文献类型：期刊文献

英文题名：Divergent roles of IL-35 and IL-39 in rheumatoid arthritis: restoring cytokine balance within the IL-12 family

作者：Ling, Xingyan[1];Zhang, Xuhui[2];Hu, Jieliang[3];Hambly, Brett D.[1];Bao, Shisan[1]

第一作者：Ling, Xingyan

通信作者：Bao, SS[1];Hu, JL[2]

机构：[1]Gansu Univ Chinese Med, Affiliated Hosp 3, Sci Res Sect, Baiyin, Peoples R China;[2]Gansu Univ Chinese Med, Affiliated Hosp 3, Resp Ctr, Baiyin, Peoples R China;[3]Gansu Univ Chinese Med, Peoples Hosp Baiyin 1, Affiliated Hosp 3, Joint Surg, Baiyin, Peoples R China

第一机构：甘肃中医药大学

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Affiliated Hosp 3, Sci Res Sect, Baiyin, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, Peoples Hosp Baiyin 1, Affiliated Hosp 3, Joint Surg, Baiyin, Peoples R China.|[10735]甘肃中医药大学;

年份：2026

卷号：17

起止页码：1810466

外文期刊名：FRONTIERS IN IMMUNOLOGY

收录：;Scopus(收录号：2-s2.0-105037425908);WOS:【SCI-EXPANDED(收录号:WOS:001748206600001)】；

基金：The author(s) declared that financial support was received for this work and/or its publication. Grants: this study is supported by a from Gansu Provincial Science and Technology Project (25RCKD001), Strengthen international cooperation to improve comprehensive treatment technologies for acute and critical patients and also a grant; The role of collagen density in myeloma bone disease and drug response mechanisms (22JR5RA584).

语种：英文

外文关键词：divergent role; IL-35; IL-39; rheumatoid arthritis; therapeutic potential

摘要：Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent synovial inflammation, progressive cartilage destruction, and irreversible bone erosion. Although substantial progress has been made in identifying downstream inflammatory mediators, the upstream regulatory architecture governing immune imbalance in RA remains incompletely understood. Members of the interleukin-12 (IL-12) cytokine family are key regulators of T-cell differentiation and inflammatory amplification. Among them, IL-35 and IL-39 represent functionally opposing yet incompletely characterised cytokines with emerging relevance to RA pathogenesis. IL-35, predominantly produced by regulatory T and B cells, exerts immunosuppressive effects by inhibiting T helper 17 (Th17) responses, expanding regulatory lymphocyte populations, and modulating macrophage polarisation. Evidence suggests dysregulation of the IL-35 axis in RA, characterised by reduced systemic levels but relative synovial upregulation, possibly reflecting a compensatory response to persistent inflammation. In contrast, IL-39, derived from activated B cells and myeloid cells, promotes inflammatory cascades through STAT1/STAT3 signalling. Circulating IL-39 levels correlate with disease activity and inflammatory biomarkers, supporting its potential role in sustaining immune activation. This mini-review synthesises current evidence on the divergent immunobiology of IL-35 and IL-39 in RA, evaluates their mechanistic pathways, and discusses their translational implications as biomarkers and therapeutic targets. By examining IL-35 alongside the relatively understudied cytokine IL-39, we highlight the added value of this pairing in clarifying their shared and distinct biological functions. We propose that disruption of regulatory-inflammatory equilibrium within the IL-12 cytokine family provides a conceptual framework for understanding immune dysregulation in RA and may inform precision immunomodulatory strategies.