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

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.