Interleukin-35 signaling pathway (IL-35 signaling pathway)

The Interleukin-35 signaling pathway comprises the cell surface binding of IL-35, a heterodimeric cytokine consisting of IL-12α (p35) and EBI3 subunits, to its unique set of receptors (predominantly IL-12Rβ2/gp130 heterodimer, and also homodimers of either chain). This initiates phosphorylation and nuclear translocation of STAT family transcription factors (mainly STAT1 and STAT4) through JAK2 and Tyk2 kinases, resulting in potent immunosuppressive effects: suppression of effector T cell proliferation, induction of Foxp3-negative regulatory T cells (iTr35), and expansion of regulatory B cells. IL-35 signaling is implicated in immune regulation, tumor progression, autoimmune disease pathogenesis, infectious disease response, and endothelial cell function. Therapeutic modulation of this pathway, either by inhibition (anti-IL-35 antibodies) or pharmacological targeting of downstream JAK-STAT events (JAK inhibitors), is under investigation for a range of diseases, but such approaches carry safety risks related to excessive suppression of immune responses.

Other names

IL-35 pathwayInterleukin-35 pathwayIL-35/JAK-STAT signaling pathway

IL-35 receptor activation triggers JAK2, Tyk2, STAT1, and STAT4 phosphorylation, leading to immunosuppressive gene expression. JAK inhibitors block downstream signaling by interfering with STAT activation. Anti-IL-35 antibodies block cytokine-receptor interactions.