IL-12 Family Signaling Pathway

IL-12Rβ2 IL-12Rβ1 IL-12 p35/p40 IL-23R IL-12Rβ1 L-23 p19/p40 WSX-1 gp130 IL-27 p28/EBI3 IL-12Rβ2 gp130 IL-35 p35/EBI3 IL-23R gp130 IL-39 p19/EBI3

Background

The interleukin-12 (IL-12) family plays a pivotal regulatory role in the pathogenesis of autoimmune diseases. This family includes IL-12, IL-23, IL-27, IL-35, and IL-39, which form unique molecular structures through the combination of shared subunits such as p19, p28, p35, p40, and Ebi3.

In autoimmune disorders, IL-12 and IL-23 primarily exhibit pro-inflammatory functions. IL-12 contributes to disease development in conditions such as rheumatoid arthritis and multiple sclerosis by promoting Th1 differentiation and interferon-γ production. IL-23 is critical for maintaining Th17 cell function and IL-17 production, playing a central role in the pathogenesis of psoriasis, ankylosing spondylitis, and inflammatory bowel disease. Hyperactivation of IL-23 is closely associated with the formation and persistence of psoriatic lesions, providing a strong rationale for IL-23-targeted therapies.

Conversely, IL-27 and IL-35 mainly exhibit immunosuppressive properties. IL-27 exerts dual regulatory effects by modulating different T-cell responses during autoimmune processes. IL-35, produced by regulatory T cells, effectively suppresses effector T-cell function and is crucial for maintaining immune tolerance and limiting excessive immune responses.

Therapeutic strategies targeting the IL-12 family have made significant progress. Monoclonal antibodies against the IL-12/IL-23 p40 subunit, as well as selective anti-IL-23 p19 antibodies, have demonstrated strong clinical efficacy in treating psoriasis and inflammatory bowel disease. As our understanding of IL-12 family member functions continues to deepen, these insights are expected to pave the way for more precise and effective treatments for autoimmune diseases.