Alternative titles; symbols
HGNC Approved Gene Symbol: IL27
Cytogenetic location: 16p12.1-p11.2 Genomic coordinates (GRCh38) : 16:28,499,362-28,506,834 (from NCBI)
IL30, a member of the long-chain 4-helix bundle cytokine family, and EBI3 (605816), form the IL27 heterodimer, which is expressed by antigen-presenting cells. IL27 triggers expansion of antigen-specific naive CD4 (186940)-positive T cells and promotes polarization towards a Th1 phenotype with expression of gamma-interferon (IFNG; 147570). IL27 acts in synergy with IL12 (see IL12B; 161561) and binds to WSX1 (IL27RA; 605350) (Pflanz et al., 2002).
By searching sequence databases for IL6 (147620)-related proteins, Pflanz et al. (2002) identified IL30, which they termed p28 because of its apparent molecular mass as determined by SDS-PAGE. The predicted 243-amino acid protein, which is 73% identical to the mouse protein, contains an N-terminal signal peptide, several O-glycosylation sites, and a stretch of 13 glutamate residues between helices C and D.
Pflanz et al. (2002) showed that coexpression of IL30 with EBI3, but not with other IL6 family members, permitted the release of IL30 from an intracellular location and its secretion. Real-time quantitative PCR and ELISA analysis detected coexpression of EBI3 and IL30 in lipopolysaccharide-activated monocytes and dendritic cells; only EBI3 was detected in placenta. Naive, but not memory, T cells proliferated in response to the heterodimer formed by IL30 and EBI3, which Pflanz et al. (2002) termed IL27, and did so synergistically in response to IL27 and IL12. Secretion of IFNG by T cells and natural killer cells required the presence of both IL27 and IL12; IL27 did not promote the production of Th2 cytokines. Screening of cells expressing members of the IL6/IL12 family of signaling receptors and coimmunoprecipitation experiments demonstrated that only WSX1 bound IL27. Kinetic analysis showed that IL30 was transiently expressed prior to IL12A (161560) and IL12B. EBI3 expression was also rapidly upregulated, but it persisted somewhat longer than that of IL30. Pflanz et al. (2002) proposed that IL27, IL12, and IL23 (605580) act sequentially, with some overlap, on naive and memory Th1 cells in response to pathogen challenge.
Takeda et al. (2003) showed that STAT1 (600555) interacted with a conserved cytoplasmic domain tyrosine residue of WSX1 after the residue was phosphorylated. IL27 stimulation induced phosphorylation of STAT1 and expression of TBET (TBX21; 604895) and IL12RB2 (601642) in wildtype, but not WSX1-deficient, naive CD4-positive T cells. Together with IL12, IL27 augmented IFNG secretion in wildtype, but not WSX1-deficient, naive CD4-positive T cells. Takeda et al. (2003) concluded that the IL27-WSX1 signaling system acts before the IL12R system in STAT1-mediated TBET induction during the initiation of Th1 differentiation.
Pflanz et al. (2004) found that transfection of WSX1 into a cell line expressing gp130 (600694) but only low levels of WSX1 resulted in IL27-dependent phosphorylation of STAT1 and STAT3 (102582). In addition, they showed that anti-gp130 blocked IL27-mediated cellular effects. Quantitative PCR analysis indicated that, in addition to naive CD4-positive T cells, numerous cell types expressed both gp130 and WSX1, including mast cells. IL27 stimulation of mast cells resulted in upregulation of proinflammatory cytokine expression. Pflanz et al. (2004) concluded that IL27 not only contributes to the development of an adaptive immune response through its action on CD4-positive T cells, but also directly acts on cells of the innate immune system.
