesion molecule-1/LFA-1/ERK1/2-dependent pathways." Owaki T., Asakawa M., Fukai F., Mizuguchi J., Yoshimoto T. J. Immunol. 177:7579-7587(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[16]	"Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells." Batten M., Li J., Yi S., Kljavin N.M., Danilenko D.M., Lucas S., Lee J., de Sauvage F.J., Ghilardi N. Nat. Immunol. 7:929-936(2006) [PubMed] [Europe PMC] [Abstract] Cited for: MOUSE MODEL OF EXPERIMENTAL AUTOIMMUNE ENCEPHALITIS, FUNCTION.
[17]	"Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system." Stumhofer J.S., Laurence A., Wilson E.H., Huang E., Tato C.M., Johnson L.M., Villarino A.V., Huang Q., Yoshimura A., Sehy D., Saris C.J.M., O'Shea J.J., Hennighausen L., Ernst M., Hunter C.A. Nat. Immunol. 7:937-945(2006) [PubMed] [Europe PMC] [Abstract] Cited for: MOUSE MODEL OF EXPERIMENTAL AUTOIMMUNE ENCEPHALITIS, FUNCTION, INDUCTION.
[18]	"IL-27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1." Neufert C., Becker C., Wirtz S., Fantini M.C., Weigmann B., Galle P.R., Neurath M.F. Eur. J. Immunol. 37:1809-1816(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[19]	"IL-27 synthesis induced by TLR ligation critically depends on IFN regulatory factor 3." Molle C., Nguyen M., Flamand V., Renneson J., Trottein F., De Wit D., Willems F., Goldman M., Goriely S. J. Immunol. 178:7607-7615(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
[20]	"Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis." Fitzgerald D.C., Ciric B., Touil T., Harle H., Grammatikopolou J., Das Sarma J., Gran B., Zhang G.-X., Rostami A. J. Immunol. 179:3268-3275(2007) [PubMed] [Europe PMC] [Abstract] Cited for: MOUSE MODEL OF EXPERIMENTAL AUTOIMMUNE ENCEPHALITIS, INDUCTION.
[21]	"The biology and therapeutic potential of interleukin 27." Batten M., Ghilardi N. J. Mol. Med. 85:661-672(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[22]	"Peroxisome proliferator-activated receptor-alpha agonist fenofibrate regulates IL-12 family cytokine expression in the CNS: relevance to multiple sclerosis." Xu J., Racke M.K., Drew P.D. J. Neurochem. 103:1801-1810(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INDUCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AY099297 mRNA. Translation: AAM34499.1. AK152114 mRNA. Translation: BAE30958.1. AK153466 mRNA. Translation: BAE32017.1. BC119402 mRNA. Translation: AAI19403.1.
IPI	IPI00170089.
RefSeq	NP_663611.1. NM_145636.1.
UniGene	Mm.222632.
3D structure databases
ProteinModelPortal	Q8K3I6.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q8K3I6. 1 interaction.
STRING	10090.ENSMUSP00000054637.
PTM databases
PhosphoSite	Q8K3I6.
Proteomic databases
PRIDE	Q8K3I6.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000058429; ENSMUSP00000054637; ENSMUSG00000044701.
GeneID	246779.
KEGG	mmu:246779.
UCSC	uc009jsc.1. mouse.
Organism-specific databases
CTD	246778.
MGI	MGI:2384409. Il27.
Phylogenomic databases
eggNOG	NOG45660.
GeneTree	ENSGT00390000018206.
HOGENOM	HOG000113043.
HOVERGEN	HBG097312.
InParanoid	Q8K3I6.
OMA	PAQVSWP.
OrthoDB	EOG42NJ1B.
Gene expression databases
Bgee	Q8K3I6.
CleanEx	MM_IL27.
Genevestigator	Q8K3I6.
Family and domain databases
InterPro	IPR026207. IL27-A. [Graphical view]
PANTHER	PTHR20879. PTHR20879. 1 hit.
ProtoNet	Search...
Other
NextBio	387308.
SOURCE	Search...

Entry information

Entry name

IL27A_MOUSE

Accession

Primary (citable) accession number: Q8K3I6

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 26, 2008
Last sequence update:	October 1, 2002
Last modified:	April 3, 2013
This is version 73 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program