Authors
Beiping Miao, Ruishi Zhang, Yanyu Ye, Liguo Li, Pengyuan Zheng, Haoyue Zheng, Gui Yang, Pingchang Yang
Published in
Frontiers in immunology. Volume 17. Pages 1858675. Epub Jul 27, 2026.
Abstract
Epstein-Barr virus-induced gene 3(EBI3) is conventionally viewed as a subunit of IL-27 and IL-35, yet the function of uncomplexed "free" EBI3 is unknown. We show that free EBI3 is an autonomous immunosuppressive cytokine that acts via a gp130/WSX-1/STAT3 axis and epigenetic reprogramming. A free-EBI3-specific sandwich ELISA revealed 23.3 ± 2.2 ng/mL in healthy human sera and equivalent levels in mice; no cross-reactivity with IL-27/IL-35 was observed. Serum free EBI3 was reduced in rheumatoid arthritis(RA; 12.4 ± 1.4 ng/mL) and multiple sclerosis (MS; 14.6 ± 1.4 ng/mL; both p< 0.001) and inversely correlated with disease activity(RA-DAS28-ESR r=-0.67; MS-EDSS r=-0.61). Baseline<15 ng/mL predicted higher flare risk(RA HR = 2.8;MS HR = 3.2;p<0.01). Recombinant free EBI3 activated STAT3 exclusively(EC50≈16 nM), suppressed T-cell proliferation (-40%),IFN-y(-45%) and IL-17(-60%),and drove M2 macrophage polarization (+2.7-fold;p<0.001).Epigenetically,it reduced H3K4me3 at Ifng/Il4 promoters, induced Il10/Tgfb hypomethylation(-35%/-28%), and remodeled 1,021 chromatin-accessible STAT3/NF-kB sites. EBI3-/- mice developed spontaneous colitis and severe EAE; daily free EBI3(1 mg/kg) reversed pathology, whereas IL-27/IL-35 did not. Tissue-targeted delivery(liposomes or nanoparticles) outperformed systemic therapy. Ex-vivo free EBI3 normalized RA/MS patient PBMCs(proliferation-50%; IL-17-52%; p< 0.001). Thus, free EBI3 is a distinct cytokine whose gp130/WSX-1 axis constitutes a biomarker and therapeutic target for inflammatory diseases.
PMID:
42577052
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.
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