The composition and signaling of the IL-35 receptor are unconventional
NATURE IMMUNOLOGY
Authors: Collison, Lauren W.; Delgoffe, Greg M.; Guy, Clifford S.; Vignali, Kate M.; Chaturvedi, Vandana; Fairweather, DeLisa; Satoskar, Abhay R.; Garcia, K. Christopher; Hunter, Christopher A.; Drake, Charles G.; Murray, Peter J.; Vignali, Dario A. A.
Abstract
Interleukin 35 (IL-35) belongs to the IL-12 family of heterodimeric cytokines but has a distinct functional profile. IL-35 suppresses T cell proliferation and converts naive T cells into IL-35-producing induced regulatory T cells (iTr35 cells). Here we found that IL-35 signaled through a unique heterodimer of receptor chains IL-12Rb2 and gp130 or homodimers of each chain. Conventional T cells were sensitive to IL-35-mediated suppression in the absence of one receptor chain but not both receptor chains, whereas signaling through both chains was required for IL-35 expression and conversion into iTr35 cells. Signaling through the IL-35 receptor required the transcription factors STAT1 and STAT4, which formed a unique heterodimer that bound to distinct sites in the promoters of the genes encoding the IL-12 subunits p35 and Ebi3. This unconventional mode of signaling, distinct from that of other members of the IL-12 family, may broaden the spectrum and specificity of IL-35-mediated suppression.
Interleukin 35 Polymorphisms Are Associated with Decreased Risk of Premature Coronary Artery Disease, Metabolic Parameters, and IL-35 Levels: The Genetics of Atherosclerotic Disease (GEA) Study
MEDIATORS OF INFLAMMATION
Authors: Posadas-Sanchez, Rosalinda; Perez-Hernandez, Nonanzit; Angeles-Martinez, Javier; Lopez-Bautista, Fabiola; Villarreal-Molina, Teresa; Manuel Rodriguez-Perez, Jose; Manuel Fragoso, Jose; Posadas-Romero, Carlos; Vargas-Alarcon, Gilberto
Abstract
Interleukin 35 (IL-35) is a heterodimeric cytokine involved in the development of atherosclerosis. The aim of the present study was to establish if the polymorphisms of IL-12A and EBI3 genes that encode the IL-35 subunits are associated with the development of premature coronary artery disease (CAD) in Mexican individuals. The IL-12A and EBI3 polymorphisms were determined in 1162 patients with premature CAD and 873 controls. Under different models, the EBI3 rs428253 (OR = 0.831,P-add = 0.036; OR = 0.614,P-rec = 0.033; OR = 0.591, P-cod2 = 0.027) and IL-12A rs2243115 (OR = 0.674,P (add) = 0.010; OR = 0.676,P-dom = 0.014; OR = 0.698,P-het = 0.027; OR = 0.694, P(cod)1 = 0.024) polymorphisms were associated with decreased risk of developing premature CAD. Some polymorphisms were associated with clinical andmetabolic parameters. Significant different levels of IL-35 were observed in EBI3 rs4740 and rs4905 genotypes only in the group of healthy controls. In summary, our study suggests that the EBI3 and IL-12A polymorphisms play an important role in decreasing the risk of developing premature CAD; it also demonstrates the relationship of the EBI3 rs4740 and rs4905 genotypes with IL-35 levels in healthy individuals.
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