Batten et al. (2006) found that Il27ra -/- mice were hypersusceptible to experimental autoimmune encephalomyelitis (EAE), with significantly increased demyelination and inflammation, and had more inflammatory Il17 (IL17A; 603149)-producing T (Th17) cells in draining lymph nodes compared with wildtype mice. Flow cytometric analysis showed that increased Il17 production also occurred in the central nervous system of mutant mice. In vitro, Il27 was more efficient than Ifng in suppressing Th17 cell differentiation, and it could overcome the Th17-promoting effects of Il6. The suppressive activity of Il27 was dependent on Stat1 activation. EAE was ameliorated in Il27ra -/- mice treated with anti-Il17, but it was more severe in mice lacking both Il27ra and Ifngr (107470). Batten et al. (2006) concluded that IL27 inhibits Th17 differentiation in a STAT1-dependent, IFNG-independent manner, and that IL27 functions by antagonizing IL6, which is required for Th17 cell differentiation and EAE pathogenesis.
Using RT-PCR, Stumhofer et al. (2006) found that mice with toxoplasmic encephalitis showed a dramatic increase in expression of Il27 and a much smaller increase in expression of Ebi3. T. gondii-infected mice lacking Il27ra were protected from acute lethality by Ctla4 (123890)-Ig treatment, but they succumbed during the chronic phase of infection due to inflammation and necrosis associated with pathogenic Cd4-positive, Il17-expressing T cells infiltrating the brain. Treatment of T cells with anti-Il6 or Il27 inhibited Il17 production. Il27-mediated inhibition of Il17 production was dependent on Stat1 and independent of inhibition of Il6 signaling mediated by Socs3 (604176). Stumhofer et al. (2006) proposed that IL27 may be a useful target in treating inflammatory diseases mediated by Th17 cells.
By genomic sequence analysis, Pflanz et al. (2002) mapped the IL30 gene to chromosome 16p11.
Holscher et al. (2005) found that Wsx1-deficient mice infected with Mycobacterium tuberculosis exhibited increased production of Tnf (191160) and Il12b, leading to increased Cd4-positive T-cell activation and Ifng production and reduced bacterial loads. However, the increased inflammatory response accelerated death in Wsx1-deficient mice. Stimulation of activated peritoneal macrophages in vitro with Il27 induced Stat3 phosphorylation and inhibition of Tnf and Il12 production, indicating that Il27 modulates excessive inflammation. Holscher et al. (2005) concluded that IL27 prevents optimal protection against M. tuberculosis, but also limits chronic inflammatory pathology.
Batten, M., Li, J., Yi, S., Kljavin, N. M., Danilenko, D. M., Lucas, S., Lee, J., de Sauvage, F. J., Ghilardi, N. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nature Immun. 7: 929-936, 2006. [PubMed: 16906167] [Full Text: https://doi.org/10.1038/ni1375]
Holscher, C., Holscher, A., Ruckerl, D., Yoshimoto, T., Yoshida, H., Mak, T., Saris, C., Ehlers, S. The IL-27 receptor chain WSX-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis. J. Immun. 174: 3534-3544, 2005. [PubMed: 15749890] [Full Text: https://doi.org/10.4049/jimmunol.174.6.3534]
Pflanz, S., Hibbert, L., Mattson, J., Rosales, R., Vaisberg, E., Bazan, J. F., Phillips, J. H., McClanahan, T. K., de Waal Malefyt, R., Kastelein, R. A. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immun. 172: 2225-2231, 2004. [PubMed: 14764690] [Full Text: https://doi.org/10.4049/jimmunol.172.4.2225]
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., and 9 others. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16: 779-790, 2002. [PubMed: 12121660] [Full Text: https://doi.org/10.1016/s1074-7613(02)00324-2]
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. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nature Immun. 7: 937-945, 2006. [PubMed: 16906166] [Full Text: https://doi.org/10.1038/ni1376]
Takeda, A., Hamano, S., Yamanaka, A., Hanada, T., Ishibashi, T., Mak, T. W., Yoshimura, A., Yoshida, H. Cutting edge: role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment. J. Immun. 170: 4886-4890, 2003. [PubMed: 12734330] [Full Text: https://doi.org/10.4049/jimmunol.170.10.4886]