New insights into the IL-12 and IL-23: From a molecular basis to clinical application in immune-mediated inflammation and cancers

The cytokines interleukin-12 (IL-12) and IL-23 share a common IL-12/IL-23p40 subunit in structure and play a central role in T cell-mediated responses in inflammation. Over-activated IL-12 and IL-23 signaling drives aberrant T helper (Th) 1 and Th17 immune responses and contributes to immune-mediated diseases. Evidence from genome-wide association studies has shown that genetic alterations in the IL-12/IL-23 signaling pathways have significant links with chronic inflammation. In addition, accumulating evidence from animal models and clinical trials has provided insights into the effectiveness of blocking the IL-12/IL-23 pathways in immune regulation, broadening the clinical indications of IL-12/IL-23 pathway effectors in immune-mediated diseases. More recently, it has been addressed that the balance between IL and 12 and IL-23 is also critical in carcinogenesis. IL-12- and IL-23-driven T cell cytokines are especially important in controlling tumor initiation, growth, and metastasis, and thus, the IL-12/IL-23 pathway may be a promising target for immunotherapy. This review focuses on IL-12/IL-23 signal transduction and biological functionality in autoimmunity and oncoimmunology. We discuss the therapeutic rationale for targeting these cytokines to treat immune-mediated diseases and issues regarding their inadvertent consequences in the balance of host defense and tumor surveillance and summarize their recent clinical applications in immune-mediated diseases.